Aktivitas Listrik Jantung

Aktivitas Listrik Jantung
Untuk dapat memompa darah, jantung harus berkontraksi yang dicetuskan oleh potensial aksi yang
menyebar melalui membran sel sel otot. Jantung berkontraksi secara berirama akibat potensial aksi
yang ditimbulkannya sendiri, disebut sebagai otoritmisitas.
Terdapat dua jenis sel otot jantung :
Sel kontraktil(99 %) merupakan sel yang memiliki fungsi mekanik (memompa darah), dalam
keadaan normal tidak dapat menghasilkan sendiri potensial aksinya
Sel otoritmikberfungsi mencetuskan dan menghantarkan potensial aksi yang bertanggung
jawab untuk kontraksi sel sel pekerja. Sel otoritmik ini dapat ditemukan di lokasi lokasi
berikut :
Nodus sinoatrium (SA), daerah kecil khusus di dinding atrium kanan dekat muara vena cava
superior
Nodus atrioventrikel (AV), terletak di dasar atrium kanan dekat septum, tepat di atas
hubungan antara atrium dan ventrikel
Berkas His (berkas atrioventrikel), suatu jaras sel sel khusus yang berasal dari nodus AV
dan masuk ke septum interventrikular. Pada septum interventrikular jaras ini bercabang dua
(kanan dan kiri), kemudian berjalan ke bawah melalui septum, melingkari ujung ventrikel dan
kembali ke atrium di sepanjang dinding luar.
Serat Purkinje,merupakan serat terminal halus yang berjalan dari berkas His dan menyebar
ke seluruh miokardium ventrikel.
Sel sel otoritmik
jantung tidak memiliki
potensial istirahat melainkan
mereka memiliki aktivitas
pacemaker yaitu depolarisasi
yang terjadi secara perlahan
pada membrane sel sel
tersebut hingga mencapai
ambang dan kemudian
menimbulkan potensial aksi.
Penyebab terjadinya
depolarisasi ini diperkirakan sebagai akibat dari :
1.Arus keluar K+ yang berkurang diirngi dengan arus masuk Na+ yang konstan
Permeabilitas membrane terhadap K+ menurun antara potensial potensial aksi, karena saluran K+
diinaktifkan sehingga aliran keluar ion positif menurun. Sementara itu, influks pasif Na + dalam jumlah
kecil tidak berubah akibatnya bagian dalam membrane menjadi lebih positif dan secara bertahap
mengalami depolarisasi hingga mencapai ambang.
2.Peningkatan arus masuk Ca2+
Setelah mencapai ambang dan saluran Ca2+ terbuka, terjadi influks Ca2+ secara cepat menimbulkan
fase naik dari potensial aksi spontan.
Sel sel otoritmik berbeda kecepatannya untuk menghasilkan potensial aksi karena terdapat
perbedaan kecepatan depolarisasi. Sel sel jantung yang terletak di nodus SA memiliki kecepatan
pembentukan potensial aksi tertinggi. Sekali potensial aksi timbul di salah satu sel otot jantung,
potensial aksi tersebut akan menyebar ke seluruh miokardium melalui gap junction dan penghantar
khusus.
Penjalaran Impuls Jantung ke Seluruh Jantung
potensial aksi dimulai di nodus SA kemudian menyebar ke seluruh jantung. Agar jantung berfungsi
secara efisien, penyebaran eksitasi harus memenuhi 3 kriteria :
Eksitasi dan kontraksi atrium harus selesai sebelum kontraksi ventrikel dimulai.
Eksitasi serat serat otot jantung harus dikoordinasi untuk memastikan bahwa setiap bilik
jantung berkontraksi sebagai suatu kesatuan untuk menghasilkan daya pompa yang
efisien.Apabila serat serat otot di bilik jantung tereksitasi dan berkontraksi secara acak, tidak
simultan dan terkoordinasi (fibrilasi) maka darah tidak akan dapat terpompa.
Pasangan atrium dan pasangan ventrikel harus secara fungsional terkoordinasi, sehingga
kedua pasangan tersebut berkontaksi secara simultan. Hal ini memungkinkan darah terpompa ke
sirkulasi paru dan sistemik
Eksitasi atrium.Suatu potensial aksi yang berasal dari nodus SA pertama kali menyebar ke kedua
atrium, terutama dari sel ke sel melalui gap junction. Selain itu, terdapat jalur penghantar khusus yang
mempercepat penghantaran impuls dari atrium, yaitu :
Jalur antaratrium, berjalan dari nodus SA di atrium kanan ke atrium kiri.
Jalur antarnodus, berjalan dari nodus SA ke nodus AV. Karena atrium dan ventrikel
dihubungkan oleh jaringan ikat yang tidak menghantarkan listrik, maka satu satunya cara agar
potensial aksi dapat menyebar ke ventrikel adalah dengan melewati nodus AV.
Transmisi antara Atrium dan Ventrikel. Potensial aksi dihantarkan relative lebih lambat melalui
nodus AV. Kelambanan ini memberikan waktu untuk memungkinkan atrium mengalami depolarisasi
sempurna dan berkontraksi sebelum depolarisasi dan kontraksi ventrikel terjadi. Hal ini bertujuan agar
ventrikel dapat terisi sempurna.
Eksitasi ventrikel.Setelah perlambatan itu, kemudian impuls dengan cepat berjalan melalui berkas
His dan ke seluruh miokardium ventrikel melalui serat serat purkinje. Sistem penghantar ventrikel
lebih terorganisasi dan lebih penting daripada jalur antaratrium dan antarnodus, karena massa ventrikel
jauh lebih besar daripada massa atrium.
Potensial Aksi Pada Sel Kontraktil Otot Jantung
Potensial aksi yang terjadi pada sel kontraktil otot jantung memperlihatkan fase datar (plateu) yang
khas. Pada saat membran mengalami eksitasi, terjadi perubahan gradien membran secara cepat akibat
masuknya Na+. Membran pun mengalami potensial aksi. Segera setelah potensial aksi dicapai,
permeabilitas membran terhadap Na+ berkurang. Namun uniknya, membran potensial dipertahankan
selama beberapa ratus milidetik sehingga menghasilkan fase datar (plateu) potensial aksi.Perubahan
voltase yang mendadak selama fase naik menuju potensial aksi menimbulkan 2 perubahan yang turut
serta mempertahankan fase datar tersebut, yaitu pengaktifan slow L-type Ca 2+ channel dan penurunan
permeabilitas K+. Pembukaan Ca2+ channel menyebabkan influks Ca2+ yang bermuatan positif.
Penurunan aliran K+ mencegah repolarisasi cepat membran sehingga mempertahankan fase datar. Fase
turun potensial aksi yang berlangsung cepat terjadi akibat inaktivasi Ca 2+ channel dan peningkatan
permeabilitas K+.
Mekanisme dasar terjadinya kontraksi sel miokardium apabila terdapat potensial aksi serupa dengan
proses eksitasi-kontraksi otot rangka. Bedanya, selama potensial aksi sel miokardium berlangsung,
sejumlah besar ion Ca akan berdifusi dari ekstrasel ke sitosol, menembus membran plasma untuk
mempertahankan potensial aksi sel miokardium, melewati T-tubule dan memicu terbukanya kanal ion
Ca dari lateral sacs retikulum sarkoplasma memperpanjang masa kontraksi cukup waktu untuk
memompa darah. Peran Ca2+ di sitosol adalah untuk berikatan dengan kompleks troponin-tropomiosin
sehingga memungkinkan terjadinya kontraksi.
Siklus Jantung
Siklus jantung adalah periode dimulainya satu denyutan jantung dan awal dari denyutan selanjutnya.
Setiap siklus dimulai oleh pembentukan potensial aksi yang spontan di nodus sinus. Siklus jantung
terdiri dari periode sistol dan diastol. Sistol adalah periode kontraksi dari ventrikel, dimana darah akan
dikeluarkan dari jantung. Diastol adalah periode relaksasi dari ventrikel, dimana terjadi pengisian
darah.
Diastol dapat dibagi menjadi dua proses yaitu relaksasi isovolumetrik dan ventricular filling. Pada
relaksasi isovolumetrik terjadi ventrikel yang mulai relaksaasi, katup semilunar dan katup
atrioventrikularis tertutup dan volume ventrikel tetap tidak berubah. Pada ventricular filling dimana
tekanan dari atrium lebih tinggi dari tekanan di ventrikel, katup mitral dan katup trikuspid akan
terbuka sehingga ventrikel akan terisi 80% dan akan mencapai 100 % jika atrium berkontraksi.
Volume total yang masuk ke dalam diastol disebut End Diastolic Volume.
Sistolik dapat dibagi menjadi dua proses yaitu kontraksi isovolumetrik dan ejeksi ventrikel. Pada
kontraksi isovolumetrik, kontraksi sudah dimulai tetapi katup katup tetap tertutup. Tekanan juga
telah dihasilkan tetapi tidak dijumpai adanya pemendekan dari otot. Pada ejeksi ventrikel , tekanan
dalam ventrikel lebih tinggi dibandingkan dengan tekanan pada aorta dan pulmoner sehingga katup
aorta dan katup pulmoner terbuka dan akhirnya darah akan dipompa ke seluruh tubuh. Pada saat ini
terjadi pemendekan dari otot. Sisa darah yang terdapat di ventrikel disebut End Systolic Volume.
Cardiac Output.Merupakan volume darah yang dipompa oleh setiap ventrikel per menitnya. CO dari
setiap ventrikel secara normal sama, walaupun terdapat sedikit variasi. Penentu utama CO adalah
detak jantung dan stroke volume (= Volume darah yang dikeluarkan masing-masing ventrikel). Jika
dalam keadaan istirahat, detak jantung = 70 x/menit dan SV = 70 ml/detak, maka: Cardiac Output=
Detak jantung x SV. Dalam keadaan istirahat, curah jantung (cardiac output) dapat mencapai 5 L per
menit. Saat berolahraga, curah jantung yang dihasilkan dapat mencapai sekitar 20-25 L per menit.
Selisih antara curah jantung saat istirahat dengan curah jantung maksimal disebut cardiac reserve.
faktor yang mempengaruhi CO : Heart Rate (detak Jantung).Dalam keadaan normal nodus SA
merupakan pacemaker jantung dan mengatur HR. Karena nodus SA ini dipersarafi oleh Saraf otonom
(simpatis dan parasimpatis) maka secara tidak langsung HR juga dipengaruhi oleh saraf otonom.
Stroke Volume.Diatur oleh dua factor , yaitu intrinsic (aliran vena) dan ekstrinsik (stimulasi
simpatik). Factor intrinsic diatur oleh mekanisme hukum Franks Starling pada jantung. Semakin
banyak aliran vena yang masuk ke dalam jantung semakin besar pula volume diastole akhir
dan jantung menjadi semaikn tertarik dan melebar. Karena keadaan otot jantung yang semakin
panjang sebelum kontraksi ini, maka semakin kuat pula kontraksinya.
Caldesmon
From Wikipedia, the free encyclopedia
Caldesmon is a protein that in humans is encoded by the CALD1 gene .[1][2]
Caldesmon is a calmodulin binding protein . Like calponin , caldesmon tonically inhibits the
ATPase activity of myosin in smooth muscle.
This gene encodes a calmodulin- and actin-binding protein that plays an essential role in the regulation
of smooth muscle and nonmuscle contraction. The conserved domain of this protein possesses the
binding activities to Ca++-calmodulin, actin, tropomyosin, myosin, and phospholipids. This protein is a
potent inhibitor of the actin-tropomyosin activated myosin MgATPase, and serves as a mediating
factor for Ca++-dependent inhibition of smooth muscle contraction. Alternative splicing of this gene
results in multiple transcript variants encoding distinct isoforms. [2]
Calponin
Calponin is a calcium binding protein . Calponin tonically inhibits the ATPase activity of
myosin in smooth muscle. Phosphorylation of calponin by a protein kinase , which is dependent
upon calcium binding to calmodulin , releases the calponin's inhibition of the smooth muscle
ATPase.
Structure and function

Calponin is mainly made up of -helices with hydrogen bond turns. It is a binding protein and is
made up of three domains. These domains in order of appearance are Calponin Homology (CH),
regulatory domain (RD), and Click-23, domain that contains the calponin repeats . At the CH
domain calponin binds to -actin and filamin and binds to actin within the RD domain. Calponin does
not bind to actin in the CH domain as generally described due to the fact that the CH domain is known
to bind calcium to calmodulin which then inhibits actin binding. Calponin is responsible for binding
many actin binding proteins, phospholipids, and regulates the actin/myosin interaction. Calponin is
also thought to negatively affect the bone making process due to being expressed in high amounts in
osteoblasts .[2]
Desmin
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Desmin is a protein that in humans is encoded by the DES gene .[1][2]
Desmin is a type III[3] intermediate filament found near the Z line in sarcomeres . It was first
described in 1976,[4] first purified in 1977,[5] the gene was cloned in 1989,[2] and the first knockout mouse was created in 1996.[6] Desmin is only expressed in vertebrates, however homologous
proteins are found in many organisms.[7] It is a 52kD protein that is a subunit of intermediate
filaments in skeletal muscle tissue, smooth muscle tissue, and cardiac muscle tissue.[8]
Putative functions
The function of desmin has been deduced through studies in knockout mice, but the underlying
mechanism of its action is not known. These possibilities may be the result of interactions with other
proteins and not desmin itself. More research needs to be done on desmin's expression and interactions
in the muscle cell in order to determine its exact function.
Desmin is one of the earliest protein markers for muscle tissue in embryogenesis as it is detected in the
somites of myoblasts .[7] Although it is present early in the development of muscle cells it is
expressed at low levels and increases as the cell nears terminal differentiation the muscle cell matures
only desmin is present. A similar protein, vimentin , is present in higher amounts during
embryogenesis while desmin is present in higher amounts after differentiation. This suggests that there
may be some interaction between the two in determining muscle cell differentiation. However desmin
knockout mice develop normally and only experience defects later in life. [8] Since desmin is
expressed at a low level during differentiation another protein may be able to compensate for desmin's
function early in development but not later on.[9]
Desmin is also important in muscle cell architecture and structure since it connects many components
of the cytoplasm . The sarcomere is a component of muscle cells composed of actin and
myosin motor proteins which allow the cell to contract. Desmin forms a scaffold around the Z-disk
of the sarcomere and connects the Z-disk to the subsarcolemmal cytoskeleton (the cytoplasmic
part of the muscle cell plasma membrane).[10] It links the myofibrils laterally by connecting the
Z-disks.[7] Through its connection to the sarcomere Desmin connects the contractile apparatus to the
cell nucleus , mitochondria , and post-synaptic areas of motor endplates.[7] These connections
maintain the structural and mechanical integrity of the cell during contraction while also helping in
force transmission and longitudinal load bearing.[10][11] There is some evidence that desmin may
also connect the sarcomere to the extracellular matrix (ECM) through desmosomes which could
be important in signalling between the ECM and the sarcomere which could regulate muscle
contraction and movement.[11]
Finally, desmin may be important in mitochondria function. When desmin is not functioning
properly there is improper mitochondrial distribution, number, morphology and function. [12] Since
desmin links the mitochondria to the sarcomere it may transmit information about contractions and
energy need and through this regulate the aerobic respiration rate of the muscle cell.
Knockout phenotype
When the gene for desmin is knocked out it is no longer able to function properly. Mice with the
desmin knockout gene develop normally and are fertile, however soon after birth they begin to show
defects in skeletal, smooth and cardiac muscle; in particular the diaphragm and heart are
affected.[8] The mice without desmin are weaker and fatigue more easily than wild type mice [8] but
the muscle fibers are less likely to be damaged during contraction [13] Mice without desmin also have
impaired mitochondrial function.
Associated diseases
Main article: Desmin-related myofibrillar myopathy
Desmin-related myopathy (DRM or Desminopathy) is a subgroup of the myofibrillar myopathy
diseases and is the result of a mutation in the gene that codes for desmin which prevents it from
forming protein filaments , instead forming aggregates of desmin and other proteins throughout
the cell.[7]
It is also associated with Sarcoma botryoides (rhabdomyosarcoma variant) - a spindle-shaped
vaginal carcinoma that affects girls < 4 years of age.
Structure
There are three major domains to this protein: a conserved alpha helix rod, a variable non alpha
helix head, and a carboxy-terminal tail.[7] Desmin, as all intermediate filaments , shows no
polarity when assembled.[7] The rod domain consists of 308 amino acids with parallel alpha helical
coiled coil dimers and three linkers to disrupt it.[7] The rod connects to the head domain. The head
domain 84 amino acids with many arginine, serine, and aromatic residues is important in filament
assembly and dimer-dimer interactions.[7] The tail domain is responsible for the integration of
filaments and interaction with proteins and organelles.
Calmodulin
Calmodulin 3D structure
Calmodulin (CaM) (an
abbreviation for CALciumMODULated proteIN) is a
calcium -binding messenger
protein expressed in all
eukaryotic cells . CaM is a
multifunctional intermediate
messenger protein that
transduces calcium signals by binding calcium ions and then modifying its interactions with various
target proteins.[1][2]
Function
CaM mediates many crucial processes such as inflammation , metabolism , apoptosis ,
smooth muscle contraction, intracellular movement, short-term and long-term memory ,
and the immune response . CaM is expressed in many cell types and can have different subcellular
locations, including the cytoplasm , within organelles , or associated with the plasma or
organelle membranes. Many of the proteins that CaM binds are unable to bind calcium themselves,
and use CaM as a calcium sensor and signal transducer. CaM can also make use of the calcium stores
in the endoplasmic reticulum , and the sarcoplasmic reticulum . CaM can undergo posttranslational modifications, such as phosphorylation , acetylation , methylation and
proteolytic cleavage , each of which has potential to modulate its actions.
Structure
Calmodulin is a small, highly conserved protein approximately 148 amino acids long (16706
Daltons ). It contains four EF-hand motifs , each of which binds a Ca2+ ion. The protein has
two approximately symmetrical globular domains (the N- and C-domain), separated by a flexible
linker region. Calcium participates in an intracellular signalling system by acting as a diffusible
second messenger to the initial stimuli.
Mechanism
Up to four calcium ions are bound by calmodulin via its four EF hand motifs. EF hands supply an
electronegative environment for ion coordination. After calcium binding, hydrophobic
methyl groups from methionine residues become exposed on the protein via conformational
change . This presents hydrophobic surfaces, which can in turn bind to Basic Amphiphilic Helices
(BAA helices) on the target protein. These helices contain complementary hydrophobic regions. The
flexibility of Calmodulin's hinged region allows the molecule to "wrap around" its target. This
property allows it to tightly bind to a wide range of different target proteins.
Dynamic features
Compared to the X-ray crystal structure , the C-terminal domain solution structure is
similar while the EF hands of the N-terminal domain are considerably less open. The backbone
flexibility within calmodulin is key to its ability to bind a wide range of targets.[3]
Other calcium-binding proteins

Calmodulin belongs to one of the two main groups of calcium-binding proteins, called EF hand
proteins. The other group, called annexins , bind calcium and phospholipid (e.g., lipocortin ).
Many other proteins bind calcium, although binding calcium may not be considered their principal
function in the cell.
AKT
(Redirected from Protein Kinase B )
Akt, also known as Protein Kinase B (PKB), is a serine/threonine-specific protein kinase that
plays a key role in multiple cellular processes such as glucose metabolism, apoptosis , cell
proliferation , transcription and cell migration.
Family members
Akt1 is involved in cellular survival pathways, by inhibiting apoptotic processes. Akt1 is also able
to induce protein synthesis pathways, and is therefore a key signaling protein in the cellular
pathways that lead to skeletal muscle hypertrophy, and general tissue growth. Since it can block
apoptosis, and thereby promote cell survival, Akt1 has been implicated as a major factor in many types
of cancer. Akt (now also called Akt1) was originally identified as the oncogene in the transforming
retrovirus , AKT8.[3]
Akt2 is an important signaling molecule in the Insulin signaling pathway. It is required to induce
glucose transport. In a mouse which is null for Akt1 but normal for Akt2, glucose homeostasis is
unperturbed, but the animals are smaller, consistent with a role for Akt1 in growth. In contrast, mice
which do not have Akt2, but have normal Akt1, have mild growth deficiency and display a diabetic
phenotype (insulin resistance ), again consistent with the idea that Akt2 is more specific for the
insulin receptor signaling pathway.[4]
The role of Akt3 is less clear, though it appears to be predominantly expressed in the brain. It has been
reported that mice lacking Akt3 have small brains.[5]
Name
The name Akt does not refer to its function. The "Ak" in Akt was a temporary classification name for a
mouse strain originally bred and maintained by Jacob Furth that developed spontaneous thymic
lymphomas. The "t" stands for 'thymoma '; the letter was added when a transforming retrovirus was
isolated from the Ak strain, which was termed "Akt-8". When the oncogene encoded in this virus was
discovered, it was termed v-Akt. Thus, the later identified human analogues were named accordingly.
Regulation
Akt[1] is involved in the PI3K/AKT/mTOR pathway and other signaling pathways.
Binding phospholipids
Akt possesses a protein domain known as a PH domain, or Pleckstrin Homology domain ,
named after Pleckstrin , the protein in which it was first discovered. This domain binds to
phosphoinositides with high affinity. In the case of the PH domain of Akt, it binds either PIP3
(phosphatidylinositol (3,4,5)-trisphosphate , PtdIns(3,4,5)P3) or PIP2 (phosphatidylinositol
(3,4)-bisphosphate , PtdIns(3,4)P2).[6] This is useful for control of cellular signaling because the
di-phosphorylated phosphoinositide PIP2 is only phosphorylated by the family of enzymes, PI 3kinases (phosphoinositide 3-kinase or PI3-K), and only upon receipt of chemical messengers
which tell the cell to begin the growth process. For example, PI 3-kinases may be activated by a G
protein coupled receptor or receptor tyrosine kinase such as the insulin receptor . Once
activated, PI 3-kinase phosphorylates PIP2 to form PIP3.
Phosphorylation
Once correctly positioned at the membrane via binding of PIP3 , Akt can then be phosphorylated by
its activating kinases, phosphoinositide dependent kinase 1 (PDPK1 at threonine 308) and
mTORC2 (at serine 473).[citation needed] First, the mammalian target of rapamycin complex 2
(mTORC2); mTORC2 therefore functionally acts as the long-sought PDK2 molecule, although other
molecules, including Integrin-linked kinase (ILK) and Mitogen-Activated Protein Kinase
Activated Protein Kinase-2 (MAPKAPK2 ) can also serve as PDK2. Phosphorylation by mTORC2
stimulates the subsequent phosphorylation of Akt by PDPK1.
Activated Akt can then go on to activate or deactivate its myriad substrates (e.g. mTOR ) via its
kinase activity.
Besides being a downstream effector of PI 3-kinases, Akt may possibly also be activated in a PI 3-
kinase-independent manner. Studies have suggested that cAMP -elevating agents could activate Akt
through protein kinase A (PKA) in the presence of insulin,[7] although these studies are disputed
and the mechanism of action is unclear.[citation needed]
Lipid phosphatases and PIP3

PI3K dependent Akt activation can be regulated through the tumor suppressor PTEN , which
works essentially as the opposite of PI3K mentioned above.[8] PTEN acts as a phosphatase to
dephosphorylate PtdIns(3,4,5)P3 back to PtdIns(4,5)P2 . This removes the membranelocalization factor from the Akt signaling pathway. Without this localization, the rate of Akt activation
decreases significantly, as do all of the downstream pathways that depend on Akt for activation.
PIP3 can also be de-phosphorylated at the "5" position by the SHIP family of inositol phosphatases,
SHIP1 and SHIP2 . These poly-phosphate inositil phosphatases dephosphorylate
PtdIns(3,4,5)P3 to form PtdIns(3,4)P2 .
Protein phosphatases
The phosphatases in the PHLPP family, PHLPP1 and PHLPP2 have been shown to directly
de-phosphorylate, and therefore inactivate, distinct Akt isoforms. PHLPP2 dephosphorylates Akt1 and
Akt3, whereas PHLPP1 is specific for Akt 2 and Akt3.
Function
Akt regulates cellular survival[9] and metabolism by binding and regulating many downstream
effectors, e.g. Nuclear Factor-B , Bcl-2 family proteins and murine double minute 2 (MDM2 ).
Cell survival
Overview of signal
transduction pathways involved
in apoptosis .
Akt could promote growth
factor-mediated cell survival
both directly and indirectly.
BAD is a pro-apoptotic
protein of the Bcl-2 family.
Akt could phosphorylate BAD on Ser136,[10] which makes BAD dissociate from the Bcl-2/Bcl-X
complex and lose the pro-apoptotic function.[11] Akt could also activate NF-B via regulating IB
kinase (IKK), thus result in transcription of pro-survival genes.[12]
Cell Cycle
Akt is known to play a role in the cell cycle . Under various circumstances, activation of Akt was
shown to overcome cell cycle arrest in G1[13] and G2[14] phases. Moreover, activated Akt may
enable proliferation and survival of cells that have sustained a potentially mutagenic impact and,
therefore, may contribute to acquisition of mutations in other genes.
Metabolism
Akt2 is required for the insulin-induced translocation of glucose transporter 4 ( GLUT4 ) to the
plasma membrane . Glycogen synthase kinase 3 (GSK-3 ) could be inhibited upon
phosphorylation by Akt, which results in increase of glycogen synthesis. GSK3 is also involved in
Wnt signaling cascade, so Akt might be also implicated in the Wnt pathway. Still unknown role in
HCV induced steatosis .
Angiogenesis
Akt1 has also been implicated in angiogenesis and tumor development. Although deficiency of
Akt1 in mice inhibited physiological angiogenesis, it enhanced pathological angiogenesis and tumor
growth associated with matrix abnormalities in skin and blood vessels.[15][16]
Ras subfamily
(Redirected from Ras protein )
This article is about the p21/Ras protein. For the p21/waf1 protein see p21 .
H-Ras structure PDB 121p, surface colored by conservation in Pfam seed alignment: gold,
most conserved; dark cyan, least conserved.
Identifiers
Symbol
Pfam
InterPro
PROSITE
SCOP
SUPERFA
MILY
OPM
protein
CDD
Ras
PF00071
IPR013753
PDOC00017
5p21
5p21
1uad
cd04138
[show]Available protein structures:
Ras is the name given to a family of related proteins found inside cells , including human
cells. All Ras protein family members belong to a class of protein called small GTPase , and are
involved in transmitting signals within cells (cellular signal transduction ). Ras is the
prototypical member of the Ras superfamily of proteins, which are all related in 3D structure and
regulate diverse cell behaviours.
The name 'Ras' is an abbreviation of 'Rat sarcoma', reflecting the way the first members of the protein
family were discovered. The name ras is also used to refer to the family of genes encoding those
proteins.
When Ras is 'switched on' by incoming signals, it subsequently switches on other proteins, which
ultimately turn on genes involved in cell growth , differentiation and survival . As a result,
mutations in ras genes can lead to the production of permanently activated Ras proteins. This can
cause unintended and overactive signalling inside the cell, even in the absence of incoming signals.
Because these signals result in cell growth and division, overactive Ras signaling can ultimately lead
to cancer .[1] Ras is the most common oncogene in human cancer - mutations that permanently
activate Ras are found in 20-25% of all human tumors and up to 90% in certain types of cancer (e.g.
pancreatic cancer ).[2] For this reason, Ras inhibitors are being studied as a treatment for cancer,
and other diseases with Ras overexpression.
Contents
1 History
2 Structure
3 Function
o 3.1 Activation and
deactivation
o 3.2 Membrane
attachment
4 Members
5 Ras in cancer
o 5.1 Inappropriate
activation
o 5.2 Constitutively
active Ras
o 5.3 Ras-targeted
cancer treatments
6 References
7 External links
History
The first two ras genes, HRAS and KRAS , were first identified[3] from studies of two cancercausing viruses, the Harvey sarcoma virus and Kirsten sarcoma virus, by Edward M. Scolnick and
colleagues at the National Institutes of Health (NIH).[4] These viruses were discovered originally in
rats during the 1960s by Jennifer Harvey[5] and Werner Kirsten,[6] respectively, hence the name Rat
sarcoma . In 1982, activated and transforming human ras genes were discovered in human cancer
cells by Geoffrey M. Cooper at Harvard,[7] Mariano Barbacid and Stuart A. Aaronson at the
NIH[8] and by Robert Weinberg of MIT.[9] A third ras gene was subsequently discovered [10]
[11] by researchers at the Institute of Cancer Research , funded by the Cancer Research
Campaign (now Cancer Research UK ), and named NRAS , for its initial identification in
human neuroblastoma cells.
The three human ras genes encode extremely similar proteins made up of chains of 188 to 189 amino
acids, designated H-Ras , N-Ras and K-Ras4A and K-Ras4B (the two K-Ras proteins arise
from alternative splicing ).
Structure
H-Ras structure PDB
121p, ribbon showing strands in purple, helices in aqua, loops in gray. Also shown are the bound GTP
analog and magnesium ion.
This section may require cleanup to meet Wikipedia's quality standards . No
cleanup reason has been specified. Please help improve this section if you can.
(April 2009)
Ras contains a six-stranded beta sheet and 5 alpha helices :[12]
G domain (166 amino acids) which binds guanosine nucleotides, about 20kDa.
C terminal membrane targeting region (CAAX-COOH, also known as CAAX box ) which
is lipid-modified by farnesyl transferase , RCE1 and ICMT
The G domain contains five G motifs that bind GDP/GTP directly
G1 - P-loop binds the beta phosphate of GDP and GTP
G2 - threonine-35 also switch 1, binds the terminal phosphate of GTP, but makes no contacts
with GDP
G3 - DXXG motif, aspartate-57 is specific for guanine rather than adenine
G4 - LVGNKxDL motif
G5 - SAK consensus sequence, the alanine-146 is specific for guanine rather than adenine
and two switches which are the main parts of the protein that move upon activation by GTP.
switch I includes threonine-35
switch II glycine-60 in DXXG motif
Ras also binds a magnesium ion which helps to coordinate nucleotide binding.
Function
Overview of signal
transduction pathways
involved in apoptosis
.
Ras proteins function as
binary molecular
switches that control
intracellular signaling
networks. Ras-regulated
signal pathways
control such processes

as actin cytoskeletal integrity, proliferation, differentiation, cell adhesion, apoptosis , and cell
migration. Ras and ras-related proteins are often deregulated in cancers, leading to increased invasion
and metastasis , and decreased apoptosis.
This section requires expansion . (April
2009)
Ras activates several pathways, of which the mitogen-activated protein (MAP) kinase cascade
has been well-studied. This cascade transmits signals downstream and results in the transcription
of genes involved in cell growth and division.[13] There is a separate AKT pathway that inhibits
apoptosis.
Activation and deactivation

Ras is a G protein , or a guanosine -nucleotide -binding protein. Specifically, it is a single-
subunit small GTPase , which is related in structure to the G subunit of heterotrimeric G

proteins (large GTPases). G proteins function as binary signaling switches with "on" and "off"
states. In the "off" state it is bound to the nucleotide guanosine diphosphate (GDP), while in the
"on" state, Ras is bound to guanosine triphosphate (GTP), which has an extra phosphate
group as compared to GDP. This extra phosphate holds the two switch regions in a "loaded-spring"
configuration (specifically the Thr-35 and Gly-60). When released, the switch regions relax which
causes a conformational change into the inactivate state. Hence, activation and deactivation of
Ras and other small G proteins are controlled by cycling between the active GTP-bound and inactive
GDP-bound forms.
The process of exchanging the bound nucleotide is facilitated by guanine nucleotide exchange
factors (GEFs) and GTPase activating proteins (GAPs). As per its classification, Ras has an
intrinsic GTPase activity, which means that the protein on its own will hydrolyze a bound GTP
molecule into GDP. However this process is too slow for efficient function, and hence the GAP for
Ras, RasGAP, may bind to and stabilize the catalytic machinery of Ras, supplying additional catalytic
residues ("arginine finger") such that a water molecule is optimally positioned for nucleophilic
attack on the gamma-phosphate of GTP. An inorganic phosphate is released and the Ras molecule is
now bound to a GDP. Since the GDP-bound form is "off" or "inactive" for signaling, GTPase
Activating Protein inactivates Ras by activating its GTPase activity. Thus, GAPs accelerate Ras
inactivation.
GEFs catalyze a "push and pull" reaction which releases GDP from Ras. They insert close to the Ploop and magnesium cation binding site and inhibit the interaction of these with the gamma
phosphate anion . Acidic (negative) residues in switch II "pull" a lysine in the P-loop away from the
GDP which "pushes" switch I away from the guanine. The contacts holding GDP in place are broken
and it is released into the cytoplasm. Because intracellular GTP is abundant relative to GDP
(approximately 10 fold more[13]) GTP predominantly re-enters the nucleotide binding pocket of Ras
and reloads the spring. Thus GEFs facilitate Ras activation.[12] Well known GEFs include Son of
Sevenless (Sos) and cdc25 which include the RasGEF domain .
The balance between GEF and GAP activity determines the guanine nucleotide status of Ras, thereby
regulating Ras activity.
In the GTP-bound conformation, Ras has high affinity for numerous effectors which allow it to
carry out its functions. These include PI3K . Other small GTPases may bind adaptors such as
arfaptin or second messenger systems such as adenylyl cyclase . The Ras binding domain is
found in many effectors and invariably binds to one of the switch regions, because these change
conformation between the active and inactive forms. However, they may also bind to the rest of the
protein surface.
Other proteins exist which may augment the activity of Ras family proteins. One example is GDI
(GDP Disassociation Inhibitor); These function by slowing the exchange of GDP for GTP and thus,
prolonging the inactive state of Ras family members. Other proteins that further augment this cycle
may exist.
Membrane attachment
Ras is attached to the cell membrane owing to its prenylation and palmitoylation (HRAS
and NRAS ) or the combination of prenylation and a polybasic sequence adjacent to the
prenylation site (KRAS ). The C-terminal CaaX box of Ras first gets farnesylated at its Cys
residue in the cytosol, allowing Ras to loosely insert into the membrane of the endoplasmatic
reticulum and other cellular membranes. The Tripeptide (aaX) is then cleaved from the C-terminus
by a specific prenyl-protein specific endoprotease and the new C-terminus is methylated by a
methyltransferase . K-Ras procession is completed at this stage. Dynamic electrostatic interactions
between its positively charged basic sequence with negative charges at the inner leaflet of the plasma
membrane account for its predominant localization at the cell surface at steady-state. NRAS and
HRAS are further processed on the surface of the Golgi apparatus by palmitoylation of one
or two Cys residues, respectively, adjacent to the CaaX box . The proteins thereby become stably
membrane anchored and are transported to the plasma membrane on vesicles of the secretory
pathway . Depalmitoylation eventually releases the proteins from the membrane, allowing them to
enter another cycle of palmitoylation and depalmitoylation.[14] This cycle is believed to prevent the
leakage of NRAS and HRAS to other membranes over time and to maintain their steady-state
localization along the Golgi apparatus , secretory pathway , plasma membrane and interlinked endocytosis pathway.
Ras in cancer
Mutations in the Ras family of proto-oncogenes (comprising H-Ras, N-Ras and K-Ras) are very
common, being found in 20% to 30% of all human tumours.[15] it is reasonable to speculate that a
pharmacological approach that curtails Ras activity may represent a possible method to inhibit certain
cancer types. Ras point mutations are the single most common abnormality of human protooncogenes.[17] Ras inhibitor trans-farnesylthiosalicylic acid (FTS, Salirasib ) exhibits
profound anti-oncogenic effects in many cancer cell lines.[18][19]
Inappropriate activation
Inappropriate activation of the gene has been shown to play a key role in signal transduction,
proliferation and malignant transformation.[13]
Mutations in a number of different genes as well as RAS itself can have this effect. Oncogenes
such as p210BCR-ABL or the growth receptor erbB are upstream of Ras, so if they are constitutively
activated their signals will transduce through Ras.
The tumour suppressor gene NF1 encodes a Ras-GAP its mutation in neurofibromatosis
will mean that Ras is less likely to be inactivated. Ras can also be amplified, although this only occurs
occasionally in tumours.
Finally, Ras oncogenes can be activated by point mutations so that the GTPase reaction can no longer
be stimulated by GAP this increases the half life of active Ras-GTP mutants.[20]
Constitutively active Ras

Constitutively active Ras (RasD) is one which contains mutations that prevent GTP hydrolysis, thus
locking Ras in a permanently 'On' state.
The most common mutations are found at residue G12 in the P-loop and the catalytic residue Q61.
The glycine to valine mutation at residue 12 renders the GTPase domain of Ras insensitive to
inactivation by GAP and thus stuck in the "on state". Ras requires a GAP for inactivation as it is a
relatively poor catalyst on its own, as opposed to other G-domain-containing proteins such as the
alpha subunit of heterotrimeric G proteins.
Residue 61[21]is responsible for stabilizing the transition state for GTP hydrolysis. Because
enzyme catalysis in general is achieved by lowering the energy barrier between substrate and
product, mutation of Q61 to K necessarily reduces the rate of intrinsic Ras GTP hydrolysis to
physiologically meaningless levels.
See also "dominant negative" mutants such as S17N and D119N.
Ras-targeted cancer treatments
Reovirus was noted to be a potential cancer therapeutic when early studies on reovirus suggested it
reproduces well in certain cancer cell lines. It has since been shown to replicate specifically in cells
that have an activated Ras pathway (a cellular signaling pathway that is involved in cell growth and
differentiation).[22] Reovirus replicates in and eventually kills Ras-activated tumour cells and as cell
death occurs, progeny virus particles are free to infect surrounding cancer cells. This cycle of
infection, replication and cell death is believed to be repeated until all tumour cells carrying an
activated Ras pathway are destroyed. Activating mutations of the Ras protein and upstream elements
of the Ras protein may play a role in more than two thirds of all human cancers, including most
metastatic disease. Reolysin , a formulation of reovirus , is currently in clinical trials for the
treatment of various cancers.[23]
Glucose transporter
Glucose transporters are a wide group of membrane proteins that facilitate the transport of
glucose over a plasma membrane . Because glucose is a vital source of energy for all life these
transporters are present in all phyla . The GLUT or SLC2A family are a protein family that is found
in most mammalian cells .
Synthesis of free glucose

Most non-autotrophic cells are unable to produce free glucose because they lack expression of
glucose-6-phosphatase and, thus, are involved only in glucose uptake and catabolism .
Usually only produced in hepatocytes , in fasting conditions other tissues such as the intestines,
muscles, brain and kidneys are able to produce glucose following activation of gluconeogenesis .
Glucose transport in yeast

In Saccharomyces cerevisiae glucose transport takes place through facilitated diffusion .[1]
The transport proteins are mainly from the Hxt family, but many other transporters have been
identified.[2]
Glucose transport in Mammals

GLUTs are integral membrane proteins that contain 12 membrane-spanning helices with both the
amino and carboxyl termini exposed on the cytoplasmic side of the plasma membrane . GLUT
proteins transport glucose and related hexoses according to a model of alternate conformation,
[5][6][7] which predicts that the transporter exposes a single substrate binding site toward either the
outside or the inside of the cell. Binding of glucose to one site provokes a conformational change
associated with transport, and releases glucose to the other side of the membrane. The inner and outer
glucose-binding sites are, it seems, located in transmembrane segments 9, 10, 11; [8] also, the QLS
motif located in the seventh transmembrane segment could be involved in the selection and affinity of
transported substrate.[9][10]
Types
Each glucose transporter isoform plays a specific role in glucose metabolism determined by its pattern
of tissue expression, substrate specificity, transport kinetics, and regulated expression in different
physiological conditions.[11] To date, 13 members of the GLUT/SLC2 have been identified.[12] On
the basis of sequence similarities, the GLUT family has been divided into three subclasses.
Class I
Class I comprises the well-characterized glucose transporters GLUT1-GLUT4. [13]
N
a
Distribution
Notes
m
e
G Is widely distributed in fetal tissues. In the
L adult, it is expressed at highest levels in
erythrocytes and also in the endothelial
Levels in cell membranes are increased by
U
reduced glucose levels and decreased by
cells of barrier tissues such as the blood
T
increased glucose levels.
1 brain barrier . However, it is responsible
for the low-level of basal glucose uptake
required to sustain respiration in all cells.
Is a bidirectional transporter, allowing
glucose to flow in 2 directions. Is expressed
by renal tubular cells, small intestinal
epithelial cells, liver cells and pancreatic
G beta cells . Bidirectionality is required in
L liver cells to uptake glucose for glycolysis,
Is a high-capacity and low-affinity isoform.
U and release of glucose during
There is some evidence that GLUT 1 and 3
gluconeogenesis. In pancreatic beta cells, free are actually the functional transporters in beta
T flowing glucose is required so that the
cells.
2 intracellular environment of these cells can
accurately gauge the serum glucose levels. All
three monosaccharides (glucose ,
galactose and fructose ) are transported
from the intestinal mucosal cell into the portal
circulation by GLUT2
G
L
U
T
3
G
L
U
T
4
Expressed mostly in neurons (where it is

believed to be the main glucose transporter
isoform), and in the placenta .
Is a high-affinity isoform, allowing it to

transport even in times of low glucose
concentrations.
Found in adipose tissues and striated

muscle (skeletal muscle and cardiac
muscle ).
Is the insulin -regulated glucose transporter.

Responsible for insulin-regulated glucose
storage.
Classes II/III
Class II comprises:
GLUT5 (SLC2A5 ), a fructose transporter
GLUT7 - SLC2A7 - (SLC2A7 ), transporting glucose out of the endoplasmic
reticulum [14]
GLUT9 - SLC2A9 - (SLC2A9 )
GLUT11 (SLC2A11 )
Class III comprises:
GLUT6 (SLC2A6 ),
GLUT8 (SLC2A8 ),
GLUT10 (SLC2A10 ),
GLUT12 (SLC2A12 ), and
the H+/myoinositol transporter HMIT (SLC2A13 ).[15]
Most members of classes II and III have been identified recently in homology searches of EST
databases and the sequence information provided by the various genome projects.
The function of these new glucose transporter isoforms is still not clearly defined at present. Several
of them (GLUT6, GLUT8) are made of motifs that help retain them intracellularly and therefore
prevent glucose transport. Whether mechanisms exist to promote cell-surface translocation of these
transporters is not yet known, but it has clearly been established that insulin does not promote GLUT6
and GLUT8 cell-surface translocation.
Discovery of sodium-glucose cotransport

In August 1960, in Prague, Robert K. Crane presented for the first time his discovery of the
sodium-glucose cotransport as the mechanism for intestinal glucose absorption.[16] Crane 's
discovery of cotransport was the first ever proposal of flux coupling in biology. [17][18]
Neurotransmitter
For an introduction to concepts and terminology used in this article, see Chemical synapse .
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target
cell across a synapse .[1] Neurotransmitters are packaged into synaptic vesicles clustered
beneath the membrane in the axon terminal, on the presynaptic side of a synapse. They are released
into and diffuse across the synaptic cleft , where they bind to specific receptors in the membrane on
the postsynaptic side of the synapse.[2] Release of neurotransmitters usually follows arrival of an
action potential at the synapse, but may also follow graded electrical potentials . Low level
"baseline" release also occurs without electrical stimulation. Neurotransmitters are synthesized from
plentiful and simple precursors, such as amino acids , which are readily available from the diet and
which require only a small number of biosynthetic steps to convert. [3]
Types of neurotransmitters
There are many different ways to classify neurotransmitters. Dividing them into amino acids ,
peptides , and monoamines is sufficient for some classification purposes.
Major neurotransmitters:
Amino acids : glutamate ,[3] aspartate , D-serine , -aminobutyric acid
(GABA), glycine
Monoamines and other biogenic amines : dopamine (DA), norepinephrine
(noradrenaline; NE, NA), epinephrine (adrenaline), histamine , serotonin (SE, 5-HT)
Peptides : somatostatin , substance P , opioid peptides
Others: acetylcholine (ACh), adenosine , anandamide , nitric oxide , etc.
In addition, over 50 neuroactive peptides have been found, and new ones are discovered regularly.
Many of these are "co-released" along with a small-molecule transmitter, but in some cases a peptide
is the primary transmitter at a synapse. -endorphin is a relatively well known example of a
peptide neurotransmitter; it engages in highly specific interactions with opioid receptors in the
central nervous system .
Single ions , such as synaptically released zinc , are also considered neurotransmitters by some,[6]
as are some gaseous molecules such as nitric oxide (NO), hydrogen sulfide (H2S), and carbon
monoxide (CO).[7] These are not classical neurotransmitters by the strictest definition, however,
because although they have all been shown experimentally to be released by presynaptic terminals in
an activity-dependent way, they are not packaged into vesicles.
By far the most prevalent transmitter is glutamate, which is excitatory at well over 90% of the
synapses in the human brain.[3] The next most prevalent is GABA, which is inhibitory at more than
90% of the synapses that do not use glutamate. Even though other transmitters are used in far fewer
synapses, they may be very important functionallythe great majority of psychoactive drugs exert
their effects by altering the actions of some neurotransmitter systems, often acting through transmitters
other than glutamate or GABA. Addictive drugs such as cocaine and amphetamine exert their effects
primarily on the dopamine system. The addictive opiate drugs exert their effects primarily as
functional analogs of opioid peptides , which, in turn, regulate dopamine levels.
Excitatory and inhibitory

Some neurotransmitters are commonly described as "excitatory" or "inhibitory". The only direct effect
of a neurotransmitter is to activate one or more types of receptors. The effect on the postsynaptic cell
depends, therefore, entirely on the properties of those receptors. It happens that for some
neurotransmitters (for example, glutamate), the most important receptors all have excitatory effects:
that is, they increase the probability that the target cell will fire an action potential. For other
neurotransmitters, such as GABA, the most important receptors all have inhibitory effects (although
there is evidence that GABA is excitatory during early brain development). There are, however,
other neurotransmitters, such as acetylcholine, for which both excitatory and inhibitory receptors exist;
and there are some types of receptors that activate complex metabolic pathways in the postsynaptic
cell to produce effects that cannot appropriately be called either excitatory or inhibitory. Thus, it is an
oversimplification to call a neurotransmitter excitatory or inhibitorynevertheless it is so convenient
to call glutamate excitatory and GABA inhibitory that this usage is seen very frequently.
Actions
Main article: Neuromodulation
As explained above, the only direct action of a neurotransmitter is to activate a receptor. Therefore, the
effects of a neurotransmitter system depend on the connections of the neurons that use the transmitter,
and the chemical properties of the receptors that the transmitter binds to.
Here are a few examples of important neurotransmitter actions:
Glutamate is used at the great majority of fast excitatory synapses in the brain and spinal
cord. It is also used at most synapses that are "modifiable", i.e. capable of increasing or decreasing
in strength. Modifiable synapses are thought to be the main memory-storage elements in the
brain. Excessive glutamate release can lead to excitotoxicity causing cell death.
GABA is used at the great majority of fast inhibitory synapses in virtually every part of the
brain. Many sedative/tranquilizing drugs act by enhancing the effects of GABA. Correspondingly
glycine is the inhibitory transmitter in the spinal cord.
Acetylcholine is distinguished as the transmitter at the neuromuscular junction
connecting motor nerves to muscles. The paralytic arrow-poison curare acts by blocking
transmission at these synapses. Acetylcholine also operates in many regions of the brain, but using
different types of receptors .

Dopamine has a number of important functions in the brain. It plays a critical role in the
reward system , but dysfunction of the dopamine system is also implicated in Parkinson's
disease and schizophrenia .
Serotonin is a monoamine neurotransmitter . Most is produced by and found in the
intestine (approximately 90%), and the remainder in central nervous system neurons. It
functions to regulate appetite, sleep, memory and learning, temperature, mood, behaviour, muscle
contraction, and function of the cardiovascular system and endocrine system . It is
speculated to have a role in depression, as some depressed patients are seen to have lower
concentrations of metabolites of serotonin in their cerebrospinal fluid and brain tissue.[8]
Substance P is an undecapeptide responsible for transmission of pain from certain sensory
neurons to the central nervous system.
Neurons expressing certain types of neurotransmitters sometimes form distinct systems, where
activation of the system affects large volumes of the brain, called volume transmission . Major
neurotransmitter systems include the noradrenaline (norepinephrine) system, the dopamine
system, the serotonin system and the cholinergic system.
Drugs targeting the neurotransmitter of such systems affect the whole system; this fact explains the
complexity of action of some drugs. Cocaine , for example, blocks the reuptake of dopamine
back into the presynaptic neuron, leaving the neurotransmitter molecules in the synaptic gap
longer. Since the dopamine remains in the synapse longer, the neurotransmitter continues to bind to
the receptors on the postsynaptic neuron, eliciting a pleasurable emotional response. Physical
addiction to cocaine may result from prolonged exposure to excess dopamine in the synapses, which
leads to the downregulation of some postsynaptic receptors. After the effects of the drug wear off,
one might feel depressed because of the decreased probability of the neurotransmitter binding to a
receptor. Prozac is a selective serotonin reuptake inhibitor (SSRI), which blocks re-uptake
of serotonin by the presynaptic cell. This increases the amount of serotonin present at the synapse and
allows it to remain there longer, hence potentiating the effect of naturally released serotonin. [9]
AMPT prevents the conversion of tyrosine to L-DOPA , the precursor to dopamine; reserpine
prevents dopamine storage within vesicles ; and deprenyl inhibits monoamine oxidase
(MAO)-B and thus increases dopamine levels.
Diseases may affect specific neurotransmitter systems. For example, Parkinson's disease is at
least in part related to failure of dopaminergic cells in deep-brain nuclei , for example the
substantia nigra . Treatments potentiating the effect of dopamine precursors have been proposed
and effected, with moderate success.
A brief comparison of the major neurotransmitter systems follows:
Precursors of neurotransmitters
While intake of neurotransmitter precursors does increase neurotransmitter synthesis, evidence is
mixed as to whether neurotransmitter release (firing) is increased. Even with increased
neurotransmitter release, it is unclear whether this will result in a long-term increase in
neurotransmitter signal strength, since the nervous system can adapt to changes such as increased
neurotransmitter synthesis and may therefore maintain constant firing.[11] Some neurotransmitters
may have a role in depression, and there is some evidence to suggest that intake of precursors of these
neurotransmitters may be useful in the treatment of mild and moderate depression. [11][12]
Dopamine precursors
L-DOPA , a precursor of dopamine that crosses the bloodbrain barrier , is used in the
treatment of Parkinson's disease .
Norepinephrine precursors
For depressed patients where low activity of the neurotransmitter norepinephrine is implicated,
there is only little evidence for benefit of neurotransmitter precursor administration. Lphenylalanine and L-tyrosine are both precursors for dopamine , norepinephrine , and
epinephrine . These conversions require vitamin B6 , vitamin C , and Sadenosylmethionine . A few studies suggest potential antidepressant effects of L-phenylalanine
and L-tyrosine, but there is much room for further research in this area.[11]
Serotonin precursors
Administration of L-tryptophan , a precursor for serotonin , is seen to double the production of
serotonin in the brain. It is significantly more effective than a placebo in the treatment of mild and
moderate depression.[11] This conversion requires vitamin C .[8] 5-hydroxytryptophan (5HTP), also a precursor for serotonin , is also more effective than a placebo.[11]
Degradation and elimination

A neurotransmitter must be broken down once it reaches the post-synaptic cell to prevent further
excitatory or inhibitory signal transduction. For example, acetylcholine (ACh), an excitatory
neurotransmitter, is broken down by acetylcholinesterase (AChE). Choline is taken up and
recycled by the pre-synaptic neuron to synthesize more ACh. Other neurotransmitters such as
dopamine are able to diffuse away from their targeted synaptic junctions and are eliminated
from the body via the kidneys, or destroyed in the liver. Each neurotransmitter has very specific
degradation pathways at regulatory points, which may be the target of the body's own regulatory
system or recreational drugs .
Dystrophin
Dystrophin is a rod-shaped cytoplasmic protein , and a vital part of a protein complex that
connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix
through the cell membrane . This complex is variously known as the costamere or the
dystrophin-associated protein complex . Many muscle proteins, such as -dystrobrevin ,
syncoilin , synemin , sarcoglycan , dystroglycan , and sarcospan , colocalize with
dystrophin at the costamere.
The Dystrophin gene is one of the longest human genes known, covering 2.2 megabases (0.07% of the
human genome) at locus Xp21 . The primary transcript measures about 2,400 kilobases and
takes 16 hours to transcribe;[1] the mature mRNA measures 14.0 kilobases.[2] The 79 exons [3]
code for a protein of over 3500 amino acid residues.[4]
Pathology
Dystrophin deficiency has been definitively established as one of the root causes of the general class
of myopathies collectively referred to as muscular dystrophy . The large cytosolic protein was
first identified in 1987 by Louis M. Kunkel ,[5] after the 1986 discovery of the mutated gene that
causes Duchenne muscular dystrophy (DMD) .[6]

Normal skeletal muscle tissue contains only small amounts of dystrophin (about 0.002% of total
muscle protein), but its absence (or abnormal expression) leads to the development of a severe and
currently incurable constellation of symptoms most readily characterized by several aberrant
intracellular signaling pathways that ultimately yield pronounced myofiber necrosis as well as
progressive muscle weakness and fatigability. Most DMD patients become wheelchair-dependent
early in life, and the gradual development of cardiac hypertrophya result of severe myocardial
fibrosistypically results in premature death in the first two or three decades of life. Mutations in
the dystrophin gene that lead to the production of less defective, but still only partially functional
dystrophin protein, result in a display of a much milder dystrophic phenotype in affected patients,
resulting in the disease known as Becker's muscular dystrophy (BMD). In some cases the
patient's phenotype is such that experts may decide differently on whether a patient should be
diagnosed with DMD or BMD. The theory currently most commonly used to predict whether a
mutation will result in a DMD or BMD phenotype, is the reading frame rule. [7]
Though its role in airway smooth muscle is not well established, recent research indicates that
dystrophin along with other subunits of dystrophin glycoprotein complex is associated with phenotype
maturation.[8]
Interactions
Dystrophin has been shown to interact with SNTB1 ,[9] Syntrophin, alpha 1 [10][11][12]
and DTNA .[13]
Factor VIII
Coagulation factor VIII, procoagulant component
PDB rendering
based on 1d7p.
P
D
B
Symbol
s
External
IDs
Available structures
Ortholog search: PDBe, RCSB
[show]List of PDB id codes
Identifiers
F8; AHF; DXS1253E; F8B; F8C; FVIII; HEMA
OMIM: 300841MGI: 88383HomoloGene: 49153ChEMBL: 3143 GeneCards: F8 Gene
[show]Gene Ontology
RNA expression pattern
More reference expression data

Orthologs
Species
Human
Mouse
2157
ENSG00
Ensemb
0001850
l
10
UniProt P00451
RefSeq NM_000
(mRNA) 132.3
RefSeq NP_0001
(protein) 23.1
Chr X:
Location 154.06
(UCSC) 154.26
Mb
PubMed
[1]
Entrez
search
14069
ENSMUSG
000000311
96
Q06194
NM_00116
1373.1
NP_001154
845.1
Chr X:
75.17
75.38 Mb
[2]
This box:
view
talk
edit
Factor VIII (FVIII) is an essential blood-clotting protein , also known as anti-hemophilic factor
(AHF). In humans, factor VIII is encoded by the F8 gene .[1][2] Defects in this gene results in
hemophilia A , a recessive X-linked coagulation disorder.[3]
Factor VIII participates in blood coagulation ; it is a cofactor for factor IXa which, in the
presence of Ca+2 and phospholipids forms a complex that converts factor X to the activated
form Xa. The factor VIII gene produces two alternatively spliced transcripts. Transcript variant 1
encodes a large glycoprotein , isoform a, which circulates in plasma and associates with von
Willebrand factor in a noncovalent complex. This protein undergoes multiple cleavage events.
Transcript variant 2 encodes a putative small protein, isoform b, which consists primarily of the
phospholipid binding domain of factor VIIIc. This binding domain is essential for coagulant activity.
[4]
People with high levels of factor VIII are at increased risk for deep vein thrombosis and
pulmonary embolism .[5]
Contents
1 Genetics
2 Physiology
3 Therapeutic use
4 Contamination
scandal
5 See also
6 References
7 Further reading
8 External links
Genetics
The gene for factor VIII is located on the X chromosome (Xq28). The gene for factor VIII
presents an interesting primary structure, as another gene is embedded in one of its introns .[6]
Physiology
FVIII is a glycoprotein procofactor . Although the primary site of release in humans is
ambiguous, it is synthesized and released into the bloodstream by the vascular, glomerular, and tubular
endothelium , and the sinusoidal cells of the liver .[7] Hemophilia A has been corrected
by liver transplantation .[8] Transplanting hepatocytes was ineffective, but liver endothelial
cells were effective.[8]
In the blood, it mainly circulates in a stable noncovalent complex with von Willebrand factor .
Upon activation by thrombin , (factor IIa), it dissociates from the complex to interact with factor
IXa in the coagulation cascade . It is a cofactor to factor IXa in the activation of factor X ,
which, in turn, with its cofactor factor Va , activates more thrombin. Thrombin cleaves fibrinogen
into fibrin which polymerizes and crosslinks (using factor XIII ) into a blood clot.
No longer protected by vWF, activated FVIII is proteolytically inactivated in the process (most
prominently by activated protein C and factor IXa ) and quickly cleared from the blood stream.
Factor VIII is not affected by liver disease. In fact, levels usually are elevated in such instances. [9]
Therapeutic use
FVIII concentrated from donated blood plasma (Aafact or Alphanate), or alternatively
recombinant FVIII can be given to hemophiliacs to restore hemostasis .
The transfer of a plasma byproduct into the blood stream of a patient with hemophilia often led to
the transmission of diseases such as hepatitis B and C and HIV before purification methods
were improved.
Antibody formation to factor VIII can also be a major concern for patients receiving therapy against
bleeding; the incidence of these inhibitors is dependent of various factors, including the factor VIII
product itself.[10]
Proteolysis
(Redirected from Protein degradation )
Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids . This
generally occurs by the hydrolysis of the peptide bond , and is most commonly achieved by cellular
enzymes called proteases , but may also occur by intramolecular digestion, as well as by nonenzymatic methods such as the action of mineral acids and heat.
Proteolysis in organisms serves many purposes; for example, digestive enzymes break down
proteins in food to provide amino acids for the organism, while proteolytic processing of polypeptide
chain after its synthesis may be necessary for the production of an active protein. It is also important
in the regulation of some physiological and cellular processes, as well as preventing the accumulation
of unwanted or abnormal proteins in cells.
Contents
1 Post-translational proteolytic processing
o 1.1 Removal of N-terminal
methionine
o 1.2 Removal of the signal
sequence
o 1.3 Cleavage of polyprotein
o 1.4 Cleavage of precursor
proteins
2 Protein degradation
o 2.1 Lysosome and proteasome
o 2.2 Rate of intracellular

protein degradation
o 2.3 Digestion
3 Proteolysis in cellular regulation
o 3.1 Cell cycle regulation
o 3.2 Apoptosis
4 Regulatiory domains in proteolysis
5 Proteolysis and diseases

6 Laboratory applications
7 Venoms
8 See also
9 References
10 External links
Post-translational proteolytic processing

Limited proteolysis of a polypeptide during or after translation in protein synthesis often occur
for many proteins. This may involved removal of the N-terminal methionine , signal peptide ,
and/or the conversion of an inactive or non-functional protein to an active one. The precursor to the
final functional form of protein is termed proprotein , and these proproteins may be first
synthesized as preproprotein. For example, albumin is first synthesized as preproalbumin and
contains an uncleaved signal peptide. This forms the proalbumin after the signal peptide is cleaved,
and a further processing to remove the N-terminal 6-residue propeptide yields the mature form of the
protein.[1]
Removal of N-terminal methionine

The initiating methonine (and in prokaryotes, fMet ) may be removed during translation of the
nascent protein. For E. coli , fMet is efficiently removed if the second residue is small and
uncharged, but not if the second residue is bulky and charged.[2] In both prokaryotes and
eukaryotes , the exposed N-terminal residue may determine the half-life of the protein according to
the N-end rule .
Removal of the signal sequence

Proteins that are to be targeted to a particular organelle or for secretion have an N-terminal signal
peptide that directs the protein to its final destination. This signal peptide is removed by proteolysis
after their transport through a membrane .
Cleavage of polyprotein
Some proteins and most eukaryotic polypeptide hormones are synthesized as a large precursor
polypeptide known as polyprotein that require proteolytic cleavage into individual smaller polypeptide
chains. The polyprotein pro-opiomelanocortin (POMC) contains many polypeptide hormones.
The cleavage pattern of POMC however may vary between different tissues, yielding different sets of
polypeptide hormones from the same polyprotein.
Many viruses also produce their proteins initially as a single polypeptide chain that were translated
from a polycistronic mRNA. This polypeptide is subsequently cleaved into individual polypeptide
chains.[1]
Cleavage of precursor proteins

Many proteins and hormones are synthesized as in the form of their precursors - ( zymogens ,
proenzymes and prehormones ). These proteins are cleaved to form their final active structures.
Insulin , for example, is synthesized as preproinsulin and forms proinsulin after the signal peptide
has been cleaved. To form the mature insulin, the proinsulin is then cleaved at two positions to yield
two polypeptide chains linked by 2 disulphide bonds . Proinsulin is necessary for the folding of the
polypeptide chain as the 2 polypeptide chains of insulin may not correctly assemble into the correct
form while its precursor proinsulin do.
Proteases in particular are synthesized in the inactive form so that they may be safely stored in cells
and ready for released in sufficient quantity when required, and to ensure that the protease is only
activated in the correct location or context. Inappropriate activation of these proteases can be very
destructive for an organism. Proteolysis of the zymogen yield an active protein; for example, when
trypsinogen is cleaved to form trypsin , a slight rearrangement of the protein structure occurs
which completes the active site of the protease, thereby activating the protein.
Proteolysis can therefore be a method of regulating biological processes. A good example is the blood
clotting cascade whereby an initial event triggers a cascade of sequential proteolytic activation of
many specific proteases, resulting in blood coagulation. The complement system of the immune
response also involves a complex sequential proteolytic activation and interaction that result in an
attack on invading pathogens.
Protein degradation
Proteolytic cleavage breaks down proteins in food extracellularly into smaller peptides and amino
acids so that they may be absorbed and used by an organism. Proteins in cells are also constantly being
broken down into amino acids. This intracellular degradation of protein serves a number of functions it removes damaged and abnormal protein and prevent their accumulation, and it also serves to
regulate cellular processes by removing enzymes and regulatory proteins that are no longer needed.
The amino acids may then be reused for protein synthesis.
Structure of a proteasome. Its

active sites are inside the tube
(blue) where proteins are
degraded.
Lysosome and proteasome

The intracellular degradation of
protein may be achieved in two
ways - proteolysis in lysosome
, or a ubiquitin -dependent
process which targets unwanted
proteins to proteasome . The
autophagy -lysosomal
pathway is normally a nonselective process but may
become selective upon starvation
whereby protein with peptide
sequence KFERQ or similar are
selectively broken down. The
lysosome contains a large
number of proteases such as
cathepsins .
The ubiquitin-mediated process
is selective. Proteins marked for
degradation are covalently linked
to ubiquitin. Many molecules of
ubiquitin may be linked in tandem to a protein destined for degradation. The polyubiquinated protein
is targeted to an ATP-dependent protease complex, the proteasome. The ubiquitin is released and
reused, and the targeted protein is degraded.
Rate of intracellular protein degradation

Different proteins are degraded at different rate. Abnormal proteins are quickly degraded, while the
rate of degradation of normal proteins may vary widely depending on their functions. Enzymes at
important metabolic control points may be degraded much faster than those enzymes whose activity is
largely constant under all physiological conditions. One of the most rapidly degraded protein is
ornithine decarboxylase which has a half-life of 11 minutes. In contrast, other proteins like actin
and myosin have half-life of a month or more, while haemoglobin essentially lasts for the
entire life-time of erythrocyte .[3]
The N-end rule may partially determine the half-life of a protein, and proteins with segments rich
in proline , glutamine , serine , and threonine (the so-called PEST proteins ) have short
half-life.[4] Other factors suspected to affect degradation rate include the rate deamination of
glutamine and asparagine and oxidation of cystein , histidine and methionine, the absence of
stabilizing ligands, the presence of attached carbohydrate or phosphate groups, the presence of free amino group, the negative charge of protein, and the flexibility and stability of the protein. [3]
The rate of proteolysis may also depend on the physiological state of the cell, such as its hormonal
state as well as nutritional status. In time of starvation, the rate of protein degradation increases.
Digestion
In human digestion , proteins in food are broken down into smaller peptide chains by digestive
enzymes such as pepsin , trypsin , chymotrypsin , and elastase , and into amino acids by
various enzymes such as carboxypeptidase , aminopeptidase and dipeptidase . It is
necessary to break down proteins into small peptides (tripeptides and dipeptides) and amino acids so
they can be absorbed by the intestines, and the absorbed tripeptides and dipeptides are also further
broken into amino acids intracellularly before they enter the bloodstream. [5] Different enzymes have
different specificity for their substrate; trypsin for example cleaves the peptide bond after a positively
charge residue (arginine and lysine ), chymotrypsin cleaves the bond after an aromatic residue
(phenylalanine , tyrosine , and tryptophan ), elastase cleaves the bond after a small non-polar
residue such as alanine or glycine.
In order to prevent inappropriate or premature activation of the digestive enzymes (they may, for
example, trigger pancreatic self-digestion), these enzymes are secreted as inactive zymogen. The
precursor of pepsin , pepsinogen , is secreted by the stomach, and is activated only in only in the
acidic environment found in stomach. The pancreas secretes the precursors of a number of
proteases, such trypsin and chymotrypsin . The zymogen of trypsin is trypsinogen which is
activated by a very specific protease, enterokinase , which is secreted by the mucosa of the
duodenum . The trypsin, once activated, can also cleave other trypsinogen as well as the precursors
of other proteases such as chymotrypsin and carboxypeptidase.
In bacteria, a similar strategy of employing an inactive zymogen or prezymogen is used. Subtilisin
which is produced by Bacillus subtilis is produced as preprosubtilisin, and is released only if the
signal peptide is cleaved and autocatalytic proteolytic activation has occurred.
Proteolysis in cellular regulation

Proteolysis is also involved in the regulation of many cellular processes by activating or deactivating
enzymes, transcription factors, and receptors, for example in the biosynthesis of cholesterol, [6] or the
mediation of thrombin signalling through protease-activated receptors .[7]
Some enzymes at important metabolic control points such as ornithine decarboxylase is regulated
entirely by its rate of synthesis and its rate of degradation. Other rapidly degraded proteins include the
protein products of proto-oncogenes which play central roles in the regulation of cell growth.
Cell cycle regulation

Cyclins are a group of proteins that activate kinases involved in cell division. The degradation of
cyclins is the key step that governs the exit from mitosis and progress into the next cell cycle .
[8] Cyclins accumulate in the course the cell cycle, then abruptly disappear just before the anaphase
of mitosis. The cyclins are removed via a ubiquitin-mediated proteolytic pathway.
Apoptosis
Caspases are a important group of proteases involved in apoptosis .
Regulatiory domains in proteolysis

Protease may have one or more regulatory domains Calcium-binding domain - e.g. prothrombin , factor IX , X , VII , protein C in
blood clotting cascade, calpain .
Kringle domain - e.g. in prothrombin it keeps the protease inactive.
Proteolysis and diseases

Abnormal proteolytic activity are associated with many diseases.[9] In pancreatitis , leakage of
proteases and their premature activation in the pancreas results in the self-digestion of the pancreas .
People with diabetes mellitus may have increased lysosomal activity and the degradation of some
proteins can increase significantly. Chronic inflammatory diseases such as rheumatoid arthritis
may involve the release of lysosomal enzymes into extracellular space which break down surrounding
tissues. Abnormal proteolysis and generation of peptides that aggregate in cells and their ineffective
removal may result in many age-related neurological diseases such as Alzheimer .[10]
Other diseases linked to aberrant proteolysis include muscular dystrophy , degenerative skin
disorders, respiratory and gastrointestinal diseases, and malignan
CFTR inhibitory factor

Ribbon diagram of the Cif

dimer from P. aeruginosa
PA14. From PDB 3KD2 .
The CFTR inhibitory factor
(Cif) is a protein virulence
factor secreted by the
Gram-negative bacterium Pseudomonas aeruginosa .[1] Discovered at Dartmouth

Medical School , Cif is able to alter the trafficking of select ABC transporters in eukaryotic
epithelial cells , such as the cystic fibrosis transmembrane conductance regulator (CFTR),
[1] and P-glycoprotein [2] by interfering with the host deubiquitinating machinery.[3] By
promoting the ubiquitin -mediated degradation of CFTR, Cif is able to phenocopy cystic fibrosis
at the cellular level.[1][4] The cif gene is transcribed as part of a 3 gene operon , whose
expression is negatively regulated by CifR, a TetR family repressor.[5]
Cellular mechanism of action

Cif was first discovered by co-culturing P. aeruginosa with human airway epithelial cells and
monitoring the resulting effect on chloride ion efflux across a polarized monolayer. After co-culture,
the CFTR specific chloride ion efflux was found to be drastically reduced.[4] This was determined to
be caused by reduced levels of CFTR at the apical surface of these cells. This effect was later found to
be the result of a single secreted protein produced by P. aeruginosa, which was named the CFTR
inhibitory factor for this initial phenotype . Cif is secreted by P. aeruginosa PA14 as soluble protein
as well as packaged into outer membrane vesicles (OMV).[6] Cif is far more potent when
applied in OMVs, likely due to efficiency of delivery. Purified, recombinant Cif protein can be applied
to polarized monolayers of mammalian cells and promote the removal of CFTR[1][7] and Pglycoprotein[2] from the apical membrane . Cif accomplishes this by interfering with the host
deubiquitylation system.[3]
Epoxide hydrolase enzyme mechanism
The active site of Cif is shown with a C trace in gray, and side
chains of select residues playing a role in catalysis are
displayed as sticks. From PDB 3KD2 .
Cif is an epoxide hydrolase (EH) with unique substrate
selectivity.[7] Cif is the first example of an EH serving as a
virulence factor. Based on structural comparison, it appears
that the enzyme utilizes a catalytic triad of residues Asp129,
Glu153 and His297, with accessory residues His177 and Tyr239 coordinating the epoxide oxygen
during ring opening. Cif is also the first example of an EH utilizing a His-Tyr pair to coordinate an
epoxide substrate, rather than the canonical Tyr-Tyr pair.[8] In the proposed enzyme mechanism,
Asp129 nucleophilically attacks a carbon of the epoxide moiety of a substrate, forming an ester linked
enzyme-acyl intermediate. The preference for which carbon is attacked varies depending upon the
substrate. In the second step of the reaction, a water molecule is activated by the charge-relay His297Glu153 pair, and undergoes nucleophilic attack on the C of Asp129. This hydrolyzes the ester group,
liberating the hydrolysis product as a vicinal diol.[7]
Structure
Cif belongs to the / hydrolase family of proteins. Its structure was determined by X-ray
crystallography and consists of the canonical / hydrolase fold with a cap domain, which it uses to
constitutively homo-dimerize in solution. The active site is burred in the interior of the protein at the
interface between the / hydrolase core and the cap.[7][9]
Apolipoprotein B
Apolipoprotein B (including Ag(x) antigen)
Identifiers
Symbol
s
External
IDs
APOB; FLDB; LDLCQ4

OMIM: 107730MGI: 88052HomoloGene: 328ChEMBL: 4549 GeneCards: APOB
Gene
[show]Gene Ontology
RNA expression pattern
More reference expression data

Orthologs
Species
Human
Mouse
Entrez
338
ENSG00
0000846
74
P04114
238055
ENSMUSG
000000206
09
E9Q1Y3
Ensemb
l
UniProt
NM_000
384.2
RefSeq NP_000
(protein) 375.2
Chr 2:
Location 21.22
(UCSC) 21.27
Mb
PubMed
[1]
RefSeq
(mRNA)
search
NM_00969
3.2
NP_033823
.2
Chr 12:
7.98 8.02
Mb
[2]
This box:
view
talk
edit
Apolipoprotein B (APOB or ApoB) are the primary apolipoproteins of chylomicrons and

low-density lipoproteins (LDL - known commonly by the misnomer "bad cholesterol "
when in reference to heart disease ), which is responsible for carrying cholesterol to tissues .
While it is unclear exactly what functional role APOB plays in LDL, it is the primary apolipoprotein
component and is absolutely required for its formation. What is clear is that the APOB on the LDL
particle acts as a ligand for LDL receptors in various cells throughout the body (i.e. less formally,
APOB "unlocks" the doors to cells and thereby delivers cholesterol to them). Through a mechanism
that is not fully understood, high levels of APOB can lead to plaques that cause vascular disease
(atherosclerosis ), leading to heart disease . There is considerable evidence that levels of
APOB are a better indicator of heart disease risk than total cholesterol or LDL. However, primarily for
historic reasons, cholesterol, and more specifically, LDL-cholesterol , remains the primary lipid
test for the risk factor of atherosclerosis.
Contents
1 Genetic disorders
2 Mouse studies
3 Molecular biology
4 Role in Innate Immune System
5 Role in lipoproteins and
atherosclerosis
6 Interactions
7 Interactive pathway map
8 Regulation
9 RNA editing
o 9.1 Type
o 9.2 Location
o 9.3 Regulation
o 9.4 Conservation
9.5 Consequences
9.5.1 Structure
9.5.2 Function
10 See also
11 References
12 Further reading
13 External links
Genetic disorders
High levels of APOB are related to heart disease. Hypobetalipoproteinemia is a genetic
disorder that can be caused by a mutation in the APOB gene, APOB. Abetalipoproteinaemia is
usually caused by a mutation in the MTP gene, MTP.
Mutations in gene ApoB100 can also cause Familial hypercholesterolemia , a hereditary
(autosomal dominant) form of metabolic disorder Hypercholesterolemia .
Mouse studies
Most relevant information regarding mouse APOB homologue, mApoB, has come from mouse
studies. Mice overexpressing mApoB have increased levels of LDL "bad cholesterol" and decreased
levels of HDL "good cholesterol".[1] Mice containing only one functional copy of the mApoB
gene show the opposite effect, being resistant to hypercholesterolemia . Mice containing no
functional copies of the gene are not viable.[2]
Molecular biology
The protein occurs in the plasma in 2 main isoforms, APOB48 and APOB100. The first is
synthesized exclusively by the small intestine , the second by the liver . Both isoforms are coded
by APOB and by a single mRNA transcript larger than 16 kb. APOB48 is generated when a stop
codon (UAA) at residue 2153 is created by RNA editing . There appears to be a trans-acting
tissue-specific splicing gene that determines which isoform is ultimately produced. Alternatively, there
is some evidence that a cis-acting element several thousand bp upstream determines which isoform
is produced.
As a result of the RNA editing, APOB48 and APOB100 share a common N-terminal sequence, but
APOB48 lacks APOB100's C-terminal LDL receptor binding region. In fact, APOB48 is so called
because it constitutes 48% of the sequence for APOB100.
APOB 48 is a unique protein to chylomicrons from the small intestine. After most of the lipids in the
chylomicron have been digested, APOB48 returns to the liver as part of the chylomicron remnant,
where it is endocytosed and degraded.
Role in Innate Immune System

VLDL and LDL interfere with the quorum sensing system that upregulates genes required
for invasive Staphylococcus aureus infection. The mechanism of antagonism entails binding
Apolipoprotein B, to a S. aureus autoinducer pheromone, preventing signaling through its receptor.
Mice deficient in apolipoprotein B are more susceptible to invasive bacterial infection. [3]
Role in lipoproteins and atherosclerosis
APOB100 is found in lipoproteins originating from the liver (VLDL , IDL , LDL ).
Importantly, there is one APOB100 molecule per hepatic-derived lipoprotein. Hence, using that fact,
one can quantify the number of lipoprotein particles by noting the total APOB100 concentration in the
circulation. Since there is one and only one APOB100 per particle, the number of particles is reflected
by the APOB100 concentration. The same technique can be applied to individual lipoprotein classes
(e.g. LDL) and thereby enable one to count them as well.
It is well established that APOB100 levels are associated with coronary heart disease , and are
even a better predictor of it than is LDL level. A naive way of explaining this observation is to use the
idea that APOB100 reflects lipoprotein particle number (independent of their cholesterol content). In
this way, one can infer that the number of APOB100-containing lipoprotein particles is a determinant
of atherosclerosis and heart disease.
One way to explain the above is to consider that large numbers of lipoprotein particles, and, in
particular large numbers of LDL particles, lead to competition at the APOB100 receptor (i.e. LDL
receptor) of peripheral cells. Since such a competition will prolong the residence time of LDL particles
in the circulation, it may lead to greater opportunity for them to undergo oxidation and/or other
chemical modifications. Such modifications may lessen the particles' ability to be cleared by the
classic LDL receptor and/or increase their ability to interact with so-called "scavenger" receptors. The
net result is shunting of LDL particles to these scavenger receptors. Scavenger receptors typically are
found on macrophages , with cholesterol laden macrophages being better known as "foam cells ".
Foam cells characterize atherosclerotic lesions. In addition to this possible mechanism of foam cell
generation, an increase in the levels of chemically modified LDL particles may also lead to an increase
in endothelial damage. This occurs as a result of modified-LDL's toxic effect on vascular
endothelium as well its ability both to recruit immune effector cells and to promote platelet
activation.
Recently, the INTERHEART study found that the ApoB100 / ApoA1 ratio is more effective at
predicting heart attack risk, in patients who had had an acute myocardial infarction, than either the
ApoB100 or ApoA1 measure alone.[4] In the general population this remains unclear although in a
recent study apoB was the strongest risk marker for cardiovascular events. [5] A small study suggests
that added to fluvastatatin treatment, omega 3 fatty acids daily, containing 460 mg of E-EPA and 380
mg of E-DHA (ethyl esters), may lower apo B48 in hyperlipemic type 2 diabetics.[6

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Structure and function

Other calcium-binding proteins

Lipid phosphatases and PIP3

H-Ras structure PDB

control such processes

Activation and deactivation

subunit small GTPase , which is related in structure to the G subunit of heterotrimeric G

Constitutively active Ras

Ras-targeted cancer treatments

Synthesis of free glucose

Glucose transport in yeast

Glucose transport in Mammals

Expressed mostly in neurons (where it is

Is a high-affinity isoform, allowing it to

Found in adipose tissues and striated

Is the insulin -regulated glucose transporter.

Discovery of sodium-glucose cotransport

Excitatory and inhibitory

different types of receptors .

treatment of Parkinson's disease .

Degradation and elimination

causes Duchenne muscular dystrophy (DMD) .[6]

More reference expression data

o 2.2 Rate of intracellular

5 Proteolysis and diseases

Post-translational proteolytic processing

Removal of N-terminal methionine

the N-end rule .

Removal of the signal sequence

Cleavage of precursor proteins

Structure of a proteasome. Its

Lysosome and proteasome

Rate of intracellular protein degradation

Proteolysis in cellular regulation

Cell cycle regulation

Regulatiory domains in proteolysis

Proteolysis and diseases

CFTR inhibitory factor

Ribbon diagram of the Cif

Gram-negative bacterium Pseudomonas aeruginosa .[1] Discovered at Dartmouth

Cellular mechanism of action

Epoxide hydrolase enzyme mechanism

APOB; FLDB; LDLCQ4

More reference expression data

Apolipoprotein B (APOB or ApoB) are the primary apolipoproteins of chylomicrons and

Role in Innate Immune System

Role in lipoproteins and atherosclerosis

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