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Carbohydrate

Metabolism

Department of Biochemistry
An Overview of Metabolism
Summary of Metabolism
DIET

Fats Carbohydrates Proteins

Free fatty acids + glycerol

Protein
Glycogenesis Amino synthesis
Glucose acids
Fat Lipogenesis
Lipogenesis

stores Excess glucose


Glycogen Body
stores protein
Lipolysis Urine
Glycogenolysis
Glucose pool
Gluconeogenesis
Free fatty
Range of normal
acid pool Amino acid
plasma glucose
pool

Metabolism in
most tissues Brain
Excess nutrients metabolism

Copyright © 2007 Pearson Education, Inc., publishing as Benjamin Cummings Figure 22-2
Summary of Metabolism
DIET

Carbohydrates

Glycogenesis
Glucose
Fat Lipogenesis
stores Excess glucose
Glycogen
stores
Urine
Glycogenolysis
Glucose pool
Range of normal
plasma glucose

Metabolism in
most tissues Brain
metabolism

Copyright © 2007 Pearson Education, Inc., publishing as Benjamin Cummings Figure 22-2 (1 of 4)
Metabolism
Summary of biochemical pathways for energy production

Glycogen

Glucose Glucose 6–phosphate


Liver only
G Cytoplasm
L
Y
C
Glycerol O
L 2 ATP
Y
S
I
NH3 S
Anaerobic conditions
Some
amino Pyruvate Lactate
acids Aerobic conditions
Pyruvate Mitochondria
Fatty
Acetyl CoA acids
CoA
Ketone
CO2 bodies
Citric (in liver)
acid 2 ATP
Electron transport cycle
system NH3 Some
amino
O2 ATP + H2O acids

Copyright © 2007 Pearson Education, Inc., publishing as Benjamin Cummings Figure 22-3
Metabolism
Push-pull control of metabolism

Copyright © 2007 Pearson Education, Inc., publishing as Benjamin Cummings Figure 22-4
Metabolism

Copyright © 2007 Pearson Education, Inc., publishing as Benjamin Cummings


Carbohydrate Metabolism
 Primarily glucose
 Fruktosa dan galaktosa memasuki jalur-jalur pada
berbagai titik
 Semua sel dapat memanfaatkan glukosa untuk
produksi energi
 Glukosa serapan dari darah ke sel-sel biasanya

dimediasi oleh insulin dan transporter


 Liver is central site for carbohydrate metabolism
 Glucose uptake independent of insulin
 The only exporter of glucose
Blood Glucose Homeostasis
 Beberapa jenis sel lebih memilih glukosa
sebagai sumber energi (ex., CNS)
 80-126 mg/dl is normal range of blood glucose in
fasted state
 < 200 mg/dl is normal range of blood glucose in
post prandial
 Uses of glucose:
 Energy source for cells
 Muscle glycogen
 Fat synthesis if in excess of needs
Fates of Glucose
 Fed state Synthesis and
 Storage as glycogen breakdown occur at all
Liver

 Skeletal muscle
times
 Storage as lipids regardless of state...
 Adipose tissue
 Fasted state The relative rates of
 Metabolized for energy synthesis and
 New glucose synthesized breakdown change
High Blood Glucose

Pancreas

Insulin:
Muscle Glucagon Glycogen

Glucose absorbed Glucose absorbed


Adipose
Cells

Glucose absorbed

immediately after eating a meal…


Glucose Metabolism
 Four major metabolic pathways:
 Immediate source of energy
 Pentophosphate pathway
 Glycogen synthesis in liver/muscle
 Precursor for triacylglycerol synthesis
 Energy status of body regulates which pathway
gets energy
Fate of Absorbed Glucose
 1st Priority: glycogen storage
 Stored in muscle and liver
 2nd Priority: provide energy
 Oxidized to ATP
 3rd Priority: stored as fat
 Only excess glucose
 Stored as triglycerides in adipose
Glucose Utilization

Energy
Adipose Stores Glycogen

Glucose

Pentose Glycolysis
Phosphate
Pathway

Ribose-5-phosphate Pyruvate
Glucose Utilization

Energy
Adipose Stores Glycogen

Glucose

Pentose Glycolysis
Phosphate
Pathway

Ribose-5-phosphate Pyruvate
Glycogenesis
 Liver
 7–10% of wet weight
 Use glycogen to export glucose to the
bloodstream when blood sugar is low
 Glycogen stores are depleted after
approximately 24 hrs of fasting (in humans)
 De novo synthesis of glucose for glycogen
Glycogenesis
 Skeletal muscle
 1% of wet weight
 More muscle than liver, therefore more glycogen in
muscle, overall
 Use glycogen (i.e., glucose) for energy only (no
export of glucose to blood)
 Use already-made glucose for synthesis of
glycogen
Glucose Utilization

Energy
Adipose Stores Glycogen

Glucose

Pentose Glycolysis
Phosphate
Pathway

Ribose-5-phosphate Pyruvate
Glycolysis
 Urutan reaksi yang mengubah glukosa
menjadi piruvat
 Jumlah energi yang dihasilkan relatif kecil
Reaksi glikolisis terjadi dalam sitoplasma
Tidak memerlukan oksigen
Lactate (animals)
Glucose → Pyruvate → Acetyl-CoA (TCA cycle)
Ethanol (yeast)
Glycolysis

Glucose + 2 ADP + 2 Pi
2 Lactate + 2 ATP + 2 H2O
First Reaction of Glycolysis

Perangkap glukosa dalam sel (ireversibel dalam sel otot)

Heksokinase digunakan oleh sebagian besar tanaman, hewan,


dan mikroba untuk memfosforilasi glukosa

Glukokinase dalam jaringan hati


Glycolysis - Summary
Glucose
2 ATP
4 ADP
2 ADP
4 ATP

2 NAD

2 NADH + H

2 Pyruvate
carbohydrate metabolism
Pyruvate Metabolism
 Three fates of pyruvate:
 Conversion to lactate (anaerobic)
 Conversion to alanine (amino acid)
 Entry into the TCA cycle via pyruvate
dehydrogenase pathway
Anaerobic Metabolism of
Pyruvate
 Problem:
 Selama glikolisis, NADH terbentuk dari NAD +
 Tanpa O2, NADH tidak dapat dioksidasi menjadi NAD +
 Tidak ada lagi NAD +
Semua dikonversi menjadi NADH
 Tanpa NAD +, glikolisis berhenti ...
Anaerobic Metabolism of
Pyruvate
 Solution:
 Hidupkan NADH kembali ke NAD + dengan membuat laktat (asam
(reduced) (oxidized)
laktat)

NADH + H+ NAD+
COO– COO–
C O HC OH
Lactate dehydrogenase
CH3 CH3
Pyruvate Lactate
(oxidized) (reduced)
Anaerobic Metabolism of
Pyruvate
 ATP yield
 Two ATPs (net) are produced
in the anaerobic breakdown of one glucose
 The 2 NADHs are used to reduce 2 pyruvate
to 2 lactate
 Reaction is fast and doesn’t require oxygen
Pyruvate Metabolism - Anaerobic
Lactate Dehydrogenase
Pyruvate Lactate

NADH NAD+

Laktat dapat diangkut oleh darah ke hati dan


digunakan dalam glukoneogenesis
Cori Cycle

Laktat diubah menjadi


piruvat di hati
Pyruvate Metabolism
 Three fates of pyruvate:
 Conversion to lactate (anaerobic)
 Conversion to alanine (amino acid)
 Entry into the TCA cycle via pyruvate
dehydrogenase pathway
Pyruvate metabolism
 Convert to alanine and export to blood
Glutamate -Ketoglutarate
COO– COO–
C O HC NH 3+
Alanine amino transferase
CH3 (AAT) CH3
Pyruvate Alanine
Keto acid Amino acid
Pyruvate Metabolism
 Three fates of pyruvate:
 Conversion to lactate (anaerobic)
 Conversion to alanine (amino acid)
 Entry into the TCA cycle via pyruvate
dehydrogenase pathway
Glycolysis
Pyruvate Dehydrogenase Complex
(PDH)
 Prepares pyruvate to enter the TCA cycle

Aerobic Conditions Electron TCA Cycle


Transport
Chain
PDH - Summary
Pyruvate

2 NAD

2 NADH + H
CO2

Acetyl CoA
TCA Cycle
 Dalam kondisi aerobik Link siklus TCA piruvat untuk
fosforilasi oksidatif
 Terjadi pada mitokondria
 Menghasilkan 90% dari energi yang dilepaskan dari
makanan
 Metabolizes carbohydrate, protein, and fat
 Strateginya adalah untuk mengoksidasi asetil-KoA
menjadi CO2 dan menangkap energi NADH
(FADH2) dan ATP
TCA Cycle - Summary
Acetyl CoA

1 ATP 3 NAD

1 ADP 3 NADH + H

1 FAD
1 FADH2
Oxidative Phosphorylation
Oxidative Phosphorylation and the
Electron Transport System
 Membutuhkan koenzim sebagai pembawa H+
dan mengkonsumsi oksigen
 Key reactions take place in the electron
transport system (ETS)
 Sitokrom dari ETS melewati elektron ke oksigen,
membentuk air
 The basic chemical reaction is:
2 H2 + O2  2 H2O
Oxidation and Electron Transport
 Oksidasi nutrisi melepaskan energi yang
tersimpan
 mendonorkan elektron disertai dengan H +
 Electrons transferred to co-substrate

NAD+ + 2H+ + 2e- NADH + H+


FAD + 2H+ + 2e- FADH2
So, What Goes to the ETS???

From each molecule of glucose entering glycolysis:


1. From glycolysis: 2 NADH
2. From the TCA preparation step (pyruvate to acetyl-CoA): 2 NADH
3. From TCA cycle (TCA) : 6 NADH and 2 FADH2

TOTAL: 10 NADH + 2 FADH2


Electron Transport Chain
 NADH + H+ and FADH2 enter ETC
 Perjalanan melalui kompleks I - IV
 H + mengalir melalui ETC dan akhirnya
menempel pada O2 membentuk air
NADH + H+ 3 ATP
FADH2 2 ATP
Electron Transport Chain
Glucose Utilization
Energy
Adipose Stores Glycogen

Glucose
Pentose Glycolysis
Phosphate
Pathway

Ribose-5-phosphate Pyruvate
Pentose Phosphate Pathway
 Secondary metabolism of glucose
 Produces NADPH
 Similar to NADH
 Required for fatty acid synthesis
 Generates essential pentoses
 Ribose
 Used for synthesis of nucleic acids
Pentose Phosphate Pathway
Glucose-6- 6-Phospho- 6-Phospho-
phosphate glucono- gluconate
lactone

D-Ribulose-5-
phosphate

D-Ribose- 5-
RNA or DNA phosphate
Glucose Utilization
Energy
Adipose Stores Glycogen

Glucose
Pentose Glycolysis
Phosphate
Pathway

Ribose-5-phosphate Pyruvate
Energy Storage
 Energi dari kelebihan karbohidrat (glukosa)
disimpan sebagai lemak dalam jaringan adiposa
 Asetil-KoA (dari siklus TCA) didorong ke sintesis
asam lemak pada saat kelebihan energi
 Ditentukan oleh rasio ATP: ADP
 High ATP, acetyl-CoA goes to fatty acid synthesis
 Low ATP, acetyl CoA enters TCA cycle to generate MORE
ATP
Fates of Glucose
 Fed state Synthesis and
 Storage as glycogen breakdown occur at all
Liver

 Skeletal muscle
times
 Storage as lipids regardless of state...
 Adipose tissue
 Fasted state The relative rates of
 Metabolized for energy synthesis and
 New glucose synthesized breakdown change
Gluconeogenesis
 Necessary process
 Glucose is an important fuel
 Central nervous system
 Red blood cells
 Not simply a reversal of glycolysis
 Insulin and glucagon are primary regulators
Fasting Situation
 Where does required glucose come from?
 Glycogenolysis
Kerusakan atau mobilisasi glikogen yang disimpan oleh glukagon
Glukagon - hormon yang disekresi oleh pankreas selama masa puasa

Lipolysis
 Mobilization of fat stores stimulated by glucagon and epinephrine
 Triglyceride = glycerol + 3 free fatty acids
 Glycerol can be used as a glucose precursor

Proteolysis
 Pemecahan protein otot dengan pelepasan asam amino
Alanin dapat digunakan sebagai prekursor glukosa
Low Blood Glucose

Pancreas

Insulin:
Muscle Glucagon Glycogen

Proteins Broken Down Glucose released

Adipose
Cells

Glycerol, fatty acids released

Dalam keadaan berpuasa, substrat untuk sintesis glukosa


(glukoneogenesis) dilepaskan dari "penyimpanan" ...
Fasted-State Metabolism
FASTED-STATE METABOLISM

Liver glycogen becomes glucose.

Liver
glycogen
stores
Glycogenolysis

Energy
production Glucose Energy production

Glycogen

Gluconeogenesis
Pyruvate
or
Lactate

Glucose

Energy production

Copyright © 2007 Pearson Education, Inc., publishing as Benjamin Cummings Figure 22-7 (2 of 5)
Gluconeogenesis
 Synthesis of glucose from non-carbohydrate
precursors during fasting in monogastrics
 Glycerol
 Amino acids
 Lactate Supply carbon skeleton
 Pyruvate
 Propionate
 There is no glucose synthesis from fatty acids

 Terjadi terutama dalam hati, tetapi juga dapat terjadi


pada ginjal dan usus halus
Fasted-State Metabolism
Adipose lipids
FASTED-STATE METABOLISM become free
fatty acids and Triglyceride stores
Liver glycogen becomes glucose. glycerol that
enter blood.
Liver Free fatty
glycogen Free fatty
acids Glycerol
stores acids
Glycogenolysis b-oxidation
Gluconeogenesis

Energy Ketone
production Glucose bodies Energy production

Glycogen Proteins

Gluconeogenesis
Pyruvate
or
Lactate
Ketone Amino
Glucose acids
bodies

Energy production
Muscle glycogen can be used for energy.
Brain can
Muscles also use fatty acids and break
use only glucose
down their proteins to amino acids that
and ketones for energy.
enter the blood.

Copyright © 2007 Pearson Education, Inc., publishing as Benjamin Cummings Figure 22-7
Fasted-State Metabolism
FASTED-STATE METABOLISM

Liver glycogen becomes glucose.

Liver
glycogen
stores
Glycogenolysis

Energy
production Glucose

Glucose

Energy production

Copyright © 2007 Pearson Education, Inc., publishing as Benjamin Cummings Figure 22-7 (1 of 5)
Fasted-State Metabolism
FASTED-STATE METABOLISM

Liver glycogen becomes glucose.

Liver
glycogen
stores
Glycogenolysis

Energy
production Glucose Energy production

Glycogen Proteins

Gluconeogenesis
Pyruvate
or
Lactate
Amino
Glucose acids

Energy production

Copyright © 2007 Pearson Education, Inc., publishing as Benjamin Cummings Figure 22-7 (3 of 5)
Fasted-State Metabolism
Adipose lipids
FASTED-STATE METABOLISM become free
fatty acids and Triglyceride stores
Liver glycogen becomes glucose. glycerol that
enter blood.
Liver Free fatty
glycogen Free fatty
acids Glycerol
stores acids
Glycogenolysis
Gluconeogenesis

Energy
production Glucose Energy production

Glycogen Proteins

Gluconeogenesis
Pyruvate
or
Lactate
Amino
Glucose acids

Energy production
Muscle glycogen can be used for energy.
Muscles also use fatty acids and break
down their proteins to amino acids that
enter the blood.

Copyright © 2007 Pearson Education, Inc., publishing as Benjamin Cummings Figure 22-7 (4 of 5)
Fasted-State Metabolism
Adipose lipids
FASTED-STATE METABOLISM become free
fatty acids and Triglyceride stores
Liver glycogen becomes glucose. glycerol that
enter blood.
Liver Free fatty
glycogen Free fatty
acids Glycerol
stores acids
Glycogenolysis b-oxidation
Gluconeogenesis

Energy Ketone
production Glucose bodies Energy production

Glycogen Proteins

Gluconeogenesis
Pyruvate
or
Lactate
Ketone Amino
Glucose acids
bodies

Energy production
Muscle glycogen can be used for energy.
Brain can
Muscles also use fatty acids and break
use only glucose
down their proteins to amino acids that
and ketones for energy.
enter the blood.

Copyright © 2007 Pearson Education, Inc., publishing as Benjamin Cummings Figure 22-7 (5 of 5)
Ketogenesis
KETOGENESIS

Ketogenesis adalah proses dimana


BADAN KETON atau senyawa
yang dihasilkan dari molekul
asetil CoA sebagai hasil dari
degradasi asam lemak.
Ketogenesis and Ketone Bodies
In ketogenesis:

 Lemak tubuh terurai


untuk memenuhi
kebutuhan energi.
 Senyawa Keto yang
disebut bentuk
badan keton.

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Ketogenesis and Ketone Bodies
In ketogenesis:
 Sejumlah besar asetil KoA menumpuk.

 Dua molekul asetil KoA bergabung membentuk


asetoasetil KoA
 Asetoasetil KoA menghidrolisis untuk asetoasetat, tubuh

keton.
 Asetoasetat tereduksi menjadi b-hydroxybutyrate atau
kehilangan CO2 untuk membentuk aseton, kedua badan
keton.
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Reactions of Ketogenesis

Ketone bodies

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KETOGENESIS
 Badan keton diproduksi terutama di mitokondria
hepatosit.
 Sintesis terjadi sebagai respons terhadap kadar
glukosa rendah dalam darah, dan setelah kehabisan
simpanan karbohidrat seluler, seperti glikogen.
 Produksi badan keton kemudian berinisiatif untuk
membuat energi tersedia yang disimpan sebagai
asam lemak.
KETOGENESIS

 Namun, jika jumlah asetil-KoA yang dihasilkan


dalam fatty-acid β-oxidation menentang
kapasitas pengolahan dari siklus TCA atau jika
aktivitas dalam siklus TCA rendah karena jumlah
rendah intermediet seperti oksaloasetat, acetyl-
CoA kemudian digunakan sebagai pengganti
dalam biosintesis badan keton melalui
acetoacyl-CoA and β-hydroxy-β-methylglutaryl-
CoA (HMG-CoA).
KETOGENESIS
REVIEW!
 Asam lemak menjalani β-
oxidation to form acetyl-
CoA.
 Biasanya, asetil-CoA
selanjutnya teroksidasi dan
energinya ditransfer sebagai
elektron untuk NADH, FADH2,
dan GTP dalam siklus Krebs.
KETOGENESIS
KETOGENESIS
 The three ketone bodies are:
 Acetoacetate - if not oxidized to form usable energy, it is
the source of the two other ketone bodies below.
 Acetone - is not used as an energy source, but is instead
exhaled or excreted as waste.
 β-hydroxybutyrate - it is not technically a ketone
according to IUPAC nomenclature.

 Each of these compounds are synthesized from acetyl-CoA


molecules.
KETOGENESIS
 Ketogenesis mungkin atau tidak mungkin terjadi,
tergantung pada tingkat karbohidrat yang tersedia
di sel atau tubuh.
 When the body has ample carbohydrates available as
energy source, glucose is completely oxidized to CO2.
 When the body has excess carbohydrates available, some
glucose is fully metabolized, and some of it is stored by
using acetyl-CoA to create fatty acids.
KETOGENESIS

 Ketika tubuh tidak memiliki karbohidrat bebas yang


tersedia, lemak harus dipecah menjadi asetil-KoA untuk
mendapatkan energi. Asetil-KoA tidak didaur ulang
melalui siklus asam sitrat karena intermediet siklus asam
sitrat (terutama oksaloasetat) telah habis untuk memberi
makan jalur glukoneogenesis, dan akumulasi dihasilkan
asetil-CoA mengaktifkan ketogenesis.
 Ketogenesis menyediakan energi untuk fungsi-fungsi
organ vital 'selama kelaparan yang berkepanjangan
KETOGENESIS
KETOGENESIS
KETOGENESIS

 Badan keton dibuat pada tingkat moderat dalam


tubuh kita, seperti saat tidur dan waktu lain bila
tidak ada karbohidrat yang tersedia.
 Namun, ketika ketogenesis yang terjadi lebih tinggi
dari tingkat normal, tubuh dikatakan dalam
keadaan ketosis. Badan keton terakumulasi dalam
tubuh dapat menyebabkan efek negatif jangka
panjang.
KETOGENESIS

 Konsentrasi tinggi abnormal badan keton pada


tubuh menghasilkan penurunan tingkat pH darah.
kondisi ini disebut ketoasidosis.
 Ketoasidosis sangat jarang terjadi. Hal ini,
bagaimanapun, lebih terlihat pada orang yang
menderita Diabetes mellitus (DM) dan pada mereka
pecandu alkohol setelah pesta minuman keras dan
kelaparan berikutnya.
Diabetes and Ketoacidosis
 Bila tidak ada cukup insulin dalam darah, glukosa tidak
digunakan secara efisien untuk menghasilkan energi.
Dengan demikian, tubuh harus memecah lipid untuk
energi.
 Degradasi lipid menyebabkan keton menambah dalam
darah. Keton kemudian meluas ke urin sehingga tubuh
bisa menyingkirkan mereka. Aseton dapat
dihembuskan melalui paru-paru. Keton yang
membangun di dalam tubuh untuk waktu yang lama
menyebabkan penyakit serius dan koma. (Ketoasidosis
diabetik)
Ketosis
Ketosis occurs:
 In diabetes, diets high in
fat, and starvation.
 As ketone bodies
accumulate.
 When acidic ketone
bodies lowers blood pH
below 7.4 (acidosis).

87
Ketone Bodies and Diabetes
 The blood glucose is elevated within
30 min following a meal containing
carbohydrates
 The elevated level of glucose
stimulates the secretion of insulin,
which increases the flow of glucose
into muscle and adipose tissue for
synthesis of glycogen (+ stimulates
glycolysis)
 As blood glucose levels drop, the
secretion of glucagon increases,
which stimulates the breakdown of
glycogen in the liver to yield glucose

88
Ketone Bodies and Diabetes
In diabetes:
 Insulin does not function properly.
 Glucose levels in muscle, liver, and adipose
tissue are insufficient for energy needs.
 As a result, liver cells synthesize
glucose from non-carbohydrate
sources (gluconeogenesis) and fats are
broken down to acetyl CoA.
 The level of acetyl CoA is elevated.
 Excess acetyl CoA undergoes ketogenesis.
 Ketogenesis produces ketone bodies.
 Ketone bodies accumulate in the blood.

89