Metab Purin - Pirimidin
Metab Purin - Pirimidin
I. Pendahuluan
Nukleoprotein
protein majemuk
terdapat dalam inti sel
penyusun material inti sel
tersusun atas :
Kromatin
Konstituen penting dalam sel, tersusun atas
nukleoprotein
kelainan pembentukan nukleoprotein
perubahan dlm pertumbuhan /reproduksi sel
sebab kromatin
pembelahan sel
Nukleosida Purin
Adenosin
Guanosin
adenosin deaminase
fosforilase
NH3
purin nukleosida
Inosin
Guanin
purin nukleosida
fosforilase
Hipoxantin
Xantin oksidase
Xantin + O2
asam urat
urin
Xantin oksidase
Penyelamatan Purin
Untuk pembentukan nukleotida bbrp jaringan
manusia
tgt pd purin /purin ribonukleosida eksogen
Ada 2 jalan penyelamatan :
1. Fosforibosilasi purin bebas dgn enzim yang
membutuhkan PRPP sbg donor ribosa fosfat
2. Fosforilasi nukleosida purin pd gugus 5-hidroksi
oleh enzim adenosin kinase
Contoh :
1. Adenin menjadi AMP dg enzim adenin fosforibosa
transferase
2. Hipoxantin dan Guanin menjadi IMP dan GMP
dengan enzim hipoxantin-guanin fosforibosa
transferase
Nukleosida pirimidin
Sitidin
Deoksisitidin
deaminasi
Uridin
deaminasi
Deoksiuridin Deoksitimidin
fosforilse
degradasi
Kepentingan biomedis
kemampuan nukleotid menyerap sinar UV
nukleat
disintesis secara de novo, dg sumber :
N1 dari as. Aspartat,
C6 dr CO2 respirasi,
N7 dari glisin,
C8 dari N5,N10-metenilFH4,
N3 dan N9 dari nitrogen amida der. Glutamin dan
C2 dari N-formil -tetrahidroksi folat
jarum jam
Basa Pirimidin
nama lebih panjang dari purin ttp hy
Nitrogenous Bases
Planar, aromatic, and heterocyclic
Derived from purine or pyrimidine
Numbering of bases is unprimed
Pyrimidines
Sugars
Pentoses (5-C sugars)
Numbering of sugars is primed
Sugars
D-Ribose and 2-Deoxyribose
Nucleosides
Result from linking one of the sugars with a
their N9 atoms
Pyrimidines bond to the C1 carbon of the sugar
at their N1 atoms
Nucleosides
Phosphate Groups
Mono-, di- or triphosphates
Phosphates can be bonded to either C3 or C5
Nucleotides
Result from linking one or more phosphates
terikat
pada N9 basa purin dan pada N1 basa
pirimidin (kecuali U pd C5 ikatan C-C) dan
semuanya mrpk ikatan -N-glikosidik
Nukleosida yang dimanfaatkan untuk
menghambat pertumbuhan sel:
5-fluorourasil
- 5-iodo-2deoksiuridin
6-tioguanin
- 6-merkaptopurin
6-azauridin
- arabinosil sitosin
Nukleotida
Mrpk unit struktural as nukleat, mrpk komponen seluler
yg mudah dpt diketahui krn menyerap kuat sinar UV, der. basa
purin absorbsinya lebih kuat dari der. basa pirimidin
Tersusun: - basa purin/ basa pirimidin
- gula (ribosa atau 2-deoksiribosa),
- asam fosfat
Basa
Nukleosida
Nukleotida
Singkatan
RNA
Adenin
Adenosin
Asam adenilat
Guanin
Guanosin
Asam guanilat
Sitosin
Urasil
Timin
Sitidin
Uridin
Timidin
Asam Sitidilat
Asam uridilat
Asam timidilat
A
G
C
U
T
DNA
dA
dG
dC
dU
dT
Lanjutan nukleotida
-
Fungsi nukleotida
1. Berperan dlm metabolisme energi
Contoh: ATP - bentuk energi kimia yang diperlukan
untuk sel, dihasilkan dari fosforilasi
oksidatif atau fosforilasi tingkt
substrat
- terlibat dalam kontraksi otot
- transport aktif
- mempertahankan gradien/ion
- membantu sbg donor fosfat untuk
sintesis nukleosida 5-trifosfat
substrat untuk reaksi yg dikatalisis
oleh RNA dan DNA polimerase
Sintesis nukleotida
- Di dalam sel mamalia disintesis secara de novo
- Tidak semua sel mampu mensintesis nukleotid
purin
Contoh; sel-sel darah merah
- Pada akhir reaksi menghasilkan ITP prekursor
adenosin 5-monofosfat (AMP) dan guanosin 5mono- Fosfat (GMP)
Nucleotide
Metabolism
PURINE RIBONUCLEOTIDES: formed de novo
i.e., purines are not initially synthesized as free bases
First purine derivative formed is Inosine Mono-
phosphate (IMP)
Purine Nucleotides
Get broken down into Uric Acid (a purine)
CO2
Aspartate
Formyl-THF
Glycine
H
C
HN
HC
Glutamine
N
H
H
N
C
N
H
Formyl-THF
Glutamine
H
C
HN
HC
H
N
CH
N
H
N
H
Glycine
Glutamine (2)
Aspartate
N10-Formyl-THF (2)
CO2
H
C
HN
CH
HC
CH
N
H
Purine
Pyrimidine
(C5H7N4)
(C4H6N2)
Glutamine
Aspartate
CO2
2-
O3P O CH2
H
OH
OH
OH
O3P O CH2
ADP
+ Pi
C
HC
N
H
CH2
N
SAICAR Synthetase
AIR
Car boxylase
ADP + Pi
COO
H
OH
Ribose-5-Phosphate
Fumarate
AIR
Synthetase
Glutamine
+ H2O
Amidophosphoribosyl
Transferase
NH2
OH
OH
HN
ADP
+ Pi
H2C
NH2
NH
H2 C
C
N10-Formyl-THF
THF
GAR Transformylase
C
H
CH
NH
Ribose-5-Phosphate
5-Formaminoimidazole-4-carboxamide
ribotide (FAICAR)
ATP +
Glutamine +
H2O
IMP
Cyclohydrolase
O
C
CH
HN
HC
C5
NH
H
OH
H2O
H
N
H
OH
ADP +
Glutamate + Pi
FGAM
Synthetase
GAR Synthetase
Ribose-5-Phosphate
C4
NH
Ribose-5-Phosphate
Formylglycinamide ribotide (FGAR)
AICAR
Transformylase
THF
C
H2N
Glycine
+ ATP
CH
-5-Phosphoribosylamine (PRA)
O3P O CH2
N10-FormylTHF
2-
5-Aminoimidazole-4-carboxamide
ribotide (AICAR)
H
N
H2C
O3P O CH2
Ribose-5-Phosphate
ATP
Glutamate
+ PPi
2-
CH
H2N
Ribose-5-Phosphate
5-Phosphoribosyl--pyrophosphate (PRPP)
C4
H2N
Adenylosuccinate
Lyase
H2N
CH
5-Aminoimidazole-4-(N-succinylocarboxamide)
ribotide (SAICAR)
HC 4
CH
H2N
ATP
+HCO3
C4
Ribose-5-Phosphate
Ribose
Phosphate
Pyrophosphokinase
H
OH
AMP
2-
Aspartate
+ ATP
CH
H2N
-D-Ribose-5-Phosphate (R5P)
ATP
C4
O
COO
CH
N
N
2-
O3P O CH2
H
H
OH
H
H
OH
O
HN
HC
C
C
GDP + Pi
Fumarate
NH2
N
CH
HC
CH
Ribose-P
H2O + NAD+
Ribose-P
IMP
AMP
NADH + H+
O
HN
HO
C
C
ATP
Glutamine
ADP + Pi
Glutamate
HN
CH
H2N
C
C
CH
N
Ribose-P
Ribose-P
XMP
GMP
Pyrophosphokinase
Amidophosphoribosyl transferase is activated by PRPP levels
APRT activity has negative feedback at two sites
Adeosine deaminase)
Adenosine Degradation
Xanthosine Degradation
GMP
Guanosin
AMP
IMP
Guanin
Inosin
Hipoxantin
Xantin
Purine Salvage
(Jalur penyelamatan purin)
Adenine phosphoribosyl transferase (APRT)
transferase (HGPRT)
nukleosida
Sering nukleosida diputus basa bebas +
gula
nukleosida & basa dibawa ke jar lain
of uric acid
Uric acid crystals precipitate into joints
(Gouty Arthritis), kidneys, ureters
(stones)
Lead impairs uric acid excretion lead
poisoning from pewter drinking goblets
Fall of Roman Empire?
Pyrimidine Ribonucleotide
Synthesis
Uridine Monophosphate (UMP) is synthesized
first
CTP is synthesized from UMP
Pyrimidine Synthesis
Carbamoyl
Phosphate
Synthetase II
NH2
CH
C
N
H
PO3-2
PRPP
PPi
2-
O3P
Orotate Phosphoribosyl
Transferase
Pi
HO
N
H
H2O
Dihydroorotase
Orotidine-5'-monophosphate
(OMP)
OMP
Decarboxylase
CO2
C
CH
HN
C
N
H
Dihydroorotate
COO
O3P
CH2
CH
N
O
2-
CH
COO
Carbamoyl Aspartate
OH
OH
CH2
HN
C
CH
Quinone
CH2
COO
Dihydroorotate
Dehydrogenase
NH2
Reduced
Quinone
Orotate
Aspartate
Transcarbamoylase
(ATCase)
CH2
COO
Carbamoyl Phosphate
Aspartate
HN
CH
HN
OH
OH
Uridine Monophosphate
(UMP)
animals
Regulatory Control of
Pyrimidine
Synthesis
Animals regulation
at carbamoyl phosphate
synthetase II
UDP and UTP inhibit enzyme; ATP and PRPP
activate it
UMP and CMP competitively inhibit OMP
Decarboxylase
Degradation of
Pyrimidines
CMP and UMP degraded to bases similarly to
purines
Dephosphorylation
Deamination
Glycosidic bond cleavage
Deoxyribonucleotide
Formation
Purine/Pyrimidine degradation are the same
for ribonucleotides and deoxyribonucleotides
Biosynthetic pathways are only for
ribonucleotide production
Deoxyribonucleotides are synthesized from
corresponding ribonucleotides
Pd tingkat difosfat,gugus ribosa direduksi mjd