Metab Purin - Pirimidin
Metab Purin - Pirimidin
I. Pendahuluan
II. Basa Purin dan Basa Pirimidin
III. Nukleosida
IV. Nukleotida
V. Asam Nukleat
I. Pendahuluan
Nukleoprotein
protein majemuk
terdapat dalam inti sel
penyusun material inti sel
tersusun atas :
protein: histon / protamin
gugus non protein
semua sel hidup mengandung nukleoprotein
Kromatin
Konstituen penting dalam sel, tersusun atas
nukleoprotein
kelainan pembentukan nukleoprotein
perubahan dlm pertumbuhan /reproduksi sel
sebab kromatin pembelahan sel
Nukleoprotein
Enzim proteolitik
- Protein sederhana - Asam nukleat
trtm: histon & protamin (RNase / DNase)
polinukleotida
polinukleotidase
(fosfoesterse)
mononukleotida
purin/pirimidin nukleotidase (fosfatase)
Adenosin Guanosin
adenosin deaminase purin nukleosida fosforilase
NH3 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
Urasil dan Timin
degradasi
urine
Banyak tdp pd penderita tumor yang dikhemoterapi
( DNA degradasi )
Kepentingan biomedis
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 sin-
tesis nukleosida 5’-trifosfat
substrat untuk reaksi yg dikatalisis
oleh RNA dan DNA polimerase
Lanjutan fungsi nukleotida
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 5’-mono-
- Fosfat (GMP)
Lanjutan sintesis nukleotida
- IMP AMP energinya dari GTP
- IMP GMP energinya dari ATP
- Apabila terjadi defek dlm reaksi metabolik
menyebabkan kehilangan pengaturan sintesis
nukleotida purin over produksi purin
asam urat meningkat
Artritis gout
Pembentukan deoksi ribonukleotida
- pada keadaan sel tidak proliferasi rendah
- pada saat replikasi sintesis DNA sintesis
deoksiribonukleotida meningkat untuk
mensuport sintesis DNA
IV. Asam nukleat (Polinukleotid)
dibentuk dari ikatan fosfodiester yg terikat
pada C3’- dan C5’ monomer yg berdekatan
ada mol. yg berakhir 5’ dan 3’
masing-masing mol. memp. struktur
primernya, contoh 5’-3’p Gp Gp Ap Tp Cp A
Ada 2 macam asam nukleat besar: DNA & RNA
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)
The purine base is hypoxanthine
AMP and GMP are formed from IMP
Purine Nucleotides
Get broken down into Uric Acid (a purine)
Buchanan (mid 1900s) showed where purine ring
components came from:
Purine Pyrimidine
(C5H7N4) (C4H6N2)
O
Purine Nucleotide Synthesis OOC
COO
C
2-
O3P O CH2 H N HC N N
O C4 Aspartate ADP C4
H H CH + ATP + Pi H
CH
5 CH2 5
H C C
OH N N
OH OH H2N SAICAR Synthetase COO H2N
-D-Ribose-5-Phosphate (R5P)
Ribose-5-Phosphate Ribose-5-Phosphate
ATP Carboxyamidoimidazole Ribotide (CAIR) 5-Aminoimidazole-4-(N-succinylocarboxamide)
Ribose
Phosphate ribotide (SAICAR)
ADP + Pi
Pyrophosphokinase AIR
Car boxylase
AMP Fumarate Adenylosuccinate
ATP Lyase
+HCO3 O
N
2-
O3P O CH2 H HC 4 C
O O H2N N
O CH
H H C4
5
H O P O P O C CH
OH N C
5
OH
H2N N
O O H2N
Ribose-5-Phosphate
Ribose-5-Phosphate
5-Aminoimidazole Ribotide (AIR)
5-Phosphoribosyl--pyrophosphate (PRPP) 5-Aminoimidazole-4-carboxamide
ADP + Pi ribotide (AICAR)
AIR
Glutamine Synthetase N10-Formyl-
+ H2O Amidophosphoribosyl THF
ATP AICAR
Transferase
Transformylase
Glutamate H O THF
+ PPi N
H2C CH C
H2N N
2- NH2 C4
O3P O CH2
O CH
H H C O 5
HN NH C
N
H H O C NH
OH OH H
Ribose-5-Phosphate Ribose-5-Phosphate
-5-Phosphoribosylamine (PRA)
Formylglycinamidine ribotide (FGAM) 5-Formaminoimidazole-4-carboxamide
Glycine ADP + ribotide (FAICAR)
+ ATP Glutamate + Pi
FGAM
GAR Synthetase H2O
Synthetase IMP
ATP + Cyclohydrolase
ADP Glutamine +
+ Pi H2O O
H
H2C NH2 N C N
H 2C CH HN C
4
O C CH
HC C5
2-
C O N
O3P O CH2 NH N
O N10-Formyl-THF THF O NH 2-
O3P O CH2
H H O
H H
H H H
OH
GAR Transformylase Ribose-5-Phosphate H
OH OH OH
O GTP GDP + Pi
NH2
Aspartate Fumarate
C N C
HN C N
N C
CH CH
HC C HC C
N N N
N
Ribose-P Ribose-P
H2O + NAD+
IMP AMP
NADH + H+
O
O ATP ADP + Pi
Glutamine Glutamate C N
C N HN C
HN C CH
CH C C
C C H2N N N
HO N N
Ribose-P
Ribose-P
XMP GMP
Regulatory Control of Purine Nucleotide
Biosynthesis
GTP is involved in AMP synthesis and ATP is involved in
GMP synthesis (reciprocal control of production)
PRPP is a biosynthetically “central” molecule (why?)
ADP/GDP levels – negative feedback on Ribose Phosphate
Pyrophosphokinase
Amidophosphoribosyl transferase is activated by PRPP levels
APRT activity has negative feedback at two sites
ATP, ADP, AMP bound at one site
GTP,GDP AND GMP bound at the other site
Rate of AMP production increases with increasing
concentrations of GTP; rate of GMP production increases
with increasing concentrations of ATP
Regulatory Control of Purine Biosynthesis
At level of IMP production:
Independent control
Synergistic control
Feedforward activation by PRPP
Below level of IMP production
Reciprocal control
Xantin
↓٭
O C
O HN CH
C
HO C C CH
HN CH2 N
CH2 O
NH2 H2O
2-
C CH O3P O CH2
O
C CH O N H H
Dihydroorotase
O N H COO H H
H COO OH
OH
Dihydroorotate
Carbamoyl Aspartate Uridine Monophosphate
(UMP)
UMP UTP and CTP
Nucleoside monophosphate kinase catalyzes
transfer of Pi to UMP to form UDP; nucleoside
diphosphate kinase catalyzes transfer of Pi from
ATP to UDP to form UTP