Metabolisme Nukleotida

SAA
 Outline
• Pengertian Nukleotida
• Struktur
• Fungsi
• Kepentingan Biomedis
• Metabolisme Purin dan Pirimidin
• Asam Nukleat
 Apa itu nukleotida
• Basa heterosiklik aromatik
• Purin
• Pirimidin
• Unit monomer asam nukleat
• Komponen koenzim
• Nukleosida ?
struktur
 Tata Nama
• Adenin (A)
• Guanin (G)
• Timin (T)
• Sitosin (C)
• Angka 3
• Angka 5
• Adanya ikatan fosfodiester
 Fungsi
• Pemindahan fosfat
• Fungsi regulasi
• Fungsi second messenger
• Prekursor monomer materi genetik
 Kepentingan Biomedis
• Analog purin dan pirimidin digunakan dlm
terapi penyakit kanker
• Pengobatan penyakit gout
• Supresi sistem imun
• Hasil metabolisme sebagai komponen
batu sal kencing
 Metabolisme Nukleotida
• Pencernaan
• Katabolisme
• Biosintesis
• Kelainan
 Pencernaan
• Adanya enzim-enzim RNA ase, DAN ase
dan polinukleotidase (endonuklease dan
fosfodiesterase))
• Enzim fosfatase
• Tidak ada incorporasi nukleotida lewat
pencernaan
• Asam nukleat diet ------- purin + pirimidin
 Katabolisme
• Purin ----------- asam urat
• Pirimidin --------- CO2, amoniak, beta
aminoisobutirat,alanin
• Tidak membutuhkan nukleotida dari diet
 Biosintesis
• Bersifat de novo ; inosin monopospat
• Fosforibosilasi purin
• Fosforilasi nukleosida purin
Synthesis of the first fully formed purine nucleotide, inosine monophosphate, IMP begins
with 5-phospho-a-ribosyl-1-pyrophosphate, PRPP. Through a series of reactions utilizing
ATP, tetrahydrofolate (THF) derivatives, glutamine, glycine and aspartate this pathway
yields IMP. The two indicated enzymes (A and B) are those catalyzing the rate limiting
step and the reaction necessary for the purine nucleotide cycle, respectively. The
structure of the nucleobase of IMP (hypoxanthine) is shown.
Abbreviations:
PRP: 5-phosphoribosylamine; 
GAR: 5-phosphoribosylglycinamide; 
FGAR:  5-phosphoribosyl-N-formylglycinamide
FGAM:  5-phosphoribosyl-N-formylglycinamidine
AIR: 5-phosphoribosylaminoimidazole
CAIR:  1-(5-phosphoribosyl)-5-amino-4-carboxyimidazole
SAICAR: 1-(5-phosphoribosyl)-4-(N-succinocarboxamide)-5-aminoimidazole
AICAR: 1-(5-phosphoribosyl)-5-amino-4-imidazolecarboxamide
FAICAR: 1-(5-phosphoribosyl)-5-formamido-4-imidazolecarboxamide
Katabolisme Purin
 Sintesis IMP
• Dari alfa D ribosa 5 pospat
• Melalui 11 reaksi
• Membuat 2 cabang (AMP dan GMP)
• Urutan reaksinya sbb
 Pemindahan Fosfat
• Pospat dari ATP dipindah ke AMP dan
GMP
• Enzim nukleosidase monofasfat kinase
• nukleosidase difosfat kinase
 Reaksi Penyelamatan
• Fosforibosilasi purin bebas oleh PRPP
• Fosoforilasi ribonukleosida secara
langsung
Biosintesis Nukleotida Purin di Hati
• Adanya ukuran depot PRPP
• AMP dan GMP mengatur enzim PRPP
• AMP dan GMP mengatur
pembentukannya dari IMP melalui feed
back
• Reduksi NDP membentuk dNDP
 Biosintesis Pirimidin
• Pembentukan karbamoil fosfat dari
glutamin ATP dan CO2
• 12 langkah lihat di gambar
Regulasi Biosintesis Pirimidin
 Regulasi Biosintesis Pirimidin
• Terjadi pada ekspresi gen dan aktifitas
enzim
• Pengaturan secara terkoordinasi
 Kelainan Met Purin
• Gout/Hiperurisemia
• Sindrom lesch Nyhan
• Penyakit Von Gierke
• Hipourisemia
• Defisiensi Adenosin deaminase dan
nukleosida purin fosforilsase
 Kelainan Met Pirimidin
• Ekskresi Beta Aminoisobutirat meningkat
pada leukimia
• Gen resesif
• Tinggi pada orang jepang dan cina
• Ekskresi pseudouridin tetap tanpa
perubahan
• Asiduria Orotat
• Defisiensi ornitin karboksilasi
 Disorders of Purine Metabolism

Disorder Defect Nature of Defect Comments

increased enzyme activity

Gout PRPP synthetase hyperuricemia
due to elevated Vmax

enzyme is resistant to feed-

Gout PRPP synthetase hyperuricemia
back inhibition
enzyme has increased
Gout PRPP synthetase affinity for ribose-5- hyperuricemia
phosphate (lowered Km) 
loss of feed-back inhibition
Gout PRPP amidotransferase hyperuricemia
of enzyme

Gout HGPRTa partially defective enzyme hyperuricemia

Lesch-Nyhan syndrome HGPRT lack of enzyme see above

SCID ADAb lack of enzyme see above
Immunodeficiency PNPc lack of enzyme see above
2,8-dihydroxyadenine
Renal lithiasis APRTd lack of enzyme
renal lithiasis
hypouricemia and xanthine
Xanthinuria Xanthine oxidase lack of enzyme
renal lithiasis
von Gierke's disease a Glucose-6-phosphatase
Hypoxanthine-guanine enzyme deficiency
phosphoribosyltransferase; b
adenosine deaminase; see above
c
purine nucleotide phosphorylase; adenosine phosphoribosyltransferase 
d
 Disorders of Pyrimidine Metabolism

Disorder Defective Enzyme Comments

Orotic aciduria, Type orotate phosphoribosyl transferase and

see above
I OMP decarboxylase

Orotic aciduria, Type

OMP decarboxylase see above
II

Orotic aciduria (mild, increased mitochondrial carbamoyl phosphate exits

the urea cycle enzyme, ornithine
no hematologic and augments pyrimidine biosynthesis; hepatic
transcarbamoylase, is deficient
component)  encephalopathy

Transaminase, affects urea cycle function

b-aminoisobutyric
during deamination of a-amino acids to of benign, frequent in Orientals
aciduria
-keto acids

Allopurinol and 6-azauridine treatments cause orotic

Drug induced orotic
OMP decarboxylase acidurias without a hematologic component; their
aciduria
catabolic by-products inhibit OMP decarboxylase