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

Gout

Defect
PRPP synthetase

Nature of Defect
increased enzyme activity due to elevated Vmax enzyme is resistant to feed-back inhibition enzyme has increased affinity for ribose-5phosphate (lowered Km) loss of feed-back inhibition of enzyme partially defective enzyme lack of enzyme lack of enzyme lack of enzyme lack of enzyme lack of enzyme enzyme deficiency

Comments
hyperuricemia

Gout

PRPP synthetase

hyperuricemia

Gout

PRPP synthetase

hyperuricemia

Gout Gout Lesch-Nyhan syndrome SCID Immunodeficiency Renal lithiasis Xanthinuria von Gierke's disease

PRPP amidotransferase HGPRTa HGPRT ADAb PNPc APRTd Xanthine oxidase Glucose-6-phosphatase
aHypoxanthine-guanine

hyperuricemia hyperuricemia see above see above see above 2,8-dihydroxyadenine

renal lithiasis

hypouricemia and xanthine renal lithiasis see above

phosphoribosyltransferase; badenosine deaminase; cpurine nucleotide phosphorylase; dadenosine phosphoribosyltransferase

Disorders of Pyrimidine Metabolism Disorder Defective Enzyme Comments

Orotic aciduria, Type I Orotic aciduria, Type II

orotate phosphoribosyl transferase and OMP decarboxylase

see above

OMP decarboxylase

see above

Orotic aciduria (mild, no hematologic component)

the urea cycle enzyme, ornithine transcarbamoylase, is deficient

increased mitochondrial carbamoyl phosphate exits and augments pyrimidine biosynthesis; hepatic encephalopathy

b-aminoisobutyric aciduria

Transaminase, affects urea cycle function during deamination of a-amino acids to of a-keto acids

benign, frequent in Orientals

Drug induced orotic aciduria

OMP decarboxylase

Allopurinol and 6-azauridine treatments cause orotic acidurias without a hematologic component; their catabolic by-products inhibit OMP decarboxylase