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

Gout PRPP synthetaseincreased enzyme

activity due to elevated Vmax

hyperuricemia

Gout PRPP synthetaseenzyme is resistant to feed-back inhibition

hyperuricemia

Gout PRPP synthetase

enzyme has increased affinity for ribose-5-phosphate (lowered

Km) 

hyperuricemia

Gout PRPP amidotransferaseloss of feed-back

inhibition of enzymehyperuricemia

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

Renal lithiasis APRTd lack of enzyme 2,8-dihydroxyadenine renal lithiasis

Xanthinuria Xanthine oxidase lack of enzymehypouricemia and

xanthine renal lithiasis

von Gierke's disease Glucose-6-phosphatase enzyme deficiency see aboveaHypoxanthine-guanine phosphoribosyltransferase; badenosine deaminase; cpurine nucleotide phosphorylase; dadenosine phosphoribosyltransferase 

Disorders of Pyrimidine Metabolism

Disorder Defective Enzyme Comments

Orotic aciduria, Type I

orotate phosphoribosyl transferase and OMP decarboxylase

see above

Orotic aciduria, Type II

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 -keto acidsbenign, 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