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
