Metabolisme Nukleotida
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Transcript of Metabolisme Nukleotida
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