METABOLISME

NUKLEOTIDA
Ika Nurzijah
Department of Pharmacology and Clinical
Pharmacy
 Rute Metabolik Nukleotida

u De novo synthesis

u U ptake/pengambilan/absorpsi oleh
usus
u Endogenous turnover (Degradasi dan
Penyelamatan/Recycle/Salvage)
u Degradasi dan Ekskresi
METABOLISME PURIN
OVERVIEW SINTESIS PURIN

5′-phosphoribosyl-1′- pyrophosphate

hypoxanthine
SINTESIS IMP (1)
(5′-phosphoribosyl-1′- pyrophosphate)

ribose phosphate diphosphokinase

glutamine-PRPP- amidotransferase

glycinamide ribotide synthetase

 SINTESIS IMP (2)
AIR synthetase 5′-
GAR transformylase FGAM synthetase aminoimidazole
ribotide

formylglycinamide ribotide formylglycinamidine ribotide

AIR carboxylase

SAICAR synthetase
adenylosuccinate lyase

succinyl-aminoimidazole-
aminoimidazole-carboxamido-ribotide 4′-carboxy-5′-aminoimidazole
carboxamido-ribotide
ribotide
 SINTESIS IMP (3)

AICAR transformylase

IMP cyclohydrolase

aminoimidazole-carboxamido-ribotide
BIFUNCTIONAL ENZYME
succinyl-aminoimidazole-
carboxamido-ribotide (SAICAR)

SAICAR synthetase AIR carboxylase

SINTESIS AMP DARI IMP
SINTESIS GMP DARI IMP

xanthosine monophosphate
Feedback Regulation pada Sintesis
Purin

Competitive inhibition

Cross utilization
EATING DNA

Kapan
dibutuhkan ?

1.  Gut injury

2.  Kekurangan
protein
3.  Imunodefisiensi
4.  Masa
pertumbuhan

Clifford and Story, 1979

DIETARY NUCLEIC ACID
Lumen Enterocyte
Utilisasi Ribosa dan Deoxyribosa
 Hexose Monophosphate Shunt

1.  NADPH Regeneration (Hexose Monophosphate Shunt)

2.  Nucleotide Biosynthesis
3.  Ribose Utilization
Utilisasi Ribosa dan Deoxyribosa
GLYCOLYSIS
GLYCOLYSIS
ACETALDEHID DAN METABOLISME ETANOL
Degradasi Purine

Enzymes: 1 à AMP deaminase; 2àIMP dehydrogenase; 3àadenosine

deaminase; 4àguanase; 5àxanthine dehydrogenase or oxidase
 Degradasi Nukleotida Adenin

AMP deaminase (1), IMP dehydrogenase (2), 5′-nucleotidase (3), purine nucleoside
phosphorylase (4), and xanthine dehydrogenase/oxidase (5)
Degradasi guanine

Allopurinol

The oxidase activity is found in extracellular enzyme molecules,

which lack a supply of NAD+ anyway à O2 sebagai reduktor
Eliminasi asam urat : tubular reuptake +
glomerular filtration

Pyrazinoic
acid

Proenecid
(uricosuric)
Degradasi asam urat pada non-primata

Prove of Darwin Evolution Theory ???

Purine Salvage

Enzymes: 1, adenosine kinase; 2, inosine kinase; 3, guanosine kinase; 4, adenine

phosphoribosyltransferase (APRT); 5, hypoxanthine- guanine
phosphoribosyltransferase (HGPRT)
Penyakit2 terkait degradasi Purin

Adenosine deaminase defisiensi à T cells apoptosis

HGPRT (Hypoxanthine-guanine phosphoribosyltransferase) à defect à

X related syndrome
Gout (Penyakit asam urat)
Gout
•  Genetic or dietary factors cause chronically increased
urate production or retention
•  Urate has limited solubility and may form crystalline
deposits, preferentially in joints and soft tissue
•  Urate crystals activate inflammation and lead to
arthritis that is painful and, in the long run, destructive
•  Drugs that interfere with uric acid secretion:
pyrazinamide, salicylic acid
•  Drugs that contain purines: dideoxyadenosine
(antiretroviral)
Gout : the fructose connections
Obat-obatan yang bekerja pada jalur
degradasi dan eliminasi purine
Acute Urate Nephropathy
•  Occurs during chemotherapy of malignancies,
particularly with lymphomas and leukemias (not solid
cancer)
•  Chemotherapy causes acute decay of large numbers of
tumor cells
•  Degradation of nucleic acids from decaying cells
produces large amounts of uric acid
•  Uric acid in nascent urine exceeds solubility and
precipitates, clogging up and damaging the kidney
tubules à pKa uric acid (5.75)
•  Clinically manifest as acute kidney failure with high
fatality rate
Treatment Urate Nephropathy

Uricase from Aspergillus

Nucleoside triphosphate :
1.  Energy source à aktivitas
2.  Sintesis DNA
 Nucleoside Triphosphate : ATP - GTP

Hidrolisis

Fosforilasi
Nucleoside Triphosphate for DNA synthesis
Disosiasi Energi
GTP signal transduction
Obat-obatan yang bekerja pada reseptor GPCR
Next Weeks
•  Metabolisme Pirimidine à May 16, 2018
•  Review dan Kuis à May 23, 2018