Metabolisme Nukleotida
Transcript of Metabolisme Nukleotida
METABOLISME NUKLEOTIDA
Evi Umayah Ulfa
Nucleotides
• Monomers for nucleic acid polymers
• Nucleoside Triphosphates are important energy carriers (ATP, GTP)
• Important components of coenzymes
– FAD, NAD+ and Coenzyme A
NUCLEOTIDE SYNTHESIS: DE NOVO AND SALVAGE PATHWAYS
De novo pathway
• Synthesis from low molecular weight precursors (Liver)
Salvage pathway
• Synthesis from nucleosides or bases that become available through the diet or from degradation of nucleic acids (Peripheral tissues)
DE NOVO PURINE SYNTHESIS
Source of Nitrogen
• 2 from Glutamine
• 1 from Aspartate
• 1 from Glycine
Source of Carbon
• 2 from Glycine
• 2 from N10-Formyl tetrahydrofolate
• 1 from CO2
Ribose 5 Phosphate
PRPP
5-Phosphoribosylamine
IMP
Adenylosuccinate XMP
AMP
ADP
ATP
GMP
GDP
GTP
PRPP synthetase
Amido tranferase
Adenylosuccinate
synthetase
IMP dehydrogenase
PURINES ARE NOT MADE AS FREE BASES – BUT AS NUCLEOTIDES
PPi DISPLACEMENT BY NH2
INOSINE 5’- MONOPHOSPHATE (IMP)
GLUTAMINE
GLYCINE + ATP
N10-FORMYL THF
GLUTAMINE + ATP
CO2
ASPARTATE + ATP
N10-FORMYL THF
5’-PRPP
ADDITION OF GLYCINE
FORMYL GROUP TRANSFER
NH2 GROUP TRANSFER
ATP RING CLOSURE
COO- ADDITION
ASPARTATE ADDITION
FUMARATE LOSS
FORMYL GROUP TRANSFER
RING CLOSURE
1
2
3
4
5
6
7
8
9
10
Purine Degradation
GMP
Excess bases are converted to Urate, releasedto the circulation and excreted through the Kidney
Diseases of Purine Metabolism:
Most common: Gout• Caused by excessive Urate• Urate has low solubility, high concentrations
precipitate faster than they can be cleared in Kidney• Leads to painful deposits in joints
• Underexcretion of uric acid• Diet rich in purines/alcohol; deficient in dairy products• Increased purine degradation• Increased PRPP Synthetase activity
overproduction of PRPP = increased purine synthesis = increased purine degradation = increased uric acid production
• Decreased/partial HGPRT activity1) Deficiency of HGPRT = increased HX and G2) Deficiency of HGPRT = accumulation of PRPP =
increased purine synthesis = increased uric acidlevels
3) Deficiency of HGPRT = decreased IMP and GMP = decreased inhibitors for purine synthesis
GOUT - Causes
As with Purines, there are both de novo and salvage pathways
PIRIMIDINE SYNTHESIS
De Novo PirimidineSynthesis
• Synthesis of the pyrimidine bases.
• CPSII = carbamoylphosphate synthetase II.
• RR=ribonucleotidereductase
• FH2 and FH4 forms of folate.
AspartateTranscarbamylase
Salvage of Pirimidine Base
• pyrimidinenucleoside phosphorylase converts the pyrimidinebases to their respective nucleosides
• specific nucleoside kinases react with the nucleosides, forming nucleotides
Other products derived from Purines/Pyrimidines
Nucleotide sugarse.g. UDP-Glucose or GDP MannoseCoenzyme A (Adenine)NAD (Adenine)NADP (AdenineFAD (Adenine)Vitamin B12 (Adenine)Biopterin (Guanine)