Nucleotide synthesis and metabolism Flashcards
Where does purine synthesis occur
Liver
Are purines assembled and then ribosylated, or synthesized onto an existing ribose?
Purines are synthesized onto an already phophorylated ribose-5-phosphate.
What substrates are needed for purine synthesis
Ribose-5-phosphate, glycine glutamine CO2 Aspartate N10-Formyl-THF 6ATP
What is the initial purine synthesized
Inosine-monophosphate IMP.
What is the salvage pathway for purines?
Purine BASES with no attached ribose are salvaged.
APRT, Adenine PhosphoRibosyl Transferase
and
HPRT, Hypoxanthine-guanine PhosphoRibosyl Transferase
HPRT deficiency results in Lesch-Nyan syndrome. Elevated PRPP, Uricemia,
Decreased IMP and GMP,
What is PRPP
pyro-
Phospho-Ribosyl-PyroPhosphate
This is the substrate used to add Ribose-phosphate to a Purine base.
What enzyme and co-factor is used to reduce Ribonucleotides to Deoxyribonucleotides
Ribonucleotide diphosphate reductase, and Thioredoxin cofactor, plus an ATP allosteric activator.
Thioredoxin reductase plus NADPH is then needed to reduce the oxidized thioredoxin back to useable reduced state.
What are the products of purine metabolism (degradation)
Adenosine –> Inosine –> Hypoxanthine –> Uric acid
Guanosine –> Xanthine –> Uric acid.
What is the first enzyme of Pyrimidine synthesis
Carbamoyl Phosphate Synthetase 2. CPT II.
CO2 + Glutamine + 2ATP –> Carbamoyl phosphate + 2 ADP + Pi
What are the differences between CPT 1 and CPT2
Both are in the kidney.
Substrates
CPT1: HCO3- NH3 and ATP. Bicarbonate, Amonia and ATP
CPT2: CO2 + Glutamine + 2 ATP –> Carbamoyl Phos + 2ADP + Pi
What is the first enzyme of Purine synthesis (de novo)
1) PRPP synthetase
Ribose-5-phosphate + ATP => PRPP + AMP
2) Glutamine:PRPP amidotransferase
PRPP + Glutamine => 5-phsophoribosylamine + glutamate
What are the substrates needed for Pyrimidine de novo synthesis
Asparate, Glutamine, CO2, 4 ATP, and PRPP.
What is the first pyrimidine synthesized in the de novo pathway
Orotidine 5 monophosphate, OMP
What enzyme contains the CPT 2 catalytic domain?
CAD. It contains: CPT2 Aspartate transcarbamoylase Dihydroorotase
Catalyzes:
CO + Glutamine + 2ATP + Aspartate -> -> -> Dihydro Orotate
What enzyme follows CAD?
UMP Synthetase: Contains 2 domains: Orotate phosphoribosyl transferase and OMP decarboxylase
Are pyrimidines synthesized onto and existing Ribosyl-phosphate or are they synthesized first and then phospho-ribosylated?
The pyrimidines are synthesized and the then ribose-phosphate is added.
What cofactor is used to methylate dUMP to generate dTMP
The thymidylate synthetase enzyme uses the THF tetrahydrofolate cofactor.
Pyrimidine salvage
Does not occur to a large degree, because during degradation, the pyrimidine rings are cleaved to beta-alanine (from CMP and UMP) and beta-aminoisobutyrate (from TMP).
Pyrimidine bases can be salvaged by uracil phosphorylase or pyrimidine nucleoside phosphorylase, which adds ribose-1-phosphate. Then uridine/cytidine/tyhmidine kinase removes the 1 phos and adds 5 phos.
Deoxynucleoside salvage
deoxycytidine kinase. Salvages base-riboses, by phosphorylating them.
Salvages deoxy- Adeonsine, deoxy-Guanosine, AND deoxy-Cytidine
Targeted in leukemias because it is lymphoid specific.
Thymidine kinase
Very specific to salvage Thymidine (deoxyribose-thymine
Expressed only during active S-phase of cells.
Gancyclovir/Acyclovir are antibiotics which target this enzyme to kill rapidly dividing cells.
