Purine & pyrimidine metabolism Flashcards
Is the purine built on top of ribose or attached to it?
Made on top of it
What is the first formal step in the formation of purines?
Activation of the ribose, which forms 5-phospho-alpha-D-ribose-1-pyrophosphoric acid (PRPP)
What gives the pyrophosphate group to PRPP?
ATP
What is the second step in the formation of purines?
Formation of 5-phosphoribosylamine, with the amine group coming from glutamine
What is the regulated step in purine biosynthesis?
Formation of 5-phosphoribosylamine, catalyzed by glutamine PRPP amidotransferase
Nucleotide IMP
Formed by step 11 in purine synthesis, which is a precursor for both GTP and ATP
What is the enzyme catalyzing the formation of PRPP?
Ribosephosphate pyrophosphokinase
Why is tumor treatment by purine synthesis inhibition helpful?
Tumor cells are more affected by a disruption in de novo synthesis of purines; others rely more on recycling of purines
6-mercaptopurine
Converted to a nucleotide by the purine salvage pathway, then inhibiting the enzymes in the purine synthesis pathway, including glutamine PRPP amidotransferase
What is the regulated step in pyrimidine synthesis?
Formation of carbamoyl phosphate, catalyzed by carbamoyl phosphate synthetase II
Is the pyrimidine ring formed on top of ribose-5P or is it attached afterward?
Attached after
Precursor for synthesis of other pyrimidines
UMP
Leflunomide
Rheumatoid arthritis drug that blocks the formation of pyrimidines by inhibition of dihydroorotate dehydrogenase
How is dTMP made?
By conversion of dUMP through thymidylate synthase
5-fluorouracil
Becomes f-dUMP, which is an inhibitor of thymidylate synthase and blocks dTMP formation. Used as anticancer agent
Methotrexate
Blocks the reduction of dihydrofolate back to tetrahydrofolate, which is necessary for the reaction of thymidylate synthase. In the presence of methotrexate, thymidylate sythase is nonfunctional due to overaccumulation of DHF
Ribonucleotide reductase
Acts on ribonucleotide-5-diphosphates (ADP, GDP, UDP, CDP) to make corresponding deoxyribonucleotide
What happens in the reaction catalyzed by ribonucleotide reductase?
The 2’-OH is replaced with a hydrogen
What factors are needed in the reaction catalyzed by ribonucleotide reductase?
Thioredoxin
What enzymes are upregulated during the S phase of the cell cycle?
Ribonucleotide reductase and thymidylate synthase
Order of degradation of DNA/RNA
DNA/RNA -> nucleotides -> nucleosides -> bases
What is the order of enzymes needed to catalyze breakdown of DNA/RNA?
Nucleases, nucleotidases, nucleoside phosphorylases
What does adenine become after degradation?
Hypoxanthine
What percentage of purines are recycled after use?
90%
What is the enzyme needed in the purine salvage pathway?
Hypoxanthine-guanine phosphoribosyltransferase (HGPRTase)
Genetic deficiency in HGPRTase
Results in Lesch-Nyhan syndrome, characterized by mental retardation and self-mutilation
What percentage of purines are not reused, and what do they become?
10%; uric acid
What is the enzyme catalyzing the reaction of purines to uric acid?
Xanthine oxidase
What are the bases attached to in the reaction catalyzed by HGPRTase?
PRPP
What are the two forms of uric acid, and which one can form urate?
Keto form and enol form; enol form can be deprotonated to become urate
Where is urate more abundant? Uric acid?
Urate: blood
Uric acid: urine
What happens when there is overproduction or underexcretion of gout?
Uric acid builds up in the body. Stored in joint spaces, causing gout; crystallized in kidney tubules, causing kidney stones.
Allopurinol
Inhibitor of xanthine oxidase: prevents overproduction of uric acid, treating gout
