MCP - Schmitt - Nucleotide Synthesis Flashcards
Defects in what enzyme contribute to gout?
HGPRT = Hypoxanthine-guanine phosphoribosyl transferase
HGPRT catalyzes the formation of nucleotides from either hypoxanthine or guanine. HGPRT is inhibited by IMP and GMP.
What step in the synthesis of pryimidine nucleotides is shared with the urea cycle?
NH3 + CO2 –> carbamoyl phosphate
Why do patients with urea cycle ornithine transcarbamoylase (OTC) deficiency build up high levels of pyrimidines in their serum and urine.
Bc the 1st step in the urea cycle is the rate-limiting step. With too much carbamoyl phosphate around, that cannot become citrulline bc of low/deficient OTC, the excess is converted into pyrimidines
What is orotic aciduria?
Orotic aciduria is a genetic disorder of pyrimidine biosynthesis. It can be alleviated by feeding cytidine or uridine, which supplies the body with needed pyrimidine bases, and inhibits CPII.
Many enzymes use glutamine as an NH3 donor. All are inhibited by what drug?
Azaserine, which is an analog of glutamine
Examples of enzymes azaserine inhibits: CPSII CTP Synthase FGAR Aminotransferase GMP Synthase PRPP Aminotransferase Asparagine Synthase
What is the function of sulfonamide drugs?
Sulfonamide drugs block the synthesis of folic acid in bacteria, which further prevents nucleotide sythesis. For example, sulfonamides block the formation of IMP, which requires folate at 2 steps.
What is the function of ribonucleotide reductase? What inhibits its activity?
Ribonucleotide reductase catalyzes the reduction of ribonucleoside diphosphates to make deoxyribonucleotides.
Hydroxyurea blocks this enzyme, and is a potent chemotherapy agent.
What are the necessary steps in purine degradation?
- dephosphorylation
- deamination
- separation of the base from the ribose
- oxidation to uric acid
steps 1-3 do not have a specific order
Why is allopurinol often given as a pretreatment for chemotherapy?
Allopurinol is a treatment for gout, and blocks the production of uric acid. Allopurinol becomes oxypurinol in the body, which inhibits xanthine oxidase’s ability to oxidiza xanthine or hypoxanthine (suicide inhibition).
In chemo, large quantities of nucleotides get released from dying cancer cells. Allopurinol prevents the breakdown of these to uric acid, preventing gout/uricemia.
Severe or complete deficiency of HGPRT activity leads to what disorder?
Lesch-Nyhan syndrome
What is ADA deficiency?
Adenosine deaminase deficiency
Without ADA deaminase, deoxyadenosine and adenosine are not degraded to deoxyinosine and inosine, and build up. However, in WBCs, deoxyadenosine and adenosine are converted into nucleotides. High levels of dATP inhibit ribonucleotide reductase, and DNA synthesis is inhibited. If WBCs cannot proliferate, SCID ensues.
What are the purine bases?
Adenine
Guanine
Xanthine
Hypoxanthine
What are the pyrimidine bases?
Uracil
Cytosine
Thymine
What are the purine ring precursors?
Glutamine Glycine CO2 Aspartate 2 1-carbon fragments from folate pool
What is the purine base precursor?
PRPP
