Pyrimidine Metabolism Flashcards
What is the major regulatory step of pyrimidine synthesis?
Formation of carbamoyl phosphate from glutamine and bicarbonate with CPSII.
In the pathway for pyrimidine synthesis, what is the next major product made after synthesis of carbamoyl phosphate?
Orotate.
How is CTP made?
Amino transfer from glutamine to UTP, generating CTP and glutamate. Enzyme is CTP synthase.
What are the two steps in pyrimidine salvage?
1) Addition of a ribose to the pyrimidine base
2) Addition of a phosphate with a kinase –> nucleotide
What is the clinical significance of beta-aminoisobutryate?
It is a breakdown product of pyrimidines and is used to measure cellular turnover in cancer patients undergoing chemotherapy.
Name the enzyme that makes deoxy riboses from ribonucleoside diphosphates.
Ribonucleotide reductase.
What is the starting material used to make deoxy thymine monophosphates?
Deoxy uracil monophosphate.
What is orotic aciduria?
Pediatric disease caused by the absence or either or both orotate phosphoribosyl transferase (OPRT) or orotidate decarboxylase. Orotic acid builds up if these are defective.
What is the treatment for orotic aciduria?
UMP supplementation
Which intermediates build up in ADA deficiency? How can this cause SCID?
dATP builds up, which inhibits ribonucleoside reductase which makes deoxys. If no deoxy ribonucleosides are made, cells can’t replicate. Cellular turnover is high in the development of the immune system
What does FdUMP do? How?
Inhibits thymidylate synthase (dUMP –> dTMP) by covalently binding to the enzyme (Fluorine is highly electronegative)
What does methotrexate do?
It is a DHF analogue that inhibits DHF reductase used to regenerate THF from DHF. This blocks dUTP –> dTMP, inhibiting cell proliferation, used in chemotherapy.
