Nucleotide Metabolism (Pyrimidines) Flashcards
–Enumerate the donors of C & N atoms to pyrimidine ring –Outline pyrimidine biosynthesis (UTP & CTP). Distinguish purine and pyrimidine biosynthetic pathways –Summarize the regulation of pyrimidine biosynthesis (regulatory enzymes, regulators) –Indicate the formation of deoxyribonucleotides from ribonucleotides –Explain the synthesis of dTMP –Indicate the mechanism of action of 5 fluoro uracil and methotrexate and their clinical application –Regarding orotic aciduria •Specify enzyme defic
The rate-limiting step and the committed step for pyrimidine synthesis is the synthesis of carbamoyl phosphate from glutamine and CO2 by which enzyme?
carbamoyl phosphate synthetase II(CPS II).
Compare CPS-I with CPS-II
Carbamoyl phosphate synthetase I
-involved in urea synthesis
-uses free ammonia as the source of nitrogen
-occurs in liver mitochondria
-activated by N-acetylglutamate
-not affected by UDP or UTP
Carbamoyl phosphate synthetase II
-involved in pyrimidine synthesis
-uses glutamine as the source of nitrogen
-occurs in the cytosol of all nucleated cells
-is inhibited by UDP and UTP
-not activated by N-acetylglutamate
Orotic aciduria is caused by deficiency of which two enzymes?
orotate phosphoribosyltransferase and OMP decarboxylase
orotate phosphoribosyltransferase and OMP decarboxylase are….
domains of a single polypeptide
An acquired form of Orotic aciduria may appear in patients being treated for cancer with what?
A pyrimidine analog
Describe the synthesis of CTP from UTP.
The UMP is converted to UDP and then UTP by nucleoside monophosphate kinase and nucleoside diphosphate kinase.
• The UTP is then converted to CTP by CTP synthase.
•glutamineis the nitrogendonor
The reduction of ADP, CDP, GDP, and UDP to dADP, dCDP, dGDP, and,dUDP is catalyzed by which enzyme?
ribonucleotide diphosphate reductase.
What are two important inhibitors of ribonucleotide diphosphate reductase.
dATP and
Hydroxyurea
The synthesis of deoxyribonucleotides is regulated by the _________ enzyme.
ribonucleotide reductase
Binding of what increases the activity of the ribonucleotide diphosphate reductase enzyme?
ATP
Binding of what decreases the activity of the ribonucleotide diphosphate reductase enzyme?
dATP
(which explains the toxicity of high levels of dATP seen in ADA deficiency)
Thymidylate synthase uses ______ to produce ______ from ______. This reaction is also indirectly inhibited by _______.
THF
dTMP
dUMP.
MTX
5-fluorouracil is converted to 5 fluorodeoxyridylic acid (dFUMP), which inhibits __________.
thymidilate synthase
Inhibition of _______ shows no selectivity between cancer and normal cells
Therefore, concomitant administration of ________ protects both cancer and normal cells, but incorporation of 5-fluorouracil into RNA is more toxic to cancer cells.
thymidilate synthase
thymidine
Pyrimidines can also be salvaged by _________ where PRPP is the source of the ribose phosphate.
pyrimidine phosphoribosyltransferase
