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PURINE/PYRIMIDINE INFORMATION
Disorders
Pyrimidine 5’-nucleotidase I deficiency- inherited disorder of nucleotide metabolism that results in elevated
levels of erythrocyte pyrimidine nucleotides and an accompanying anemia
Purine nucleoside phophorylase deficiency- associated with elevated levels of dGTP in cells
UMP synthase deficiency- bifunctional protein, inherited deficiency, pyrimidine metabolism deficiency leading
to anemia, can be rescued by uridine therapy
HPRT deficiency- decreased salvage of hypoxanthine and guanine, increased levels of PRPP, monomerization
of ATase, hyperuricemia gout, mental retardation with self-mutilation
Patients are able to salvage adenine because they still have HPRT
Thymidine kinase 2 deficiency- increased mutation rates and depletion of mitochondrial genome (mitochondrial
salvage enzyme)
Xanthine dehydrogenase deficiency- xanthinuria, NO uric acid produced
Levels of Synthesis
• Thymidine nucleotides are synthesized directly from deoxyuridine monophosphate using N5,N10-
methylenetetrahydrofolate as the methyl group donor.
o UMP UDP dUDP dUMP dTMP dTDP dTTP
• The de novo synthesis of the cytosine ring structure from the uracil ring structure occurs at the
ribonucleoside triphosphate level
• Hypoxanthine can be converted to adenine (HPRT)
• Cytosine can be converted to uracil during catabolism of pyrimidines
• Adenine can be converted to hypoxanthine during catabolism of purines (AMP deaminase)
• Uracil can be converted to thymine in the thymidylate synthase reaction.
• De novo synthesis of the uracil ring structure occurs at the ribonucleoside monophosphate level (end-
product of pyrimidine biosynthesis is UMP)
If there was an acute decrease in intracellular ATP levels you would expect to see:
• Release of ATase feedback inhibition
• Displacement of the adenylate kinase reaction towards ATP formation (also making AMP)
• Decrease in branchpoint synthesis leading to guanine nucleotides
• Increased AMP deaminase activity
• Increased uric acid production
Folate methyl donors used for: purine metabolism and thymine structure formation
o A cell unable to synthesize or obtain tetrahydrofolate would be most likely unable to carry out de novo
synthesis of dTMP
o Methotrexate (antifolate) chemotherapy:
Effective because consumption of methyl-bearing reduced folates continues in the presence of the drug
and results in an inadequate source of methyl donors for nucleotide synthesis (thymidylate synthase
reaction)
The reduced folate carrier system is the major route for the intracellular uptake of this compound
Normal cells may be selectively rescued from methotrexate therapy by providing them with the reduced
folate, leucovorin
• Leucovorin is a downstream metabolite of dihydrofolate and is typically administered to patients
receiving methotrexate chemotherapy
Structural alterations in the DHFR protein resulting in decreased affinity for MTX can lead to resistance
(gene amplification can also lead to resistance)
Accumulation of MTX is greatly enhanced by its conversion to a polyglutamate derivative
Inhibition of DHFR by methotrexate reduction in thymidine nucleotide synthesis
Activation is NOT a prerequisite to any chemotherapeutic effect of this drug!
5-FU resistance
• decreased availability of cofactors
• TS gene amplification
• Increased TS gene transcription
• Decreased OPRT activity
Hydroxyl radical > singlet oxygen > peroxynitrite > superoxide > hydrogen peroxide