Nucleotide Degradation

Nucleotide Degradation

SCID

50X dATP

Gout is caused by an excess of uric acid

Uric acid

DNA and RNA in diet

Xanthine

Allopurinol

Xanthine oxidase

Elion and Hichings

1988 Nobel Prize

‘Rational design of drugs’

Purine Salvage Pathways

Adenine + PRPP

Guanine + PRPP

phosphoribosyltransferaseAMP + PPi

GMP + PPi

Lesch-Nyhan Syndrome

-increasing levels of PRPP in patients (male children) suffering from Lesch-Nyhan Syndrome leads to increased de novo purine biosynthetic pathways

-gout

-brain dependent upon salvage pathways

Nucleotide Metabolism and Chemotherapy

Glutamine Amidotransferase Inhibitors

Folate Analogs

Inhibitors of dTMP synthesis

Inhibitors of dTMP synthesis

Thymidylate synthase mechanism:

FdUMP is a suicide inhibitor of thymidylate synthase

1,3 hydride shift is blocked by the presence of Fluorine