Glutamine Antagonist

Inhibitor of Purine Synthesis

Useful for treatment of rapidly-growing cancers

Methotrexate, Aminopterin,

and other folic acid analogues

Limit amount of THF (FH4) available for purine synthesis

Inhibitor of purine synthesis and dTMP formation

Useful for treatment of rapidly-growing cancers

Inherited Deficiency of HGPRT (Hypoxanthine-guanine phosphoribosyl transferase)

HGPRT is an enzyme in purine salvage

Recessive and X-linked (occurs primarily in males)

Leads to increased PRPP and de novo purine synthesis

Deficiency of Adenine Deaminase Causes SCID (Severe Combine Immunodeficiency)

Afflicted children usually die before age of 2

Buildup of dATP, which inhibits DNA synthesis

Causes T-cell dysfunction

Decreased uric acid formation

Increased purine nucleosides and nucleotides

Large buildup of dGTP, which inhibits ribonucleotide reductase (an enzyme involved in deoxyribonucleotide synthesis)

(aka Hyperuricemia)

Accumulation of uric acid crystals in extremities, causing arthritic joint inflammation

Allopurinol is the treatment, which inhibits xanthine oxidase

Other treatments:

• Anti-inflammatory drugs to relieve pain (e.g. colchichine)
• Uricosuric agents to increase renal excretion of uric acid (e.g. probenecide)
• Change in diet: decrease in protein intake

Deficiency of the Bifunctional Enzyme in Pyrimidine Biosynthesis

Enzymes: Orotate Phosphoribosyl Transferase and Orotidylate Decarboxylase

Results in orotic acid in the blood and urine

Clinical signs: growth retardation, megaloblastic anemia, leukopenia

Mild form: accumulation of carbamoyl phosphate in liver mitochondria

Treatment: Ingestion of uridine and/or cytidine

Mechanism: Oral UMP is converted to UTP, which inhibits CPS II

Inhibits Thymidylate Synthetase

A thymine analog

Chemotherapy drug

Inhibits Adenylosuccinate Synthase, IMP Dehydrogenase, and PRPP Amidotransferase

Incorporates into nucleic acids and promotes defective protein synthesis

Antineoplastic drug