Purine Biosynthesis

ADP and GDP

PRPP synthetase inhibited by this

PRPP sits at a branch point:

• feeds purine synthesis

• feeds pyrimidine synthesis

• required for salvage pathways

Loss-of-function:

• ↓ AMP, ↓ GMP (major effect)

• ↓ UMP and downstream pyrimidines (secondary effect)

Gain-of-function:

• ↑ AMP, ↑ GMP → ↑ uric acid (gout risk)

what impact would a mutation in PRPP synthetase have

glutamine PRPP amidotransferase (gee PAT)

what is the committed step of de novo purine synthesis

AMP and GMP

feedback inhibitors of glutamine PRPP amidotransferase

purinosome

multienzyme complex for purine biosynthesis

AMP branch has adenylosuccinate, adenylosuccinate synthetase and adenylosuccintate lyase; uses GTP as energy; on the other hand the GMP branch has XMP as intermediate, IMP dehydrogenase, GMP synthetase; uses ATP

enzyme specific to the GMP branch vs AMP branch

AMP synthesis needs GTP and GMP synthesis needs ATP; so, if ATP is high this will drive GMP production; this self-balancing is key to base pairing in nucleic acids (A and G); also ATP and GTP have different roles in energy vs protein synthesis

balance of purines accomplished how

inhibit the AMP branch and adenylosuccinate synthetase; more IMP available for GMP production

what would happen to the purine pathway if you added AMP

IMP dehydrogenase would be inhibited and less XMP would be made; this is because GMP signals we have enough nucleotides

what would happen to the purine pathway if you added GMP

uric acid

excess purines are degraded into

gout; alcohol interferes with uric acid excretion and meats have high amounts of nucleic acids which leads to increased uric acid production

common disease from defects in purine degradation

PRPP synthetase which leads to IMP overproduction

gout is linked to increased levels of

diet restriction of purine-rich foods and allopurinol a competitive inhibitor of xanthine oxidase

gout treatment

HGPRT; X-linked recessive genetic mutation

deficient enzyme in Lesch-Nyhan syndrome

adenosine deaminase

deficient enzyme in sever combined immunodeficiency disease (SCID)