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PP7: Nucleotide Metabolism (Big Picture (DNA vs. RNA (DNA: sugar backbone…
PP7: Nucleotide Metabolism
Big Picture
DNA vs. RNA
DNA: sugar backbone made of deoxyribose; bases are A, C, T, G
RNA: sugar backbone made of ribose; bases are A, C, U, G
Pyrimidines vs. Purines
A--T, 2 H bonds; C--G, 3 H bonds
nucleoside vs. nucleotide
nucleoside: sugar + base
nucleotide: sugar + base + phosphate
Purines
Purine Biosynthesis
PRPP --> 5-phosphoribosyl-1-amine is the committed step
10-step pathway; final product is inosinate (IMP)
IMP can become either Adenine or Guanine
Sometimes, rings within the purines become detached so there is a purine salvaging pathway; PRPP is a substrate, HGPRT is the enzyme responsible
Lesch-Nyhan Syndrome: deficiency in HGPRT enzyme, excess of PRPP, which causes increase in purine synthesis and purine breakdown; we will see an increase in uric acid/allantoin in the animal depending on what they break down purines to
Treatment for uric acid buildup: allopurinol, which inhibits xanthine oxidase and acts as a substrate for HGPRT, lowering the level of PRPP
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Purine Degradation
What purines get broken down to depends on the species of animal
Pyrimidines
Pyrimidine Biosynthesis
similar to purine ring salvaging pathway
Pyrimidine Degradation
Case Study: dairy heifers with DUMPS (deficiency in uridine monophosphate synthase)
Uridine is an intermediate in pyrimidine biosynthesis pathway, cannot synthesize pyrimidine bases this way
UMP can make dUMP, which can go on to generate dTMP
5-Fluorouracil inhibits converson of dUMP to dTMP, so it could potentially be a treatment for cancer cells to kill them by making it impossible for them to generate pyrimidine bases
BUT, 5-FU is toxic in cats and dogs so maybe not
Clinical Relevance
symptoms: primate with high levels of uric acid in urine and seems to be in pain
Cause: deficiency in HGPRT enzyme, which is part of the purine ring salvage pathway; most purines are degraded, and since uric acid is a product of purine degradation pathway the amount of uric acid increases; uric acid crystals build up in joints, gout
Treatment: allopurinol to inhibit xanthine oxidase and reduce amount of PRPP, and consequently reduce number of purines; degrade uric acid crystals and control pain
symptoms: dog straining to urinate, has blood in urine
Cause: inability to convert uric acid to allantoin due to a defect in the uptake of uric acid to the liver
Treatment: allopurinol to inhibit xanthine oxidase and act as a substrate for HGPRT, effectively lowering the amount of PRPP and subsequently purines in the body
symptoms: retarded growth, anemia, high levels of orotic acid in urine
Cause: deficiency in enzymes downstream of orotate in pyrimidine biosynthesis pathway
Treatment: feed diet high in pyrimidines
