(From Dr. Laville’s Heme Metabolism Handouts, by Brian Buschman)
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There are different biosynthetic pathways for purines and pyramidines. It begins with a common pathway from R-5-P and goes to IMP. The second step in the pathway involves the conversion of PRPP to 5-phosphoribosylamine is the committed step and is the step that is used to regulate the pathway. If there is a high level of Pi in the hepatocytes PRPP glutamyl amidotransferase, which catalyzes this reaction, is turned on. In the presence of excess AMP and GMP PRPP glutamyl amidotransferase is inhibited.
After IMP is made it is converted into AMP and GMP while it is still in the liver. At this point it can hang around or be exported. To be used it will be phosphorylated to ATP and GTP where it can be used or ATP and GTP can be converted into dATP and dGTP for use in DNA synthesis.
Purines do not have to be synthesized from scratch every time but can be converted from existing purines from food stuffs or from work out DNA and RNA. This happens by the salvage pathway where nucleic acid material is converted into IMP, GMP or AMP. It uses PRPP and requires either the enzyme hypoxanthine-guanine phosphoribosyl transferase (HGPRT) or adenine phosphoribosyl transferase. (If you forget the enzymes on an exam notice that the enzymes of purine biosynthesis have something to do with ribosyl transferase and the rest of the name can tell you what.)
The Lesch-Nyhan syndrome is a deficiency of HGPRT which is seen only in male children. It causes mental retardation, the children mutilate themselves and the increased PRPP causes gout-like tissue damage.
Degradation of AMP and GMP happens by removal of NH3 and conversion to uric acid. Buildup of uric acid crystals is called gout (to be discussed later).
Glutamine and aspartic acid are used to form UMP which is the first pyramidine synthesized in the process. The first step is catalyzed by carbamoyl phosphate synthetase II. When you get to UMP it is phosphorylated to UTP which can be converted to CTP. CTP can be converted to dCDP which can be converted to dCMP or dTMP. You will not find TMP but only dTMP since T only appears in DNA and not RNA.) The conversion of dCDP into dTMP is inhibited by 5-florouracil.
If there is a deficiency of orotate phosphoribosyl-transferase you will get a buildup or acid and a failure to produce UMP. It must be treated with oral uridine supplements which can be converted to UMP by the salvage pathway.
Hyperuricamia is associated with either increased synthesis of purines and pyramidines or an abnormality in the purine biosynthetic/degradation pathways. Excessive uric acid can precipitate (as it’s not very soluble) as crystals in the joints and epically in distal points where body temperature is slightly lower. Ultimately uric acid is excreted but if there is too much that buildup is bad.
Primary gout is the buildup of uric acid crystals due to an overproduction of uric acid.
Secondary gout is a buildup of uric acid crystals due to other factors that are usually associated with failure to get rid of the uric acid such as renal failure.
The normal treatment of gout involves three classes of drugs:
1) Anti-inflammatory drugs
2) Uricosuric drugs like probenecid which compete with uric acid for the distal tubule reuptake mechanism. This insures that more of the uric acid is excreted in the kidney.
3) Allopurinol which inhibits the conversion of xanthine oxidase. This enzyme converts xanthine to uric acid so inhibiting it will leave more of the waste product as xanthine which is more soluble and also excreteable.
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