C. PURINE ANALOGUES : 6-MERCAPTOPURINE (6-MP), 6-THIOGUANINE (6-TG), AZATHIOPRINE
Review of purine synthesis
Five critical components:
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The souce of ribose is 5-phosphoribosyl-1-pyrophosphate (PRPP). Synthesis of PRPP is catalyzed by purine nucleoside phosphorylase (PNP).
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The first committed step in purine synthesis is the formation of 5-phosphoribosylamine via the enzyme PRPP glutamylamidotransferase.
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6-MP and 6-TG enter via the "salvage pathway" where PRPP reacts with hypoxanthine or guanine bases to form IMP or GMP, respectively. This reaction is catalyzed by hypoxanthine-guanine phosphoribosyl transferase (HGPRT).
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GMP is converted to GDP by guanylyl kinase. This is the step that is blocked by 6-MP and 6-TG, causing a buildup of GMP.
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There are numerous negative feedback pathways mediated by increased concentrations of GMP. The most critical is the inhibition of the first two steps in the purine biosynthetic pathway (ribose-5-phosphate → PRPP → 5-phosphoribosylamine). 6-MP and 6-TG therefore shut down purine sythesis by limiting both the neosysnthesis and salvage pathways.