Inosine Monophosphate (IMP) is Synthesized From Amphibolic Intermediates
المؤلف:
Peter J. Kennelly, Kathleen M. Botham, Owen P. McGuinness, Victor W. Rodwell, P. Anthony Weil
المصدر:
Harpers Illustrated Biochemistry
الجزء والصفحة:
32nd edition.p338-340
2025-08-30
404
The initial reaction of purine biosynthesis, transfer of two phosphoryl groups from ATP to carbon 1 of ribose 5-phosphate forming phosphoribosyl pyrophosphate (PRPP), is catalyzed by PRPP synthetase, EC 2.7.6.1. The end product of the ten subsequent enzyme-catalyzed reactions is IMP (Figure 1).
Fig1. Purine biosynthesis from ribose 5-phosphate and ATP. See the text or explanations. ( P , PO3 2– or PO2–.)
Following synthesis of IMP, separate branches lead to AMP and GMP (Figure 2). Subsequent phosphoryl trans fer from ATP converts AMP and GMP to ADP and GDP, respectively. Conversion of GDP to GTP involves a second phosphoryl transfer from ATP, whereas conversion of ADP to ATP is achieved primarily by oxidative phosphorylation.
Fig2. Conversion of IMP to AMP and GMP.
Multifunctional Catalysts Participate in Purine Nucleotide Biosynthesis
In prokaryotes, each reaction of Figure 1 is catalyzed by a different polypeptide. By contrast, the enzymes of eukaryotes are polypeptides that possess multiple catalytic activities whose adjacent catalytic sites facilitate channeling of intermediates between sites. Three distinct multifunctional enzymes catalyze reactions ➂, ➃, and ➅; reactions ➆ and ➇; and reactions ➉ and 11 of Figure 1.
Antifolate Drugs & Glutamine Analogs Block Purine Nucleotide Biosynthesis
The carbons added in reactions ➃ and ➉ of Figure 1 are contributed by derivatives of tetrahydrofolate. Purine deficiency states, while rare in humans, generally reflect a deficiency of folic acid. Compounds that inhibit formation of tetrahydrofolates and therefore block purine synthesis have been used in cancer chemotherapy. Inhibitory compounds and the reactions they inhibit include azaserine (reaction ➄, Figure 1), diazanorleucine (reaction ➁, Figure 1), 6-mercaptopurine (reactions 13 and 14, Figure 2), and mycophenolic acid (reaction 14, Figure 2).
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