Formate, active from purines

The determination of purine nucleotide formation from purine bases in the presence of ribose-1-phosphate and deoxyri-bos0-1-phosphate was carried out using the same reaction mixture as for the purine-PRT activities, but instead of PRPP,... 

The carbon atoms 2 and 8 in the purine ring of inosinic acid are derived from C1 units. The latter are transferred as activated formate to GAR and AICR as specific formate acceptors. Therefore we have studied the tetra-hydrofolate dependent activation of formate in relation to the netto de novo synthesis of purine nucleotides in cell-free extracts of normal and leukemic leukocytes. In addition, the conversion of exogenous purines to corresponding monophosphoribonucleotides by the specific purine-phosphoribosyItransferases was determined. The aim of these investigations was to study the effect of 6-MP on the formate activating system, which is important for the de novo synthesis of purine nucleotides, on the utilization of preformed purine bases and, in addition, the interaction of allopurinol with 6-MP,... 

Activity of the enzyme catalyzing the formation of the 5-phos-phoribosyl-1-amine from PRPP is inhibited by purines. Synthesis of GMP requires ATP. 

Inhibition of nucleobase synthesis (2). Tetrahydrofolic acid (THF) is required for the synthesis of both purine bases and thymidine. Formation of THF from folic acid involves dihydrofolate reductase (p. 272). The folate analogues aminopterin and methotrexate (ame-thopterin) inhibit enzyme activity as false substrates. As cellular stores of THF are depleted, synthesis of DNA and RNA building blocks ceases. The effect of these antimetabolites can be reversed Ltillmann, Color Atlas of Pharmacology 2000 Thieme All rights reserved. Usage subject to terms and conditions of iicense. 

As the first committed step in the biosynthesis of AMP from IMP, AMPSase plays a central role in de novo purine nucleotide biosynthesis. A 6-phosphoryl-IMP intermediate appears to be formed during catalysis, and kinetic studies of E. coli AMPSase demonstrated that the substrates bind to the enzyme active sites randomly. With mammalian AMPSase, aspartate exhibits preferred binding to the E GTPTMP complex rather than to the free enzyme. Other kinetic data support the inference that Mg-aspartate complex formation occurs within the adenylosuccinate synthetase active site and that such a... 

Purine Antimetabolites. Purine synthesis can be blocked by 6-mercaptopurine (7.77) and 6-thioguanine (7.78). Both require conversion to the mononucleotide in a lethal synthesis —a mechanism distinguished from the formation of suicide substrates in that the enzyme that transforms the inactive pro-dmg to the active inhibitor is different from the enzyme that is being blocked. inhibitors are formed and bound by the same... 

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