5-Phosphoribosylpyrophosphate amidotransferase

It has been suggested that thioguanine s multistep inhibition, one step of which is the inhibition of phosphoribosylpyrophosphate amidotransferase, results in a profound lowering of the intracellular concentration of guanine nucleoside phosphates and that this depletion causes a marked depression in cellular metabolism that presumably would lead to cell death [91 ]. 

In addition to the analogues listed in Table 2.3, cordycepin [302]. 3 -amino-3 -deoxyadenosine [173], and formycin [303] can inhibit the de novo pathway by blocking the phosphoribosylpyrophosphate amidotransferase. Thus, a number ofpurine analogues—after anabolism to nucleoside phosphates—can act as feedback inhibitors, and this inhibition may be the primary cause of their cytotoxicity. 

Glutamine 5-phosphoribosyl-l-pyrophosphate amidotransferase, 38 310-311 Glutamine phosphoribosylpyrophosphate amidotransferase, ground spin state variability, 38 99-100 Glutathion... 

Cooperative An excess of any of end products causes a partial inhibition of the first common step, whereas the simultaneous excess of two or more end products results in a greater inhibition Gluteunine phosphoribosylpyrophosphate amidotransferase is inhibited by either of GMPdMP or AMP/ADP but to a greater extent by their combined presence. 

Phosphoglucomutase, phosphoribosylpyrophosphate amidotransferase, serum albumin, vitamin D-binding protein... 

Wingaarden, J.B. Ashton, D.H. (1959). The regulation of activity of phosphoribosylpyrophosphate amidotransferase by purine ribonucleotides a potential feedback control of purine biosynthesis. ]. Biol. Chem., 234, 1492-6. 

Holmes, E.W., Wyngaarden, J.B., and Kelley, W.N. Human glutamine phosphoribosylpyrophosphate amidotransferase Two molecular forms interconvertible by purine ribonucleotides and phosphoribosylpyrophosphate. J. Biol. Chem., 248 6035,1973. 

Wyngaarden, J. B. 1972. Glutamine phosphoribosylpyrophosphate amidotransferase. In Current Topics in Cellular Regulation. 

Further purification of the second fraction showed that one of its enzymic components reacted PRPP with glutamine to yield another unidentified ribose compound and equivalent amounts of glutamic acid and pyrophosphate (86, 97). 5-Phosphoribosylamine (PRA) was believed to be the unknown compoimd, since synthetic PRA replaced the biosynthetically-formed ribose derivative in the subsequent reaction with glycine and ATP to form GAR, adenosine diphosphate (ADP), and inorganic P (98). The enzyme that catalyzed the formation of PRA from glutamine and PRPP has been purified from the soluble proteins of pigeon liver and named 5-phosphoribosylpyrophosphate amidotransferase (86). Unfortunately, it was not possible to isolate the natural product of the reaction because of extreme lability of the compound. 

A specific localization of the control mechanism has been found. The enzyme, phosphoribosylpyrophosphate amidotransferase (44S) was inhibited by various purine ribonucleotides ATP and ADP were the most inhibitory (449). The regulation of enzyme activity by purine ribonucleotides offers a controlling mechanism for purine biosynthesis by maintaining a relatively constant amount of nucleotide within the cell. 

Figure 1 depicts the important steps in purine biosynthesis de novo. The first reaction which is unique to this pathway is catalyzed by the enzyme glutamine phosphoribosylpyrophosphate amidotransferase. The substrates for this reaction are phosphoribosylpyrophosphate, or PP-ribose-P, glutamine and water and the products are phosphoribosylamine, glutamate and inorganic pyrophosphate. Data obtained from the study of many species indicate that this reaction catalyzed by amidotransferase is the rate limiting step in purine biosynthesis. Phosphoribosylamine is then converted by a series of enzymatic reactions to the parent purine ribonucleotide IMP, and IMP is subsequently converted to GMP and AI IP. 

Hartman, S.C. 1963. Phosphoribosylpyrophosphate amidotransferase Purification and general catalytic properties. J. Biol. Chem. 238 3024-3035. 

Hill, D.L. and Bennett, L.L., Jr. 1969. Purification and properties of 5-phosphoribosylpyrophosphate amidotransferase from adenocarcinoma, 755 cells. Biochem. 122-130. 

Nierlich, D.P. and Magasanik, B. 1965. Regulation of purine ribonucleotide synthesis by end product inhibition The effect of adenine and guanine ribonucleotides on the 5 -phosphoribosylpyrophosphate amidotransferase in Aerobacter aerogenes. J. 

Rowe, P.B., Coleman, M.D. and Wyngaarden, J.B. 1970. Glutamine phosphoribosylpyrophosphate amidotransferase. Catalytic and conformational heterogeneity of the pigeon liver enzyme. Biochem. 1498-1505. 

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