Phosphoribosylpyrophosphate, synthesis

OPTIMAL CONDITIONS FOR PHOSPHORIBOSYLPYROPHOSPHATE SYNTHESIS IN A CRUDE EXTRACT OF LIVER CELLS... 

Phosphoribosylpyrophosphate (PRPP) synthetase is one of the very few enzymes which transfer a pyrophosphoryl group from ATP in one step. When the synthesis is carried out in lsO-enriched water, lsO is incorporated into the PRPP, but not into AMP.91 The lsO in the PRPP arises from a pre-exchange between the H2180 and the ribose phosphate, and hence the results confirm that fission of the /5-P—O bond takes place. PRPP and ATP are starting materials in the biosynthesis of histidine, and Ai-(5 -phospho-D-ribosyl)adenosine triphosphate (29) is an intermediate. The... 

The first step of this sequence, which is not unique to de novo purine nucleotide biosynthesis, is the synthesis of 5-phosphoribosylpyrophosphate (PRPP) from ribose-5-phosphate and adenosine triphosphate. Phosphoribosyl-pyrophosphate synthetase, the enzyme that catalyses this reaction [278], is under feedback control by adenosine triphosphate [279]. Cordycepin interferes with thede novo pathway [229, 280, 281), and cordycepin triphosphate inhibits the synthesis of PRPP in extracts from Ehrlich ascites tumour cells [282]. Formycin [283], probably as the triphosphate, 9-0-D-xylofuranosyladenine [157] triphosphate, and decoyinine (LXXlll) [284-286] (p. 89) also inhibit the synthesis of PRPP in tumour cells, and this is held to be the blockade most important to their cytotoxic action. It has been suggested but not established that tubercidin (triphosphate) may also be an inhibitor of this reaction [193]. 

Synthesis of phosphoribosylpyrophosphate (PRPP). This is an unusual kinase-catalyzed reaction because the group transferred is the pyrophosphate group rather than the phosphate group. 

ThiolMP and ThioGMP are feedback inhibitors of phosphoribosylpyrophosphate amido-transferase, which is the first, and rate-limiting step in the synthesis of purine. In addition, these analogs inhibit the de novo biosynthesis of purine and block the conversion of inosinic acid to adenylic acid or guanylic acid. The triphosphate nucleotides are incorporated into DNA, and this results in delayed toxicity after several cell divisions. 

When injected, azathioprine (Imuran) is rapidly converted to 6-mercaptopurine. The half-life of azathioprine after intravenous injection is 10 to 20 min, and that of 6-mercaptopurine is somewhat longer. The cytotoxic activity of these thiopurines is due to the conversion of mercaptopurine to 6-thiouric acid, a noncarcinostatic metabolite. This action is thought to block the excess synthesis of inosinic acid from its precursors, glutamine and phosphoribosylpyrophosphate. In addition, unlike cyclophosphamide, azathioprine is a potent anti-inflammatory substance that can cause a reduction in the number of monocytes and neutrophils at inflammatory sites. Antibody responses are also inhibited by azathioprine. Studies in humans have shown that azathioprine decreases the y-globulin and antibody levels, thus influencing IgG rather than IgM production. This makes azathioprine an effective immunosuppressant in the early phases of immune responses. It is less effective or completely ineffective in altering either the effector phase or already established reactivities. 

The synthesis of phosphoribosylpyrophosphate from ATP and ribose-5-phosphate is catalyzed by phosphoribosylpyrophosphate synthetase. Superactivity of this enzyme may be a cause of overproduction of uric acid, which may result in gout. 

Chorismate is converted to prephenate (the precursor of phenylalanine and tyrosine) and anthranilate (the precursor of tryptophan). (Chorismate can also be converted to 4-hydroxybenzoic acid, the precursor of the ubiquinones. 4-Hydroxyphenylpyruvate is also a precursor in the synthesis of plastoquinone and various tocopherols.) PRPP is an abbreviation for phosphoribosylpyrophosphate. 

Purine synthesis starts with ribose-5-phosphate, which can be formed from the pentosephosphate pathway either via the oxidative arm or, in the reverse fashion, via the nonoxidative arm. Many tissues have the ability to form ribose-5-phosphate and their own purines. The first reaction is with ATP, where pyrophosphate is added to ribose-5-phosphate to produce phosphoribosylpyrophosphate (PRPP). 

Phosphoribosylpyrophosphate can be used in a number of reactions. It is important in the synthesis of purines, pyrimidine nucleotides, and coenzymes such as NAD+. Therefore, it would not be prudent for strict... 

The rate-limiting enzyme in the synthesis of purine nucleotides is amidophosphoribosyl transferase (also known as phosphoribosylpyrophosphate amido transferase), which is a major target for one of the two thiol-containing purine anticancer antimetabolites on the U.S. market. 

No evidence for the presence of a known enzyme abnormality causing purine overproduction could be obtained. The erythrocyte activity of hypoxanthine-guanine phos-phoribosyltransferase (HGPRT), of adenine phosphoribosyltransferase (APRT), and of phosphoribosylpyrophosphate (PRPP) synthetase were all in the normal range. Erythrocyte PRPP generation, as well as the acitivity of the pentose phosphate pathway was also normal (Table 1). In addition, the rate of de novo synthesis of purine nucleotides in cultured skin fibroblasts from the patient was found to be normi. 

The method of synthesis ATP from adenine using Corynebacterium ammoniagenes cells as enzyme sources, which was free from enzyme purification, has been developed (33). In this system, cells were permeabilized by the treatment with surfactant and organic solvent. Phosphoribosylpyrophosphate and ATP were supplied by the metabolism of the cells from glucose. In the same manner, CDP-choline was produced by the... 

An elevated activity of this enzyme causes an increased production of PRPP (phosphoribosylpyrophosphate), a precursor in purine synthesis This increased PRPP-synthetase activity producing an elevated uric acid production could be one of the reasons for patient W s elevated purine synthesis ... 

Phosphoribosylpyrophosphate (PRPP) synthetase (E.C. 2.7.6.1) catalyzes the formation of PRPP from ribose-5-phosphate and ATP in the presence of Mg and inorganic phosphate. The product, PRPP, is a substrate of the first rate limiting step of the de novo synthesis of purine nucleotides and its availability has been shown to regulate this pathway in human tissue (l). A superactive mutant erythrocyte PRPP synthetase with decreased sensitivity to feedback inhibition has recently been found by us in a gouty family (2,3). 

It was mentioned above that the carboxyl carbon is lost in the conversion of anthranilic acid to indole. Consequently, two additional carbon atoms must be supplied to complete the pyrrole ring of the indole. The observation that various ribose derivatives could be the source of these two carbons provided the clue that led to the elucidation of the mechanism of indole synthesis in the tryptophan biosynthetic pathway (232). Yanofsky determined that sonic extracts of a tryptophan auxotroph of E. cdi (that also grew on anthranilic acid or indole) could utilize ribose, ribose 5-phosphate, and 5-phosphoribosylpyrophosphate to form indole from anthranilic acid. With the two former compounds, ATP was essential for the reaction, with the latter compound it was not. This result made it appear evident that 5-phosphoribosylpyrophosphate was the more immediate reactant in the condensation with anthranilic acid. 

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. 

Kornberg, A., Lieberman, I. and Simms, E. S. 1955. Enzymatic synthesis and properties of 5-phosphoribosylpyrophosphate. 

In the last few years, phosphoribosylpyrophosphate (PRPP) has been viewed as a most important intermediate metabolite and studies have indicated that its concentration and rate of synthesis may play a critical role in the regulation of purine biosynthesis da novo. Hershko et al (l) found increased in vitvo formation of PRPP in the erythrocytes of some gouty subjects. They further suggested that the increase in the rate of purine uptake found in these patients was attributable to enhanced PRPP formation. 

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