PRPP-synthetase

Various genetic defects in PRPP synthetase (reaction 1, Figure 34-2) present clinically as gout. Each defect— eg, an elevated increased affinity for ribose 5-... 

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... 

Primary gout can be caused by overproduction of purine catabolites due to X-linked mutations of PRPP synthetases that render the enzyme insensitive to allosteric inhibitors. 

PRPP is an "activated pentose" that participates in the synthesis of purines and pyrimidines, and in the salvage of purine bases (see p. 294). Synthesis of PRPP from ATP and ribose 5-phosphate is catalyzed by PRPP synthetase (ribose phosphate pyrophosphokinase, Figure 22.6). This enzyme is activated by inorganic phosphate (Pi) and inhibited by purine nucleotides (end-product inhibition). [Note The sugar moiety of PRPP is ribose, and therefore ribonucleotides are the end products of de novo purine synthesis. When deoxy-ribonucleotides are required for DNA synthesis, the ribose sugar moiety is reduced (see p. 295).]... 

NH3)4CoATP S-chirality at P (same as in Mg(ATP) substrate for PRPP synthetase) 1... 

C-4) Overactivity of either PRPP synthetase (which acts between ribose 5-P and PRPP) or amido-transferase (which acts between PRPP and 5-P-ribosylamine). A modification of these enzymes may lead to their overactivity, with consequent hyperuricemia. 

Phosphoribosyl-l-pyrophosphate (PRPP) synthesis is catalyzed by PRPP synthetase. Note the ribose-5-phosphate for the pathway comes from tlie Pentose Phosphate Pathway (see "PPP/Gluconeogenesis" Lecture). 

Regulation of de novo purine biosynthesis is essential because it consumes a large amount of energy as well as of glycine, glutamine, N °-formyl FH4, and aspartate. Regulation occurs at the PRPP synthetase reaction, the ami-... 

PRPP synthetase requires inorganic phosphate as an allosteric activator. Its activity depends on intracellular concentrations of several end products of pathways in which PRPP is substrate. These end products are purine and pyrimidine nucleotides (Figure 27-12). 

Increased levels of intracellular PRPP enhance de novo purine biosynthesis. For example, in patients with HPRT deficiency, the fibroblasts show accelerated rates of purine formation. Several mutations of PRPP synthetase, which exhibit increased catalytic activity with increased production of PRPP, have been described in gouty subjects. 

Feedback regulation of the de novo pathway of purine biosynthesis. Solid lines represent metabolic pathways, and broken lines represent sites of feedback regulation. , Stimulatory effect , inhibitory effect. Regulatory enzymes A, PRPP synthetase B, amidophosphoribosyltransferase C, adenylosuccinate synthetase D, IMP dehydrogenase. 

Inhibition by AMP and GMP, is competitive with respect to PRPP. The human placental enzyme exists in a small form (M.W. 133,000) and a large form (M.W. 270,000). The small form is catalytically active. Ribonucleotides convert the active form to the large form, whereas PRPP does the opposite. The regulatory actions of PRPP synthetase and amidophosphoribosyltransferase are coordinated. When there is a decrease in the intracellular concentration of adenine ribonucleotides, PRPP synthetase is activated this results in increased synthesis of PRPP, which in turn converts the inactive form of amidophosphoribosyltransferase to the active form and increases production of purine nucleotides. 

The mechanism of the hyperuricemia in most individuals who have gout is unknown. Following is a discussion of biochemical lesions that lead to hyperuricemia and may eventually lead to gout. Enhanced PRPP synthesis results from X-chromosome-linked mutants of PRPP synthetase. Several variants show increased Umax, resistance to feedback inhibition, or a low for ribose 5-phosphate. 

Nucleotide catabolism PRPP synthetase Gouty arthritis... 

The answer is c. (Ivlurray, pp 375— /O I. Scrivt i, pp 2513—2570. Sack, pp 121—138. Wilson, pp 287—320.1 Several control sites exist in the path of purine synthesis where feedback inhibition occurs, AMP, GMP, or IMP may inhibit the first step of the pathway, which is the synthesis ol 5-phosphoribosyl-l-pyrophosphate (PRPP). PRPP synthetase is specifically inhibited. All three nucleotides can inhibit glutamine PRPP aminotranslerase, which catalyzes the second step of the. pathway. AMP blocks the conversion ol IMP to adenylosuccinate. GMP inhibits the lormation ol xanthylate Irom IMP Thus, blockage rather than enhancement ol IMP metabolism to AMP and GMP effectively inhibits purine biosynthesis. 

Two enzyme abnormalities resulting in an overproduction of uric acid have been well described (Fig. 91-1). The first is an increase in the activity of phosphoribosyl pyrophosphate (PRPP) synthetase, which leads to an increased concentration of PRPP. PRPP is a key determinant of purine synthesis and thus uric acid production. The second is a deficiency of hypoxanthine guanine phosphoribosyl transferase (HGPRT). 

PURINE NUCLEOTIDES The de novo synthesis of purine nucleotides begins with the formation of 5-phospho-a-D-ribosyl- 1-pyrophosphate (PRPP) catalyzed by ribose-5-phosphate pyrophosphokinase (PRPP synthetase). 

Figure 13-6. Coupled enzymatic synthesis of PRPP from D-ribose 351 i) ribokinase it) pyruvate kinase iii) PRPP-synthetase iv) adenylate kinase.

PRPP is an intermediate in nucleotide metabolism. It is found in several de novo and salvage pathways. PRPP is formed by action of the enzyme, PRPP Synthetase, as follows ... 

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