Carbocyclic analogues of d-ribose-5-phosphate: Synthesis and behavior with 5-phosphoribosyl α-1-pyrophosphate synthetases

Parry, Ronald J.; Burns, Mark R.; Skae, Phillip N.; Hoyt, Jeffrey C.; Pal, Biman

doi:10.1016/0968-0896(96)00090-9

Cited by 15 publications

(10 citation statements)

References 48 publications

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“…Steady-state kinetic analysis of the inhibition of S. enterica or E. coli PRPP synthase by substrate analogs revealed an ordered Bi-Bi mechanism with binding of Mg 2ϩ first, followed by MgATP and then ribose 5-phosphate (41,56,57). The ordered kinetic mechanism was further confirmed by equilibrium dialysis.…”

Section: Class I Prpp Synthasesmentioning

confidence: 65%

See 1 more Smart Citation

Phosphoribosyl Diphosphate (PRPP): Biosynthesis, Enzymology, Utilization, and Metabolic Significance

Hove‐Jensen

Andersen

Kilstrup

et al. 2017

Microbiol Mol Biol Rev

162

187

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SUMMARY Phosphoribosyl diphosphate (PRPP) is an important intermediate in cellular metabolism. PRPP is synthesized by PRPP synthase, as follows: ribose 5-phosphate + ATP → PRPP + AMP. PRPP is ubiquitously found in living organisms and is used in substitution reactions with the formation of glycosidic bonds. PRPP is utilized in the biosynthesis of purine and pyrimidine nucleotides, the amino acids histidine and tryptophan, the cofactors NAD and tetrahydromethanopterin, arabinosyl monophosphodecaprenol, and certain aminoglycoside antibiotics. The participation of PRPP in each of these metabolic pathways is reviewed. Central to the metabolism of PRPP is PRPP synthase, which has been studied from all kingdoms of life by classical mechanistic procedures. The results of these analyses are unified with recent progress in molecular enzymology and the elucidation of the three-dimensional structures of PRPP synthases from eubacteria, archaea, and humans. The structures and mechanisms of catalysis of the five diphosphoryltransferases are compared, as are those of selected enzymes of diphosphoryl transfer, phosphoryl transfer, and nucleotidyl transfer reactions. PRPP is used as a substrate by a large number phosphoribosyltransferases. The protein structures and reaction mechanisms of these phosphoribosyltransferases vary and demonstrate the versatility of PRPP as an intermediate in cellular physiology. PRPP synthases appear to have originated from a phosphoribosyltransferase during evolution, as demonstrated by phylogenetic analysis. PRPP, furthermore, is an effector molecule of purine and pyrimidine nucleotide biosynthesis, either by binding to PurR or PyrR regulatory proteins or as an allosteric activator of carbamoylphosphate synthetase. Genetic analyses have disclosed a number of mutants altered in the PRPP synthase-specifying genes in humans as well as bacterial species.

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Section: Class I Prpp Synthasesmentioning

confidence: 65%

“…A chemically stable analog of PRPP has been synthesized for use as a ligand for various PRPP-binding proteins: 1-␣-diphosphoryl-2,3-␣-dihydroxy-4-␤-cyclopentanemethanol 5-phosphate (cPRPP) (41,42). Although this analog is an inhibitor of PRPP synthase activity, the compound has proven valuable as a PRPP analog in X-ray analyses of PRPP synthase.…”

mentioning

confidence: 99%

Phosphoribosyl Diphosphate (PRPP): Biosynthesis, Enzymology, Utilization, and Metabolic Significance

Hove‐Jensen

Andersen

Kilstrup

et al. 2017

Microbiol Mol Biol Rev

162

187

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“…Inhibition studies using two aminopyrimidopyrimidine nucleotide analogs 4-methoxy-8-(β- d -ribofuranosylamino)-pyrimido-[5,4- d ]-pyrimidine and 4-amino-8-(β- d -ribofuranosylamino) -pyrimido-[5,4- d ]-pyrimidine show differential levels of inhibition of human pRpp synthetases (Fry et al 1995). Carbocyclic analogs of R5P are another class of compounds that show differential inhibition when tested against Salmonella typhimurium , B. subtilis and human pRpp synthetases (Parry et al 1996). In this regard, the development of a similar library of compounds targeted for the specific inhibition of Mt-PrsA might warrant further investigation.…”

Section: Discussionmentioning

confidence: 99%

Biochemical characterization of the Mycobacterium tuberculosis phosphoribosyl-1-pyrophosphate synthetase

Alderwick

Lloyd

et al. 2010

Glycobiology

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Mycobacterium tuberculosis arabinogalactan (AG) is an essential cell wall component. It provides a molecular framework serving to connect peptidoglycan to the outer mycolic acid layer. The biosynthesis of the arabinan domains of AG and lipoarabinomannan (LAM) occurs via a combination of membrane bound arabinofuranosyltransferases, all of which utilize decaprenol-1-monophosphorabinose as a substrate. The source of arabinose ultimately destined for deposition into cell wall AG or LAM originates exclusively from phosphoribosyl-1-pyrophosphate (pRpp), a central metabolite which is also required for other essential metabolic processes, such as de novo purine and pyrimidine biosyntheses. In M. tuberculosis, a single pRpp synthetase enzyme (Mt-PrsA) is solely responsible for the generation of pRpp, by catalyzing the transfer of pyrophosphate from ATP to the C1 hydroxyl position of ribose-5-phosphate. Here, we report a detailed biochemical and biophysical study of Mt-PrsA, which exhibits the most rapid enzyme kinetics reported for a pRpp synthetase.

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“…Materials and Enzyme Purification-ATP was obtained from Roche Molecular Biochemicals, mATP and Rib-5-P were obtained from Sigma, and cRib-5-P was a gift from R. J. Parry (Rice University, Houston, TX) (26). [8-14 C]ADP was from Amersham Pharmacia Biotech.…”

Section: Methodsmentioning

confidence: 99%

Steady State Kinetic Model for the Binding of Substrates and Allosteric Effectors to Escherichia coliPhosphoribosyl-diphosphate Synthase

Willemoës¹,

Hove‐Jensen²,

Larsen³

2000

Journal of Biological Chemistry

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A steady state kinetic investigation of the P i activation of 5-phospho-D-ribosyl ␣-1-diphosphate synthase from Escherichia coli suggests that P i can bind randomly to the enzyme either before or after an ordered addition of free Mg 2؉ and substrates. Unsaturation with ribose 5-phosphate increased the apparent cooperativity of P i activation. At unsaturating P i concentrations partial substrate inhibition by ribose 5-phosphate was observed. Together these results suggest that saturation of the enzyme with P i directs the subsequent ordered binding of Mg 2؉ and substrates via a fast pathway, whereas saturation with ribose 5-phosphate leads to the binding of Mg 2؉ and substrates via a slow pathway where P i binds to the enzyme last. The random mechanism for P i binding was further supported by studies with competitive inhibitors of Mg 2؉ , MgATP, and ribose 5-phosphate that all appeared noncompetitive when varying P i at either saturating or unsaturating ribose 5-phosphate concentrations. Furthermore, none of the inhibitors induced inhibition at increasing P i concentrations. Results from ADP inhibition of P i activation suggest that these effectors compete for binding to a common regulatory site.The enzyme 5-phospho-D-ribosyl ␣-1-diphosphate (PRPP) 1 synthase (EC 2.7.6.1) catalyzes the reaction MgATP ϩ Rib-5-P 3 AMP ϩ PRPP. PRPP is a precursor of purine, pyrimidine and pyridine nucleotides and the amino acids histidine and tryptophan (1-3). In addition, PRPP is a precursor of methanopterin in Methanosarcina thermophila (4) and polyprenylphosphate-pentoses in Mycobacteria (5). The PRPP synthase reaction proceeds by attack of the 1-hydroxyl of Rib-5-P on the ␤-phosphoryl of ATP resulting in the transfer of the ␤,␥-diphosphoryl moiety of ATP to Rib-5-P (6, 7). Mg 2ϩ ions are required to form the actual substrate MgATP and as an activator of the enzyme (8 -13). PRPP synthases from Salmonella typhimurium (8,14,15), Escherichia coli (11, 16), Bacillus subtilis (10), human (17), and rat (18) possess an absolute requirement for P i as an activator and are subject to inhibition by ADP and for B. subtilis and mammalian enzymes also by GDP, which binds to a specific allosteric site. In addition, ADP competes with MgATP for binding to the active site. A second class of PRPP synthases, so far only found in plants, is independent of P i for activity (19,20).The enzymes from S. typhimurium and E. coli share identical primary sequences except for two conservative replacements (16,21,22), which is also reflected in their similar, if not identical, enzymological properties. We have previously shown that Mg 2ϩ , MgATP, and Rib-5-P bind in that order to E. coli PRPP synthase by a steady state ordered mechanism and allosteric inhibition by ADP appeared competitive against activation by free Mg 2ϩ at subsaturating Rib-5-P concentrations (11). Inhibition by ADP and GDP was also shown to increase the half-saturation constant for Mg 2ϩ activation of rat PRPP synthases I and II (18). From previous analysis of the enzymes from S. typhimuri...

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Carbocyclic analogues of d-ribose-5-phosphate: Synthesis and behavior with 5-phosphoribosyl α-1-pyrophosphate synthetases

Cited by 15 publications

References 48 publications

Phosphoribosyl Diphosphate (PRPP): Biosynthesis, Enzymology, Utilization, and Metabolic Significance

Phosphoribosyl Diphosphate (PRPP): Biosynthesis, Enzymology, Utilization, and Metabolic Significance

Biochemical characterization of the Mycobacterium tuberculosis phosphoribosyl-1-pyrophosphate synthetase

Steady State Kinetic Model for the Binding of Substrates and Allosteric Effectors to Escherichia coliPhosphoribosyl-diphosphate Synthase

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