PMID: 11311059Apr 20, 2001Paper

Bisubstrate analogue inhibitors of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase: synthesis and biochemical and crystallographic studies

Journal of Medicinal Chemistry
G ShiHonggao Yan

Abstract

6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK) catalyzes the transfer of pyrophosphate from ATP to 6-hydroxymethyl-7,8-dihydropterin (HP), leading to the biosynthesis of folate cofactors. Like other enzymes in the folate pathway, HPPK is an ideal target for the development of antimicrobial agents because the enzyme is essential for microorganisms but is absent from human and animals. Three bisubstrate analogues have been synthesized for HPPK and characterized by biochemical and X-ray crystallographic analyses. All three bisubstrate analogues consist of a pterin, an adenosine moiety, and a link composed of 2-4 phosphoryl groups. P(1)-(6-Hydroxymethylpterin)-P(2)-(5'-adenosyl)diphosphate (HP(2)A, 5) shows little affinity and inhibitory activity for E. coli HPPK. P(1)-(6-Hydroxymethylpterin)-P(3)-(5'-adenosyl)triphosphate (HP(3)A, 6) shows moderate affinity and inhibitory activity with K(d) = 4.25 microM in the presence of Mg(2+) and IC(50) = 1.27 microM. P(1)-(6-Hydroxymethylpterin)-P(4)-(5'-adenosyl)tetraphosphate (HP(4)A, 7) shows the highest affinity and inhibitory activity with K(d) = 0.47 microM in the presence of Mg(2+) and IC(50) = 0.44 microM. The affinity of MgHP(4)A for HPPK is approximately 116 and 76 times...Continue Reading

References

Aug 21, 1992·Science·B R Bloom, C J Murray
Jan 1, 1989·Journal of Medicinal Chemistry·A D Broom
Jan 1, 1980·Methods in Enzymology·C L Krumdieck, C M Baugh
Apr 1, 1993·Annals of Internal Medicine·C M Kunin
Jan 1, 1995·Advances in Experimental Medicine and Biology·C C Sanders, W E Sanders
Apr 1, 1997·Journal of Molecular Graphics & Modelling·R M Esnouf
Apr 20, 1965·Journal of the American Chemical Society·J T WONG
Jan 1, 1997·Methods in Enzymology·Z Dauter

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Citations

Jul 12, 2002·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Alun Bermingham, Jeremy P Derrick
Jan 26, 2012·PloS One·Sandeep ChhabraJames D Swarbrick
Sep 26, 2006·Drug Discovery Today·Alexis Nzila
Apr 10, 2018·Future Medicinal Chemistry·Marcio V Bertacine DiasSair M Chavez-Pacheco
Aug 16, 2018·Organic & Biomolecular Chemistry·Nathjanan JongkonM Paul Gleeson
Oct 21, 2018·Medicinal Research Reviews·Violeta Carmona-MartínezPilar García-Peñarrubia
Nov 17, 2009·Journal of Enzyme Inhibition and Medicinal Chemistry·P B Le CalvezM E Migaud
Oct 23, 2012·Dalton Transactions : an International Journal of Inorganic Chemistry·Sonia B Jiménez-PulidoMiguel N Moreno-Carretero

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