Molecular study of the enzymes involved in the folate biosynthesis pathway, alternative targets for drugs
Abstract
Folate derivates are essential co-factors in the biosynthesis of purines, pyrimidines and certain amino acids in living cells. Most microbial cells must synthesise folates de novo since they lack the carrier-mediated active transport system of mammalian cells which allows the use of preformed dietary folates.
The de novo synthesis of dihydrofolate from GTP requires the participation of several enzyme activities that are unique to microbial cells. The enzymes of the folic acid biosynthesis pathway represent, therefore, ideal targets for antimicrobial chemotherapy since they have no mammalian counter-parts, and high level selectivity should be achievable. Indeed, dihydropteroate synthase which catalyses the condensation of p- arninobenzoic acid and 6-hydroxi-rnethil-7,8-dihydropterin pyrophosphate to form dihydropteroate, is the target of sulfa drugs.
The molecular characterization of individual enzyme activities, domain folding and domain interactions within the polypeptide, should aid the design of novel antimicrobial agents.
Keywords: DHNA (dihydroneopterin aldolase), PPPK (6-hydroxyrnethyl-7,8-dibydropterin pyrophosphokinase). DHPS (dihydropteroate syntbase). DHFS (dihydrofo1ate synthase). DHFR (dihydrofolate reductase).
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Bacteriol (1992), 174:5971-5977.
(2) DALLAS, W. S., GOWEN, J. E., RA Y, P. H., COX, M. J. & DEV, 1. K. : J Bacteriol
(1992), 174:5961-5970.
(3) BOGNAR, A L., OSBORNE, C., SHANE, B., SINGER, S. C & FERONE, R.: J Biol
Chem (1985), 260:5625-5630.
(4) BOGNAR, A. L., OSBORNE, C. & SHANE, B.: J Biol Chem, (1987), 262:12337-12343 .
(5) LÓPEZ, P., GREENBERG, B. & LACKS, S. A : J Bacteriol (1990), 172:4766-4774.
(6) LÓPEZ, P., ESPINOSA, M., GREENBERG, B. & LACKS, S. A : J Bacteriol, (1987),
169:4320-4326.
(7) LÓPEZ, P. & LACKS, S. A. : J Bacteriol (1993), 175:2214-2220.
(8) BROOKS, D. R., WANG, P., READ, M., WATKlNS, W. M., SIMS, P. F. G . . & HYDE,
J. E.: Eur J Biochem (1994), 224:397-405 .
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