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Utilization of exogenous folate in the human malaria parasite Plasmodium falciparum and its critical role in antifolate drug synergy (1999)

Wang, Ping ; Brobey, Reynolds K. B. ; Horii, Toshihiro ; [et al.]

Oxford BSL : Blackwell Science Ltd

Molecular microbiology 32 (1999), S. 0

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ISSN: 1365-2958

Source: Blackwell Publishing Journal Backfiles 1879-2005

Topics: Biology , Medicine

Notes: The antifolate combination pyrimethamine/sulphadoxine (PYR/SDX; Fansidar) is frequently used to combat chloroquine-resistant malaria. Its success depends upon pronounced synergy between the two components, which target dihydrofolate reductase (DHFR) and dihydropteroate synthetase (DHPS) in the folate pathway. This synergy permits clearance of parasites resistant to either drug alone, but its molecular basis is still unexplained. Plasmodium falciparum can use exogenous folate, which is normally present in vivo, bypassing SDX inhibition of DHPS and, apparently, precluding synergy under these conditions. However, we have measured parasite inhibition by SDX/PYR combinations in assays in which folate levels are strictly controlled. In parasites that use exogenous folate efficiently, SDX inhibition can be restored by levels of PYR significantly lower than those required to inhibit DHFR. Isobolograms show that the degree of synergy between PYR and SDX is highly dependent upon prevailing folate concentrations and are indicative of PYR acting to block folate uptake and/or utilization. No significant synergy was observed at physiological drug levels when PYR/SDX acted on purified DHFR, whether wild type or mutant. We conclude that the primary basis for antifolate synergy in these organisms arises from PYR targeting a site (or sites) in addition to DHFR, which restores DHPS as a relevant target for SDX.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1046/j.1365-2958.1999.01437.x

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The shikimic acid pathway and polyketide biosynthesis (1998)

Wilson, D J ; Patton, S ; Florova, G ; [et al.]

Springer

Journal of industrial microbiology and biotechnology 20 (1998), S. 299-303

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ISSN: 1476-5535

Keywords: Keywords: shikimic acid; streptomycetes; immunosuppressant; polyketide

Source: Springer Online Journal Archives 1860-2000

Topics: Biology , Process Engineering, Biotechnology, Nutrition Technology

Notes: The shikimic acid pathway, ubiquitous in microorganisms and plants, provides precursors for the biosynthesis of primary metabolites such as the aromatic amino acids and folic acid. Several branchpoints from the primary metabolic pathway also provide aromatic and, in some unusual cases, nonaromatic precursors for the biosynthesis of secondary metabolites. We report herein recent progress in the analysis of two unusual branches of the shikimic acid pathway in streptomycetes; the formation of the cyclohexanecarboxylic acid (CHC)-derived moiety of the antifungal agent ansatrienin and the dihydroxycyclohexanecarboxylic acid (DHCHC) starter unit for the biosynthesis of the immunosuppressant ascomycin. A gene for 1-cyclohexenylcarbonyl-CoA reductase, chcA, which plays a role in catalyzing three of the reductive steps leading from shikimic acid to CHC has been characterized from Streptomyces collinus. A cluster of six open reading frames (ORFs) has been identified by sequencing in both directions from chcA and the putative role of these in CHC biosynthesis is discussed. The individual steps involved in the biosynthesis of DHCHC from shikimic acid in Streptomyces hygroscopicus var ascomyceticus has been delineated and shown to be stereochemically and enzymatically distinct from the CHC pathway. A dehydroquinate dehydratase gene (dhq) likely involved in providing shikimic acid for both DHCHC biosynthesis and primary metabolism has been cloned, sequenced and characterized.