Pterin and folate reduction by the Leishmania tarentolae H locus short-chain dehydrogenase/reductase PTR1

Archives of Biochemistry and Biophysics
J WangM Ouellette

Abstract

Overproduction of the short-chain dehydrogenase/reductase PTR1 confers resistance to the dihydrofolate reductase inhibitor methotrexate in the protozoan parasite Leishmania. Genetic analysis has previously implicated PTR1 in pterin and folate metabolism. PTR1 was purified from a fusion protein expressed in Escherichia coli. Purified PTR1 exhibits NADPH-dependent biopterin, dihydrobiopterin, folate, and dihydrofolate reductase activities. The highest activity was found with the most oxidized pterins. The active protein was found to be a tetramer as demonstrated by gel-filtration chromatography. Kinetic constants (K(m)), as determined by double-reciprocal plots, were calculated for NADPH and for several of PTR1's substrates. The PTR1 of Leishmania tarentolae had a K(m) of 16.9 microM for the cofactor NADPH and K(m) values ranging from 3.5 to 85 microM for the various substrates. The dissociation constant (KD), as determined by fluorescence titration, for NADPH was estimated to be 130 microM. The biochemical characterization of this important and novel enzyme involved in folate and pterin metabolism of Leishmania should be useful for structure-function analysis and for developing specific inhibitors against this putative important...Continue Reading

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Citations

Jan 18, 2011·The Journal of Biological Chemistry·Han B OngAlan H Fairlamb
Nov 18, 2003·Journal of Bacteriology·Moshe GiladiMoshe Mevarech
Sep 26, 2015·Journal of Enzyme Inhibition and Medicinal Chemistry·Sambamurthy ChandrasekaranRadheshyam Maurya
Aug 1, 2008·Expert Opinion on Drug Discovery·Nishikant V Wase, Phillip C Wright
Jul 12, 2008·Experimental Parasitology·Pranav KumarNeeloo Singh
Mar 20, 2003·Molecular & Cellular Proteomics : MCP·Jolyne DrummelsmithMarc Ouellette
May 12, 2012·Asian Pacific Journal of Tropical Medicine·Nisha SinghRakesh Kumar Singh
Jun 22, 2019·Current Pharmaceutical Design·Victoria WagnerChristopher Fernández-Prada
Apr 28, 2021·PLoS Neglected Tropical Diseases·Arijit BhattacharyaMarc Ouellette
Jul 23, 1999·Archives of Biochemistry and Biophysics·C F ChangJ M Whiteley
Feb 19, 2002·International Journal for Parasitology·Marc OuelletteGaétan Roy
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Aug 15, 2006·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·B PapadopoulouM Ouellette

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