Feliciano, Patricia R. published the artcileStructural and Biochemical Investigations of the [4Fe-4S] Cluster-Containing Fumarate Hydratase from Leishmania major, Recommanded Product: (S)-2-hydroxysuccinic acid, the main research area is cluster 4Fe4S containing fumarate hydratase Leishmania crystal structure.
Class I fumarate hydratases (FHs) are central metabolic enzymes that use a [4Fe-4S] cluster to catalyze the reversible conversion of fumarate to S-malate. The parasite Leishmania major, which is responsible for leishmaniasis, expresses two class I FH isoforms: mitochondrial LmFH-1 and cytosolic LmFH-2. In this study, we present kinetic characterizations of both LmFH isoforms, present thirteen crystal structures of LmFH-2 variants, and employ site-directed mutagenesis to investigate the enzyme’s mechanism. Our kinetic data confirm that both LmFH-1 and LmFH-2 are susceptible to oxygen-dependent inhibition, with data from crystallog. and ESR spectroscopy showing that oxygen exposure converts an active [4Fe-4S] cluster to an inactive [3Fe-4S] cluster. Our anaerobically-conducted kinetic studies reveal a preference for fumarate over S-malate. Our data further reveal that single alanine substitutions of T467, R421, R471, D135, and H334 decrease kcat 9-fold to 16,000-fold without substantially affecting Km, suggesting that these residues function in catalytic roles. Crystal structures of LmFH-2 variants are consistent with this idea, showing similar bidentate binding to the unique iron of the [4Fe-4S] cluster for substrate S-malate as observed in wild type FH. We further present LmFH-2 structures with substrate fumarate and weak inhibitors succinate and malonate bound in the active site, and the first structure of an LmFH that is substrate-free and inhibitor-free, the latter showing increased mobility of the C-terminal domain. Collectively, these data provide insight into the mol. basis for the reaction catalyzed by LmFHs, enzymes that are potential drug targets against leishmaniasis.
Biochemistry published new progress about Crystal structure. 97-67-6 belongs to class alcohols-buliding-blocks, name is (S)-2-hydroxysuccinic acid, and the molecular formula is C4H6O5, Recommanded Product: (S)-2-hydroxysuccinic acid.
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