The enzyme completes each cycle of fatty acid elongation by catalysing the stereospecific reduction of the double bond at position 2 of a growing fatty acid chain, while linked to the acyl-carrier protein, in an NADPH-dependent manner. This entry stands for enzymes whose stereo-specificity with respect to NADP+ is not known. [cf. EC 1.3.1.39 enoyl-[acyl-carrier-protein] reductase (NADPH, Re-specific), EC 1.3.1.10, enoyl-[acyl-carrier-protein] reductase (NADPH, Si-specific) and EC 1.3.1.9, enoyl-[acyl-carrier-protein] reductase (NADH)].
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The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
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SYSTEMATIC NAME
IUBMB Comments
acyl-[acyl-carrier protein]:NADP+ oxidoreductase
The enzyme completes each cycle of fatty acid elongation by catalysing the stereospecific reduction of the double bond at position 2 of a growing fatty acid chain, while linked to the acyl-carrier protein, in an NADPH-dependent manner. This entry stands for enzymes whose stereo-specificity with respect to NADP+ is not known. [cf. EC 1.3.1.39 enoyl-[acyl-carrier-protein] reductase (NADPH, Re-specific), EC 1.3.1.10, enoyl-[acyl-carrier-protein] reductase (NADPH, Si-specific) and EC 1.3.1.9, enoyl-[acyl-carrier-protein] reductase (NADH)].
the enzyme shows no 7-alpha hydroxysteroid dehydrogenase activity when tested with cholic acid substrate and NADH and NADPH cofactors. The purified protein does not utilize NADH as a cofactor when tested with crotonyl-[CoA] as substrate
antibiotic AFN-1252, i.e. (2E)-N-methyl-N-[(3-methyl-1-benzofuran-2-yl)methyl]-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)prop-2-enamide, only binds to the NADPH form of FabI
the whole reaction involves the formation of the covalent ene adduct and the proton transfer from Tyr79 to the substrate. In the first step the hydride of NADPH easily transfers to crotonyl-CoA to generate the substrate carbanion if the hydroxyl of Tyr79 forms a hydrogen bond chain with Ser70 and crystal water molecules. Then, the carbanion and NADP+ form a stable covalent ene adduct. The formation of the ene adduct follows the Michael addition mechanism rather than the electrocyclic ene reactions. The final electrophilic attack of the Tyr79 proton on C8 of the substrate affords the product of acyl thioester. The key crystal water molecules do not directly participate in the catalytic reactions, but they play a role in maintaining the relative stability of the substrate to NADPH
expression of isoform FabL complements the temperature-sensitive fabI defect in Escherichia coli and confers complete triclosan resistance. Knockouts of the FabL gene in Bacillus subtilis are viable, but double knockouts of isoforms FabI and FabL are not obtained. The ygaA knockout is 250fold more sensitive to triclosan than wild-type
expression of isoform FabL complements the temperature-sensitive fabI defect in Escherichia coli and confers complete triclosan resistance. Knockouts of the FabL gene in Bacillus subtilis are viable, but double knockouts of isoforms FabI and FabL are not obtained. The ygaA knockout is 250fold more sensitive to triclosan than wild-type
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
both free form and complexed with NADP+ and inhibitor triclosan, to 2.2 and 1.8 A resolution, respectively. The substrate-binding region in the apo-FabL structure is found in the open form. In addition, the beta4-alpha5 and beta5-alpha7 regions, which include the catalytic residues as well as the cofactor binding residues, get collapsed into the pocket. These differences result in a tetrameric arrangement totally different from NADH-dependent isoform FabI
mutant is resistant to antibiotic AFN-1252 and to triclosan, about 5% of wild-type catalytic activity. A strain expressing Y147H has a pronounced growth defect that is rescued by exogenous fatty acid supplementation
mutant is resistant to antibiotic AFN-1252 and to triclosan, about 5% of wild-type catalytic activity. A strain expressing Y147H has a pronounced growth defect that is rescued by exogenous fatty acid supplementation
replacement of amino acids 55-66 by CurF enoyl reductase cyclopropanase loop leads to gain-of-function activity as a cyclopropanase. With substrate 3-chloromethyl-crotonyl-[acyl-carrier-protein], the formation of both the reduced product and also the cyclopropanated productis detected at levels of about one-quarter of the total product
mutant is resistant to antibiotic AFN-1252 but susceptible to triclosan. Strains expressing M99T exhibit normal growth, and the biochemical properties of the purified protein are indistinguishable from those of FabI
mutant is resistant to antibiotic AFN-1252 but susceptible to triclosan. Strains expressing M99T exhibit normal growth, and the biochemical properties of the purified protein are indistinguishable from those of FabI
development of a simple thermal shift assay, which does not use ACP-linked substrates, to determine the binding ability of triclosan to the enzyme's active site
development of a simple thermal shift assay, which does not use ACP-linked substrates, to determine the binding ability of triclosan to the enzyme's active site