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Literature summary extracted from

  • Nanson, J.D.; Himiari, Z.; Swarbrick, C.M.; Forwood, J.K.
    Structural characterisation of the beta-ketoacyl-acyl carrier protein synthases, FabF and FabH, of Yersinia pestis (2015), Sci. Rep., 5, 14797.
    View publication on PubMedView publication on EuropePMC

Application

EC Number Application Comment Organism
2.3.1.179 drug development the enzyme is a promising target for the development of therapeutic agents Yersinia pestis
2.3.1.180 drug development the enzyme is a promising target for the development of therapeutic agents Yersinia pestis

Cloned(Commentary)

EC Number Cloned (Comment) Organism
2.3.1.179 gene fabF, recombinant expression of N-terminally His6-tagged enzyme with a TEV protease cleavage site in Escherichia coli strain BL21(DE3) pLysS Yersinia pestis
2.3.1.180 gene fabH, recombinant expression of N-terminally His6-tagged enzyme with a TEV protease cleavage site in Escherichia coli strain BL21(DE3) pLysS Yersinia pestis

Crystallization (Commentary)

EC Number Crystallization (Comment) Organism
2.3.1.179 purified recombinant enzyme, hanging drop vapour diffusion technique, mixing of 0.0015 ml of 21 mg/ml protein solution with an equal amount of reservoir solution, containing 0.2 M lithium chloride, 0.1 M HEPES sodium salt pH 7.0, and 24% PEG 6000, and equilibration against 0.3 ml of reservoir solution, 13°C, X-ray diffraction structure determination and analysis at 2.7 A resolution, molecular replacement using the enzyme structure of Escherichia coli, PDB ID 1KAS, as search model Yersinia pestis
2.3.1.180 purified recombinant enzyme in apoform or as acetylated enzyme, hanging drop vapour diffusion technique, mixing of 0.0015 ml of 20 mg/ml protein solution with an equal amount of reservoir solution, containing 10% propan-2-ol, 0.1 M HEPES, pH 7.5, 15% glycerol, 24% PEG 4000, and equilibration against 0.3 ml of reservoir solution, 13°C, acetylated-YpFabH by co-crystallisation with acetyl-CoA at a molar ratio of 5:5:1 of acetyl-CoA-malonyl-CoA-YpFabH at 10 mg/ml protein, X-ray diffraction structure determination and analysis at 18-2.2 A resolution, molecular replacement using the enzyme structure of Escherichia coli, PDB ID 1HN9, as search model Yersinia pestis

Inhibitors

EC Number Inhibitors Comment Organism Structure
2.3.1.179 cerulenin
-
 Yersinia pestis
2.3.1.179 additional information inhibitor interaction with the active site, structure analysis, docking study, overview Yersinia pestis
2.3.1.179 platencin
-
 Yersinia pestis
2.3.1.179 platensimycin
-
 Yersinia pestis
2.3.1.179 thiolactomycin
-
 Yersinia pestis
2.3.1.180 additional information inhibitor interaction with the active site, structure analysis, docking study, overview. Cerulenin is a poor inhibitor of FabH Yersinia pestis
2.3.1.180 platencin
-
 Yersinia pestis
2.3.1.180 platensimycin
-
 Yersinia pestis
2.3.1.180 thiolactomycin
-
 Yersinia pestis

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
2.3.1.180 acetyl-CoA + a malonyl-[acyl-carrier protein] Yersinia pestis
-
 an acetoacetyl-[acyl-carrier protein] + CoA + CO2
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
2.3.1.179 Yersinia pestis Q7CJ22 gene fabF
-
2.3.1.180 Yersinia pestis Q8ZFT7 gene fabH
-

Purification (Commentary)

EC Number Purification (Comment) Organism
2.3.1.179 recombinant N-terminally His6-tagged enzyme from Escherichia coli strain BL21(DE3) pLysS by nickel affinty chromatography, tag cleavage by TEV protease, gel filtration, and ultrafiltration to over 90% purity Yersinia pestis
2.3.1.180 recombinant N-terminally His6-tagged enzyme from Escherichia coli strain BL21(DE3) pLysS by nickel affinty chromatography, tag cleavage by TEV protease, gel filtration, and ultrafiltration to over 90% purity Yersinia pestis

Reaction

EC Number Reaction Comment Organism Reaction ID
2.3.1.179 a (Z)-hexadec-9-enoyl-[acyl-carrier protein] + a malonyl-[acyl-carrier protein] = a (Z)-3-oxooctadec-11-enoyl-[acyl-carrier protein] + CO2 + an [acyl-carrier protein] two-stage mechanism, driven by a dipole moment, the active site cysteine, Cys164 in YpFabF attacks the acyl group of a fatty acyl donor, transferring the acyl group to the enzyme. The bound fatty acyl donor molecule is displaced, and the receiving molecule or fatty acyl thioester to be elongated binds, initiating the transfer of the acyl group from the condensing enzyme to the recipient. The remaining residues of the catalytic triad, His304 and His341, are thought to stabilise the fatty acyl intermediate during transition states Yersinia pestis
a
2.3.1.180 acetyl-CoA + a malonyl-[acyl-carrier protein] = an acetoacetyl-[acyl-carrier protein] + CoA + CO2 two-stage mechanism, driven by a dipole moment, the active site cysteine, Cys112 in YpFabH attacks the acyl group of a fatty acyl donor, transferring the acyl group to the enzyme. The bound fatty acyl donor molecule is displaced, and the receiving molecule or fatty acyl thioester to be elongated binds, initiating the transfer of the acyl group from the condensing enzyme to the recipient. The remaining residues of the catalytic triad, His243 and Asn273, are thought to stabilise the fatty acyl intermediate during transition states Yersinia pestis
a

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2.3.1.179 additional information enzyme substrate specificity, overview Yersinia pestis ?
-
 ?
2.3.1.180 acetyl-CoA + a malonyl-[acyl-carrier protein]
-
 Yersinia pestis an acetoacetyl-[acyl-carrier protein] + CoA + CO2
-
 ?
2.3.1.180 additional information enzyme substrate specificity, overview Yersinia pestis ?
-
 ?

Subunits

EC Number Subunits Comment Organism
2.3.1.179 dimer the YpFabF monomer contains 13 alpha-helices and 14 beta-strands, the core motif of YpFabF contains a characteristic thiolase fold, dimer interface structure, structure comparison with FabH, EC 2.3.1.180 Yersinia pestis
2.3.1.180 dimer the YpFabH monomer contains 10 alpha-helices and 14 beta-strands, the core motif of YpFabH contains a characteristic thiolase fold, monomer interaction analysis, dimer interface structure, and structure comparison with FabF, EC 2.3.1.179 Yersinia pestis

Synonyms

EC Number Synonyms Comment Organism
2.3.1.179 beta-ketoacyl-acyl carrier protein synthase II
-
 Yersinia pestis
2.3.1.179 FabF
-
 Yersinia pestis
2.3.1.180 beta-ketoacyl-acyl carrier protein synthase III
-
 Yersinia pestis
2.3.1.180 FabH
-
 Yersinia pestis

Cofactor

EC Number Cofactor Comment Organism Structure
2.3.1.180 acetyl-CoA
-
 Yersinia pestis

General Information

EC Number General Information Comment Organism
2.3.1.179 metabolism the beta-ketoacyl-acyl carrier protein (ACP) synthases, FabB, FabF, and FabH, catalyse the Claisen condensation of fatty acyl-thioesters and malonyl-ACP to form a 3-oxoacyl-ACP intermediate elongated by two carbon atoms. The initial cycle of elongation is catalysed by FabH, involving condensation of malonyl-ACP and acetyl-CoA, while subsequent cycles of elongation are performed by FabB or FabF Yersinia pestis
2.3.1.179 additional information enzyme structure and active site architecture, comparison with FabH, EC 2.3.1.180. Substrate binding is controlled by residue Phe401 Yersinia pestis
2.3.1.180 metabolism the beta-ketoacyl-acyl carrier protein (ACP) synthases, FabB, FabF, and FabH, catalyse the Claisen condensation of fatty acyl-thioesters and malonyl-ACP to form a 3-oxoacyl-ACP intermediate elongated by two carbon atoms. The initial cycle of elongation is catalysed by FabH, involving condensation of malonyl-ACP and acetyl-CoA, while subsequent cycles of elongation are performed by FabB or FabF Yersinia pestis
2.3.1.180 additional information enzyme structure and active site architecture, comparison with FabF, EC 2.3.1.179. Possible substrate and inhibitor interactions of Yersinia pestis FabH, Arg151 of YpFabH clashes with the adenine ring of CoA Yersinia pestis