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Structural Characterisation of FabG from Yersinia pestis, a Key Component of Bacterial Fatty Acid Synthesis.

Nanson JD, Forwood JK - PLoS ONE (2015)

Bottom Line: Ketoacyl-acyl carrier protein reductases (FabG) are ubiquitously expressed enzymes that catalyse the reduction of acyl carrier protein (ACP) linked thioesters within the bacterial type II fatty acid synthesis (FASII) pathway.YpFabG shares a high degree of structural similarity with bacterial homologues, and the ketoreductase domain of the mammalian fatty acid synthase from both Homo sapiens and Sus scrofa.Structural characterisation of YpFabG, and comparison with other bacterial FabGs and the mammalian fatty acid synthase, provides a strong platform for virtual screening of potential inhibitors, rational drug design, and the development of new antimicrobial agents to combat Y. pestis infections.

View Article: PubMed Central - PubMed

Affiliation: School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, 2678, Australia.

ABSTRACT
Ketoacyl-acyl carrier protein reductases (FabG) are ubiquitously expressed enzymes that catalyse the reduction of acyl carrier protein (ACP) linked thioesters within the bacterial type II fatty acid synthesis (FASII) pathway. The products of these enzymes, saturated and unsaturated fatty acids, are essential components of the bacterial cell envelope. The FASII reductase enoyl-ACP reductase (FabI) has been the focus of numerous drug discovery efforts, some of which have led to clinical trials, yet few studies have focused on FabG. Like FabI, FabG appears to be essential for survival in many bacteria, similarly indicating the potential of this enzyme as a drug target. FabG enzymes are members of the short-chain alcohol dehydrogenase/reductase (SDR) family, and like other SDRs, exhibit highly conserved secondary and tertiary structures, and contain a number of conserved sequence motifs. Here we describe the crystal structures of FabG from Yersinia pestis (YpFabG), the causative agent of bubonic, pneumonic, and septicaemic plague, and three human pandemics. Y. pestis remains endemic in many parts of North America, South America, Southeast Asia, and Africa, and a threat to human health. YpFabG shares a high degree of structural similarity with bacterial homologues, and the ketoreductase domain of the mammalian fatty acid synthase from both Homo sapiens and Sus scrofa. Structural characterisation of YpFabG, and comparison with other bacterial FabGs and the mammalian fatty acid synthase, provides a strong platform for virtual screening of potential inhibitors, rational drug design, and the development of new antimicrobial agents to combat Y. pestis infections.

No MeSH data available.


Related in: MedlinePlus

The fatty acid synthesis pathway of Yersinia pestis.In contrast to the mammalian fatty acid synthesis pathway in which reactions are catalysed by a single protein (FAS or FASN), each acyltransferase, condensation, reduction, and dehydration reaction of the fatty acid synthesis pathway of Yersinia pestis is catalysed by a discrete enzyme (highlighted green). FabG (highlighted blue with red lettering) is a highly conserved and ubiquitously expressed enzyme, which performs the first of two reduction reactions within the pathway. Homologues from other organisms are not highlighted. Image adapted from the KEGG PATHWAY database [14, 15].
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pone.0141543.g001: The fatty acid synthesis pathway of Yersinia pestis.In contrast to the mammalian fatty acid synthesis pathway in which reactions are catalysed by a single protein (FAS or FASN), each acyltransferase, condensation, reduction, and dehydration reaction of the fatty acid synthesis pathway of Yersinia pestis is catalysed by a discrete enzyme (highlighted green). FabG (highlighted blue with red lettering) is a highly conserved and ubiquitously expressed enzyme, which performs the first of two reduction reactions within the pathway. Homologues from other organisms are not highlighted. Image adapted from the KEGG PATHWAY database [14, 15].

Mentions: Ketoacyl-acyl carrier protein reductases (FabG; EC 1.1.1.100) are highly conserved and ubiquitously expressed enzymes of the bacterial type II fatty acid synthesis (FASII) pathway, catalysing the reduction of the acyl carrier protein (ACP) linked β-ketoacyl molecules to β-hydroxyacyl-ACP thioesters necessary for the formation of saturated and unsaturated fatty acids. Such fatty acids are essential components of the many lipoproteins, phospholipids, and lipopolysaccharides that are incorporated into the bacterial cell envelope [1]. The FASII pathway is structurally distinct from the type I fatty acid synthesis (FASI) pathway of mammals and yeast, with the acyltransferase, condensation, reduction, and dehydration reactions of the pathway catalysed by discrete enzymes, in contrast to the multi-domain complex of the FASI pathway (FAS; also referred to by the gene name FASN) (Fig 1). In Escherichia coli and Yersinia pestis, the elongation of fatty acids typically begins with the condensation of malonyl-ACP and a fatty acyl-thioester catalysed by one of the three β-ketoacyl-ACP synthases (FabB, FabF, or FabH) forming a β-ketoacyl-ACP molecule, which is subsequently reduced by FabG. The product of this reaction is then dehydrated by a β-hydroxyacyl-ACP dehydrase (either FabA or FabZ) to yield enoyl-ACP. Another reductase of the FASII pathway, enoyl-ACP reductase (FabI), reduces enoyl-ACP, forming an acyl-ACP molecule. This acyl-ACP molecule can then re-enter the elongation cycle as a substrate for FabB or FabF, or be diverted to other pathways for the production of lipid molecules [1–3]. The structural differences between the FASI complex and the dissociated enzymes of the FASII pathway indicate the potential of FASII enzymes as antibacterial drug targets. Whilst the FASII enzyme enoyl-ACP reductase (FabI) has been the focus of numerous drug discovery efforts, some of which have led to clinical trials, few studies appear to be focused on FabG [4–9]. Like FabI, FabG appears to be essential for survival in many bacteria, similarly indicating the potential of this enzyme as a drug target [10–13].


Structural Characterisation of FabG from Yersinia pestis, a Key Component of Bacterial Fatty Acid Synthesis.

Nanson JD, Forwood JK - PLoS ONE (2015)

The fatty acid synthesis pathway of Yersinia pestis.In contrast to the mammalian fatty acid synthesis pathway in which reactions are catalysed by a single protein (FAS or FASN), each acyltransferase, condensation, reduction, and dehydration reaction of the fatty acid synthesis pathway of Yersinia pestis is catalysed by a discrete enzyme (highlighted green). FabG (highlighted blue with red lettering) is a highly conserved and ubiquitously expressed enzyme, which performs the first of two reduction reactions within the pathway. Homologues from other organisms are not highlighted. Image adapted from the KEGG PATHWAY database [14, 15].
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4635001&req=5

pone.0141543.g001: The fatty acid synthesis pathway of Yersinia pestis.In contrast to the mammalian fatty acid synthesis pathway in which reactions are catalysed by a single protein (FAS or FASN), each acyltransferase, condensation, reduction, and dehydration reaction of the fatty acid synthesis pathway of Yersinia pestis is catalysed by a discrete enzyme (highlighted green). FabG (highlighted blue with red lettering) is a highly conserved and ubiquitously expressed enzyme, which performs the first of two reduction reactions within the pathway. Homologues from other organisms are not highlighted. Image adapted from the KEGG PATHWAY database [14, 15].
Mentions: Ketoacyl-acyl carrier protein reductases (FabG; EC 1.1.1.100) are highly conserved and ubiquitously expressed enzymes of the bacterial type II fatty acid synthesis (FASII) pathway, catalysing the reduction of the acyl carrier protein (ACP) linked β-ketoacyl molecules to β-hydroxyacyl-ACP thioesters necessary for the formation of saturated and unsaturated fatty acids. Such fatty acids are essential components of the many lipoproteins, phospholipids, and lipopolysaccharides that are incorporated into the bacterial cell envelope [1]. The FASII pathway is structurally distinct from the type I fatty acid synthesis (FASI) pathway of mammals and yeast, with the acyltransferase, condensation, reduction, and dehydration reactions of the pathway catalysed by discrete enzymes, in contrast to the multi-domain complex of the FASI pathway (FAS; also referred to by the gene name FASN) (Fig 1). In Escherichia coli and Yersinia pestis, the elongation of fatty acids typically begins with the condensation of malonyl-ACP and a fatty acyl-thioester catalysed by one of the three β-ketoacyl-ACP synthases (FabB, FabF, or FabH) forming a β-ketoacyl-ACP molecule, which is subsequently reduced by FabG. The product of this reaction is then dehydrated by a β-hydroxyacyl-ACP dehydrase (either FabA or FabZ) to yield enoyl-ACP. Another reductase of the FASII pathway, enoyl-ACP reductase (FabI), reduces enoyl-ACP, forming an acyl-ACP molecule. This acyl-ACP molecule can then re-enter the elongation cycle as a substrate for FabB or FabF, or be diverted to other pathways for the production of lipid molecules [1–3]. The structural differences between the FASI complex and the dissociated enzymes of the FASII pathway indicate the potential of FASII enzymes as antibacterial drug targets. Whilst the FASII enzyme enoyl-ACP reductase (FabI) has been the focus of numerous drug discovery efforts, some of which have led to clinical trials, few studies appear to be focused on FabG [4–9]. Like FabI, FabG appears to be essential for survival in many bacteria, similarly indicating the potential of this enzyme as a drug target [10–13].

Bottom Line: Ketoacyl-acyl carrier protein reductases (FabG) are ubiquitously expressed enzymes that catalyse the reduction of acyl carrier protein (ACP) linked thioesters within the bacterial type II fatty acid synthesis (FASII) pathway.YpFabG shares a high degree of structural similarity with bacterial homologues, and the ketoreductase domain of the mammalian fatty acid synthase from both Homo sapiens and Sus scrofa.Structural characterisation of YpFabG, and comparison with other bacterial FabGs and the mammalian fatty acid synthase, provides a strong platform for virtual screening of potential inhibitors, rational drug design, and the development of new antimicrobial agents to combat Y. pestis infections.

View Article: PubMed Central - PubMed

Affiliation: School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, 2678, Australia.

ABSTRACT
Ketoacyl-acyl carrier protein reductases (FabG) are ubiquitously expressed enzymes that catalyse the reduction of acyl carrier protein (ACP) linked thioesters within the bacterial type II fatty acid synthesis (FASII) pathway. The products of these enzymes, saturated and unsaturated fatty acids, are essential components of the bacterial cell envelope. The FASII reductase enoyl-ACP reductase (FabI) has been the focus of numerous drug discovery efforts, some of which have led to clinical trials, yet few studies have focused on FabG. Like FabI, FabG appears to be essential for survival in many bacteria, similarly indicating the potential of this enzyme as a drug target. FabG enzymes are members of the short-chain alcohol dehydrogenase/reductase (SDR) family, and like other SDRs, exhibit highly conserved secondary and tertiary structures, and contain a number of conserved sequence motifs. Here we describe the crystal structures of FabG from Yersinia pestis (YpFabG), the causative agent of bubonic, pneumonic, and septicaemic plague, and three human pandemics. Y. pestis remains endemic in many parts of North America, South America, Southeast Asia, and Africa, and a threat to human health. YpFabG shares a high degree of structural similarity with bacterial homologues, and the ketoreductase domain of the mammalian fatty acid synthase from both Homo sapiens and Sus scrofa. Structural characterisation of YpFabG, and comparison with other bacterial FabGs and the mammalian fatty acid synthase, provides a strong platform for virtual screening of potential inhibitors, rational drug design, and the development of new antimicrobial agents to combat Y. pestis infections.

No MeSH data available.


Related in: MedlinePlus