Crystal Structures of Enoyl-ACP Reductases I (FabI) and III (FabL) from B. subtilis

Kim, Kook Han; Ha, Byung Hak; Kim, Su Jin; Hong, Suc-Kyoung; Hwang, Kwang Yeon; Kim, Eunice EunKyeong

doi:10.1016/j.jmb.2010.12.003

Cited by 38 publications

(32 citation statements)

References 49 publications

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“…In bacterial FabIs, this invariant tyrosine residue is flanked by a serine/threonine and a large hydrophobic residue, such as leucine or phenylalanine. Structurally, the tyrosine residue is at a spatially conserved position forming a part of the active site of the FabI enzyme in the crystal structures of FabI from S. aureus (11,40), E. coli (41), Helicobacter pylori (42), Bacillus subtilis (43), and Bacillus cereus (43). The analysis of these structures, our site-directed mutagenesis, and molecular dynamics simulations (37) all point to Tyr-147 promoting the reaction by hydrogen-bonding to the substrate thioester carbonyl.…”

Section: Discussionmentioning

confidence: 99%

Resistance to AFN-1252 Arises from Missense Mutations in Staphylococcus aureus Enoyl-acyl Carrier Protein Reductase (FabI)

Yao

Maxwell

Rock

2013

Journal of Biological Chemistry

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Background: AFN-1252 is a FabI inhibitor developed to treat Staphylococcus aureus. Results: AFN-1252 resistance arises from a single missense mutation that produces a FabI(M99T) protein. Conclusion:The interaction between Met-99 and AFN-1252 accounts for the staphylococcal selectivity of the drug. Significance: The AFN-1252-resistant strains remain susceptible to drug concentrations typically achieved in antibiotic therapy.

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Section: Discussionmentioning

confidence: 99%

Resistance to AFN-1252 Arises from Missense Mutations in Staphylococcus aureus Enoyl-acyl Carrier Protein Reductase (FabI)

Yao

Maxwell

Rock

2013

Journal of Biological Chemistry

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“…Residues Y259-N267 in each monomer and M1 of chain F are lost because of poor electron density. Each monomer adopts a classical Rossmann fold usually found in nucleotide-binding proteins with each monomer composed of a parallel b-sheet with seven strands and flanked by loops and 12 helices, including four 3 10 helices [h1-h4; Fig. 1(a)].…”

Section: Resultsmentioning

confidence: 99%

“…14,16,32,33 Like other ENRs, ClFabI has the highly conserved signature sequence motif Tyr-(Xaa) 6 -Lys. In addition, another motif dyad Gly14-(Xaa) 5 -Ser20 and Val66 and Thr194 in ClFabI are also highly conserved and contained in the hydrogen bond network of FabIs 10,11 (Fig. 3).…”

Section: Structural Comparison Of Clfabi With Other Enr Structuresmentioning

confidence: 99%

“…6,7 Consequently, this important enzyme has recently attracted tremendous attention from researchers. Several crystal structures of FabI have been reported in other bacteria and protozoans, such as Escherichia coli, 8 Staphylococcus aureus, 9 Bacillus subtilis, 10 Bacillus cereus, 11 Helicobacter pylori, 12 Francisella tularensis, 13 Plasmodium falciparum, 14 and Mycobacterium tuberculosis. 15 These homologous structures have been used as models to understand ClFabI in HLB pathogens and to develop new antimicrobial compounds for HLB control.…”

Section: Introductionmentioning

confidence: 99%

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Crystal structures and kinetic properties of enoyl‐acyl carrier protein reductase I from Candidatus Liberibacter asiaticus

Jiang

Gao

et al. 2014

Protein Science

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Huanglongbing (HLB) is a destructive citrus disease. The leading cause of HLB is Candidatus Liberibacter asiaticus. Fatty acid biosynthesis is essential for bacterial viability and has been validated as a target for the discovery of novel antibacterial agents. Enoyl2acyl carrier protein reductase (also called ENR or FabI and a product of the fabI gene) is an enzyme required in a critical step of bacterial fatty acid biosynthesis and has attracted attention as a target of novel antimicrobial agents. We determined the crystal structures of FabI from Ca. L. asiaticus in its apoform as well as in complex with b-nicotinamide adenine dinucleotide (NAD) at 1.7 and 2.7 Å resolution, respectively, to facilitate the design and screening of small molecule inhibitors of FabI. The monomeric ClFabI is highly similar to other known FabI structures as expected; however, unlike the typical tetramer, ClFabI exists as a hexamer in crystal, whereas as dimer in solution, on the other hand, the substrate binding loop which always disordered in apoform FabI structures is ordered in apo-ClFabI. Interestingly, the structure of ClFabI undergoes remarkable conformational change in the substrate-binding loop in the presence of NAD. We conclude that the signature sequence motif of FabI can be considered as Gly-(Xaa) 5 -Ser-(Xaa) n -Val-Tyr-(Xaa) 6 -Lys-(Xaa) n -Thr instead of Tyr-(Xaa) 6 -Lys. We have further identified isoniazid as a competitive inhibitor with NADH.

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“…FabL and FabV are structurally similar to FabI, but share low sequence identity and are poorly inhibited by triclosan. 25,26 S. pneumoniae and P. aeruginosa contain FabK, 24 and Vibrio cholerae, 27 P. aeruginosa, 28 Y. pestis, 29 and Burkholderia mallei 30 contain FabV. FabI is the sole ENR in F. tularensis, B. anthracis, E. coli, and S. aureus.…”

Section: ■ Introductionmentioning

confidence: 99%

3-Substituted Indole Inhibitors Against Francisella tularensis FabI Identified by Structure-Based Virtual Screening

Compton

AbdulHameed

et al. 2013

J. Med. Chem.

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In this study, we describe novel inhibitors against Francisella tularensis SchuS4 FabI identified from structure-based in silico screening with integrated molecular dynamics simulations to account for induced fit of a flexible loop crucial for inhibitor binding. Two 3-substituted indoles, 54 and 57, preferentially bound the NAD + form of the enzyme and inhibited growth of F. tularensis SchuS4 at concentrations near that of their measured K i . While 57 was species-specific, 54 showed a broader spectrum of growth inhibition against F. tularensis, Bacillus anthracis, and Staphylococcus aureus. Binding interaction analysis in conjunction with site-directed mutagenesis revealed key residues and elements that contribute to inhibitor binding and species specificity. Mutation of Arg-96, a poorly conserved residue opposite the loop, was unexpectedly found to enhance inhibitor binding in the R96G and R96M variants. This residue may affect the stability and closure of the flexible loop to enhance inhibitor (or substrate) binding.

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Crystal Structures of Enoyl-ACP Reductases I (FabI) and III (FabL) from B. subtilis

Cited by 38 publications

References 49 publications

Resistance to AFN-1252 Arises from Missense Mutations in Staphylococcus aureus Enoyl-acyl Carrier Protein Reductase (FabI)

Resistance to AFN-1252 Arises from Missense Mutations in Staphylococcus aureus Enoyl-acyl Carrier Protein Reductase (FabI)

Crystal structures and kinetic properties of enoyl‐acyl carrier protein reductase I from Candidatus Liberibacter asiaticus

3-Substituted Indole Inhibitors Against Francisella tularensis FabI Identified by Structure-Based Virtual Screening

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