ArticleProtein science : a publication of the Protein Society2008
Crystal structure of enoyl-acyl carrier protein reductase (FabK) from Streptococcus pneumoniae reveals the binding mode of an inhibitor.
Article in Protein science : a publication of the Protein Society, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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29 citing papers in PubMed, 56 citations in OpenAlex.
- Thraustochytrid PUFA synthase ER domains form a stable heterodimer.Journal of structural biology: X · 2026Article
- Structural and Biochemical Characterization ofACS bio & med chem Au · 2026Article
- Evaluation ofACS infectious diseases · 2024Article
- Antibiotic Skeletal Diversification via Differential Enoylreductase Recruitment and Module Iteration inJournal of the American Chemical Society · 2024Article
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- Identification of triazenyl indoles as inhibitors of fungal fatty acid biosynthesis with broad-spectrum activity.Cell chemical biology · 2023Article
- Synthesis and evaluation of phenylimidazole FabK inhibitors as new Anti-C. Difficile agents.Bioorganic & medicinal chemistry · 2023Article
- A Review of Fatty Acid Biosynthesis Enzyme Inhibitors as Promising Antimicrobial Drugs.Pharmaceuticals (Basel, Switzerland) · 2023Review
- Mining Fatty Acid Biosynthesis for New Antimicrobials.Annual review of microbiology · 2022Review
- Bacterial Enoyl-Reductases: The Ever-Growing List of Fabs, Their Mechanisms and Inhibition.Frontiers in microbiology · 2022Review
- Peculiarities of nitronate monooxygenases and perspectives for in vivo and in vitro applications.Applied microbiology and biotechnology · 2021Review
- The genome of a Bacteroidetes inhabitant of the human gut encodes a structurally distinct enoyl-acyl carrier protein reductase (FabI).The Journal of biological chemistry · 2020Article
- Small-Molecule Inhibition of theACS chemical biology · 2019Article
- The Fatty Acid Synthesis Protein Enoyl-ACP Reductase II (FabK) is a Target for Narrow-Spectrum Antibacterials for Clostridium difficile Infection.ACS infectious diseases · 2019Article
- The architectures of iterative type I PKS and FAS.Natural product reports · 2018Review
- Structural characterization of Porphyromonas gingivalis enoyl-ACP reductase II (FabK).Acta crystallographica. Section F, Structural biology communications · 2018Article
- Profound perturbation induced by triclosan exposure in mouse gut microbiome: a less resilient microbial community with elevated antibiotic and metal resistomes.BMC pharmacology & toxicology · 2017Article
- Catabolism of the Last Two Steroid Rings inmBio · 2017Article
- Trapping of the Enoyl-Acyl Carrier Protein Reductase-Acyl Carrier Protein Interaction.Journal of the American Chemical Society · 2016Article
- Crystal structures and kinetic properties of enoyl-acyl carrier protein reductase I from Candidatus Liberibacter asiaticus.Protein science : a publication of the Protein Society · 2014Article
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9 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
Enoyl-acyl carrier protein (ACP) reductases are critical for bacterial type II fatty acid biosynthesis and thus are attractive targets for developing novel antibiotics. We determined the crystal structure of enoyl-ACP reductase (FabK) from Streptococcus pneumoniae at 1.7 A resolution. There was one dimer per asymmetric unit. Each subunit formed a triose phosphate isomerase (TIM) barrel structure, and flavin mononucleotide (FMN) was bound as a cofactor in the active site. The overall structure was similar to the enoyl-ACP reductase (ER) of fungal fatty acid synthase and to 2-nitropropane dioxygenase (2-ND) from Pseudomonas aeruginosa, although there were some differences among these structures. We determined the crystal structure of FabK in complex with a phenylimidazole derivative inhibitor to envision the binding site interactions. The crystal structure reveals that the inhibitor binds to a hydrophobic pocket in the active site of FabK, and this is accompanied by induced-fit movements of two loop regions. The thiazole ring and part of the ureido moiety of the inhibitor are involved in a face-to-face pi-pi stacking interaction with the isoalloxazine ring of FMN. The side-chain conformation of the proposed catalytic residue, His144, changes upon complex formation. Lineweaver-Burk plots indicate that the inhibitor binds competitively with respect to NADH, and uncompetitively with respect to crotonoyl coenzyme A. We propose that the primary basis of the inhibitory activity is competition with NADH for binding to FabK, which is the first step of the two-step ping-pong catalytic mechanism.
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