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Structural characterization of Porphyromonas gingivalis enoyl-ACP reductase II (FabK)

journal contribution
posted on 06.05.2022, 16:35 by Kirk E Hevener, Bernard D Santarsiero, Hyun LeeHyun Lee, Jesse A Jones, Teuta Boci, Michael JohnsonMichael Johnson, Shahila Mehboob
Enoyl-acyl carrier protein (ACP) reductase II (FabK) is a critical rate-limiting enzyme in the bacterial type II fatty-acid synthesis (FAS II) pathway. FAS II pathway enzymes are markedly disparate from their mammalian analogs in the FAS I pathway in both structure and mechanism. Enzymes involved in bacterial fatty-acid synthesis represent viable drug targets for Gram-negative pathogens, and historical precedent exists for targeting them in the treatment of diseases of the oral cavity. The Gram-negative organism Porphyromonas gingivalis represents a key causative agent of the costly and highly prevalent disease known as chronic periodontitis, and exclusively expresses FabK as its enoyl reductase enzyme in the FAS-II pathway. Together, these characteristics distinguish P. gingivalis FabK (PgFabK) as an attractive and novel narrow-spectrum antibacterial target candidate. PgFabK is a flavoenzyme that is dependent on FMN and NADPH as cofactors for the enzymatic reaction, which reduces the enoyl substrate via a ping-pong mechanism. Here, the structure of the PgFabK enzyme as determined using X-ray crystallography is reported to 1.9 Å resolution with endogenous FMN fully resolved and the NADPH cofactor partially resolved. PgFabK possesses a TIM-barrel motif, and all flexible loops are visible. The determined structure has allowed insight into the structural basis for the NADPH dependence observed in PgFabK and the role of a monovalent cation that has been observed in previous studies to be stringently required for FabK activity. The PgFabK structure and the insights gleaned from its analysis will facilitate structure-based drug-discovery efforts towards the prevention and treatment of P. gingivalis infection.

Funding

Multidisciplinary Oral Sciences Training Program | Funder: National Institutes of Health (National Institute of Dental and Craniofacial Research) | Grant ID: T32DE018381

History

Citation

Hevener, K. E., Santarsiero, B. D., Lee, H., Jones, J. A., Boci, T., Johnson, M. E.Mehboob, S. (2018). Structural characterization of Porphyromonas gingivalis enoyl-ACP reductase II (FabK). Acta Crystallographica Section F: Structural Biology Communications, 74(2), 105-112. https://doi.org/10.1107/s2053230x18000262

Publisher

International Union of Crystallography (IUCr)

Language

en

issn

2053-230X