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

Journal Article · Fri Jan 26 00:00:00 EST 2018 · Acta Crystallographica. Section F, Structural Biology Communications

DOI:https://doi.org/10.1107/S2053230X18000262· OSTI ID:1499726

Hevener, Kirk E. ; Santarsiero, Bernard D.; Lee, Hyun; Jones, Jesse A. ; Boci, Teuta; Johnson, Michael E.; Mehboob, Shahila

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. gingivalisFabK (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.

• Research Organization: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
• Sponsoring Organization: UNIVERSITYOTHER
• OSTI ID: 1499726
• Journal Information: Acta Crystallographica. Section F, Structural Biology Communications, Vol. 74, Issue 2; ISSN 2053-230X
• Publisher: International Union of Crystallography
• Country of Publication: United States
• Language: ENGLISH