4IQL

Crystal Structure of Porphyromonas gingivalis Enoyl-ACP Reductase II (FabK) with cofactors NADPH and FMN

Summary for 4IQL

• Entry DOI: 10.2210/pdb4iql/pdb
• Descriptor: Enoyl-(Acyl-carrier-protein) reductase II, FLAVIN MONONUCLEOTIDE, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (6 entities in total)
• Functional Keywords: tim barrel, oxidoreductase, fatty acid binding, reduction
• Biological source: Porphyromonas gingivalis
• Total number of polymer chains: 2
• Total formula weight: 74754.92

Authors

Hevener, K.E.,Santarsiero, B.D.,Su, P.-C.,Boci, T.,Truong, K.,Johnson, M.E.,Mehboob, S. (deposition date: 2013-01-11, release date: 2014-01-29, Last modification date: 2024-11-06)

Primary citation

Hevener, K.E.,Santarsiero, B.D.,Lee, H.,Jones, J.A.,Boci, T.,Johnson, M.E.,Mehboob, S.
Structural characterization of Porphyromonas gingivalis enoyl-ACP reductase II (FabK).
Acta Crystallogr F Struct Biol Commun, 74:105-112, 2018

PubMed Abstract: 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.

PubMed: 29400320
DOI: 10.1107/S2053230X18000262

Experimental method

X-RAY DIFFRACTION (1.938 Å)