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• W3020223820 abstract "Fatty acids are abundant nutrients in the gut, and this work identified the biochemical pathway for fatty acid utilization in the prominent anaerobic, Gram-negative inhabitants of the gut microbiome, the phylum Bacteroidetes. Alistipes finegoldii is a representative Bacteroidetes resident of the human gut. This organism has not been well studied until recently developed culture conditions enabled growth of the organism in the laboratory setting. This study identifies two unique aspects of lipid metabolism in A. finegoldii. The glycerolipid phosphatidylethanolamine (PE) synthesis is initiated by the PlsX/PlsY/PlsC pathway, whereas the sphingolipid sulfonolipid (SL) pathway is predicted to be related to sphingolipid biosynthesis. Neither phosphatidylglycerol nor cardiolipin were present. A. finegoldii incorporates medium-chain fatty acids (£ 14 carbons) into PE or the SL after their elongation, whereas long-chain fatty acids (³ 16 carbons) are not elongated. Acyl-ACP >16 carbons were only incorporated into the 2-position due to the selectivity of PlsC, the only biosynthetic enzyme that efficiently utilizes long-chain unsaturated acyl-ACP. This ability to assimilate a broad-spectrum of fatty acid chain lengths is due to the expression of two acyl-acyl carrier protein (ACP) synthetases. Biochemical characterization of these enzymes showed that acyl-ACP synthetase 1 had a substrate preference for medium-chain fatty acids and synthetase 2 had a substrate preference for long-chain fatty acids. This unique combination of synthetases allows A. finegoldii to efficiently utilize both medium-and long-chain fatty acid nutrients available in the gut environment to assemble its membrane lipids. Bioinformatics analysis of A. finegoldii suggests the genes involved in the central fatty acid elongation cycle are present. Enoyl-acyl carrier protein reductase (FabI) catalyzes a FASII rate-controlling step. We studied A. finegoldii FabI (AfFabI) because phylogenetic analysis places enzymes from phylum Bacteroidetes in a distinct, uncharacterized 4th FabI clade. AfFabI displays typical FabI cooperative kinetics and uses NADH as a substrate, and has the prototypical α-helix β-sheet dimerization and antiparallel four-helical bundle tetramerization domains that link adjoining protomers that characterize FabI enzymes. The distinct features of AfFabI are a coiled coil domain that links the carboxy termini of adjacent protomers of the homotetramer. The AfFabI•NADH crystal structure shows each coiled coil undergoes a conformational change to form part of the NADH binding site of the adjacent protomer. Residues throughout the coiled coil contact the base of the adjacent protomer’s “flipping loop” to stabilize the open substrate-free and closed NADH-bound conformations. Deletion of the coiled coil causes a 20-fold NADH Km defect, showing the coiled coils are required for high affinity NADH binding. 4th clade enzymes are distinguished by a unique coiled coil domain involved in cooperative NADH binding and a unique active site that explains why FabI compounds in the clinic don’t affect the gut microbiome. Support or Funding Information NIH grant GM34496, American Lebanese Syrian Associated Charities Figure 1Open in figure viewerPowerPoint Phylogenetic analysis places enzymes from phylum Bacteroidetes in a distinct, uncharacterized 4th FabI clade" @default.
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• W3020223820 date "2020-04-01" @default.
• W3020223820 modified "2023-09-25" @default.
• W3020223820 title "Unique Aspects of Lipid Metabolism in the Human Gut Microbiome" @default.
• W3020223820 doi "https://doi.org/10.1096/fasebj.2020.34.s1.03425" @default.
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