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The Molecular Basis of Catalysis by SDR Family Members Ketoacyl‐ACP Reductase FabG and Enoyl‐ACP Reductase FabI in Type‐II Fatty Acid Biosynthesis
Ist Teil von
Angewandte Chemie (International ed.), 2023-11, Vol.62 (46), p.e202313109-n/a
Auflage
International ed. in English
Ort / Verlag
Weinheim: Wiley Subscription Services, Inc
Erscheinungsjahr
2023
Link zum Volltext
Quelle
Alma/SFX Local Collection
Beschreibungen/Notizen
The short‐chain dehydrogenase/reductase (SDR) superfamily members acyl‐ACP reductases FabG and FabI are indispensable core enzymatic modules and catalytic orientation controllers in type‐II fatty acid biosynthesis. Herein, we report their distinct substrate allosteric recognition and enantioselective reduction mechanisms. FabG achieves allosteric regulation of ACP and NADPH through ACP binding across two adjacent FabG monomers, while FabI follows an irreversible compulsory order of substrate binding in that NADH binding must precede that of ACP on a discrete FabI monomer. Moreover, FabG and FabI utilize a backdoor residue Phe187 or a “rheostat” α8 helix for acyl chain length selection, and their corresponding triad residues Ser142 or Tyr145 recognize the keto‐ or enoyl‐acyl substrates, respectively, facilitating initiation of nucleophilic attack by NAD(P)H. The other two triad residues (Tyr and Lys) mediate subsequent proton transfer and (R)‐3‐hydroxyacyl‐ or saturated acyl‐ACP production.
The distinct substrate allosteric recognition and reduction catalytic mechanisms of ketoacyl‐ACP reductase FabG and enoyl‐ACP reductase FabI in Type‐II fatty acid biosynthesis are reported. The enzymes use alternative catalytic tunnels and core catalytic triads to recognize different ACP, NAD(P)H and fatty acid substrates for asymmetric reduction catalysis.