   1.2.1.48 | a long-chain aldehyde + NAD+ + H2O = a long-chain carboxylate + NADH + H+ |
the human enzyme FALDH shows a unique reaction mechanism that differs from other ALDHs, modelling giving an alternative model for the reaction mechanism of FALDH, overview. The first step involves the activation of the catalytic Cys241 by deprotonation and subsequent substrate binding. Once Cys241 is deprotonated, it performs a nucleophilic attack on the carbonyl carbon of the fatty aldehyde, which forms a thiohemiacetal. Asn112 supports the orientation of the polar head group by coordinating to the substrate oxygen and subsequently stabilizes a tetrahedral reaction intermediate. In a second step, the collapse of the primarily formed oxyanion then initiates a hydride transfer to the NAD cofactor in a pro-R manner. Subsequently, a water molecule is deprotonated by Glu207 or Glu331 and triggers a nucleophilic attack of the hydroxide anion on the carbonyl carbon. In a final step, a repeated collapse of the oxyanion forms the fatty acid product and releases the covalent bond to Cys241, which remains activated or can be potentially reactivated |
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