Three-Dimensional Structure of Mitochondrial Aldehyde Dehydrogenase

Abstract

Aldehyde dehydrogenases (ALDH) comprise a diverse set of enzymes which catalyze the NAD(P)⁺ dependent oxidation of aldehydes. Crystal structures for representatives of three of the basic classes of ALDH isoenzymes now exist. The dimeric Class 3 structure being first presented at the 1996 meeting (Liu, et al. 1997a) and the tetrameric Class 1 and 2 structures are presented at this meeting. However, each of these structures represent enzymes which catalyze essentially identical chemical reactions. The basic mechanism involves the nucleophilic attack of an active site thiolate toward the aldehydic carbonyl carbon, resulting in a covalently bound thio-hemiacetal. Following hydride transfer to the coenzyme the thio-hemiacetal collapses to yield an acylated enzyme intermediate. For most of the ALDH family members, and especially for those enzymes whose 3-D structures are known, the acyl-enzyme intermediate is hydrolyzed by an activated water molecule to generate the corresponding acid product. However, several family members transfer the acyl-enzyme intermediate to another acceptor, such as to coenzyme-A in methyl-malonyl semialdehyde dehydrogenase. Thus, only the initial chemical event, namely the attack of the of the aldehyde by the active site cysteine residue, is a common reaction in all members of the aldehyde dehydrogenase gene family and that the subsequent deacylation reaction may utilize uniquely different catalytic residues. Therefore, lack of residue reaction in all members of the gene family may not necessarily eliminate that residue from catalytic involvement within certain subsets of enzymes that catalyze the same reaction chemistry.