Enantioselective Oxidation oftrans-4-Hydroxy-2-Nonenal Is Aldehyde Dehydrogenase Isozyme and Mg²⁺Dependent

Abstract

trans-4-Hydroxy-2-nonenal (HNE) is a cytotoxic alpha,beta-unsaturated aldehyde implicated in the pathology of multiple diseases involving oxidative damage. Oxidation of HNE by aldehyde dehydrogenases (ALDHs) to trans-4-hydroxy-2-nonenoic acid (HNEA) is a major route of metabolism in many organisms. HNE exists as two enantiomers, (R)-HNE and (S)-HNE, and in intact rat brain mitochondria, (R)-HNE is enantioselectively oxidized to HNEA. In this work, we further elucidated the basis of the enantioselective oxidation of HNE by brain mitochondria. Our results showed that (R)-HNE is oxidized enantioselectively by brain mitochondrial lysates with retention of stereoconfiguration of the C4 hydroxyl group. Purified rat ALDH5A enantioselectively oxidized (R)-HNE, whereas rat ALDH2 was not enantioselective. Kinetic data using (R)-HNE, (S)-HNE, and trans-2-nonenal in combination with computer-based modeling of ALDH5A suggest that the selectivity of (R)-HNE oxidation by ALDH5A is the result of the carbonyl carbon of (R)-HNE forming a more favorable Bürgi-Duntiz angle with the active site cysteine 293. The presence of Mg2+ ions altered the enantioselectivity of ALDH5A and ALDH2. Mg2+ ions suppressed (R)-HNE oxidation by ALDH5A to a greater extent than that of (S)-HNE. However, Mg2+ ions stimulated the enantioselective oxidation of (R)-HNE by ALDH2 while suppressing (S)-HNE oxidation. These results demonstrate that enantioselective utilization of substrates, including HNE, by ALDHs is dependent upon the ALDH isozyme and the presence of Mg 2+ ions.

Involvement of snapdragon benzaldehyde dehydrogenase in benzoic acid biosynthesis

“…The 3D BALDH model and substrate-docking modeling of the BALDH active site with benzaldehyde and phenylacetaldehyde were obtained based on the crystal structure of the human mitochondrial ALDH2 (Protein Data Bank code 1CW3B) as described previously (Brichac et al, 2007).…”

Role of ADH2 and ALDH2 gene polymorphisms in the development of Parkinson's disease in a Chinese population

“…In addition, ALDH2 also contributes to detoxification of the dopamine metabolite 3,4-dihydroxyphenylacetaldehyde. It has been shown that during this detoxification process, the enzyme encoded by this gene can catalyze the transformation of toxic acetaldehyde products to acetic acid (Meyer et al, 2004;Brichac et al, 2007;Leiphon and Picklo, 2007). Meyer et al (2004) and Vermeer et al (2012) reported that trans-4-hydroxy-2-nonenal and 3,4-dihydroxyphenylacetaldehyde are associated with disease of the central nervous system.…”

Roles of defective ALDH2 polymorphism on liver protection and cancer development

“…acetaldehyde to acetic acid. The major lipid peroxidation products 4-hydroxy-2-nonenal (4HNE) and malondialdehyde (MDA) are also detoxified by ALDH2 [23,24]. ALDH2 has the highest affinity for acetaldehyde, an important intermediary product of ethanol metabolism.…”

“…This is because individuals lacking ALDH2 will likely be exposed to higher levels of endogenous aldehydes from birth, such as 4HNE and MDA [23,24], thereby requiring an alternate defence system. In fact, Aldh2 knockout mice had higher levels of heme oxidase 1, an essential defensive factor against cellular oxidative stress, without any pre-treatment [54].…”