Differences in Susceptibility to Inactivation of Human Aldehyde Dehydrogenases by Lipid Peroxidation Byproducts

Abstract

Aldehyde dehydrogenases (ALDHs) are involved in the detoxification of aldehydes generated as byproducts of lipid peroxidation. In this work, it was determined that, among the three most studied human ALDH isoforms, ALDH2 showed the highest catalytic efficiency for oxidation of acrolein, 4-hydroxy-2-nonenal (4-HNE), and malondialdehyde. ALDH1A1 also exhibited significant activity with these substrates, whereas ALDH3A1 only showed activity with 4-HNE. ALDH2 was also the most sensitive isoform to irreversible inactivation by these compounds. Remarkably, ALDH3A1 was insensitive to these aldehydes even at concentrations as high as 20 mM. Formation of adducts of ALDH1A1 and ALDH2 with acrolein increased their K(d) values for NAD(+) by 2- and 3-fold, respectively. NADH exerted a higher protection than propionaldehyde to the inactivation by acrolein, and this protection was additive. These results suggested that both binding sites, those for aldehyde and NAD(+) in ALDH2, are targets for the inactivation by lipid peroxidation products. Thus, with the advantage of being relatively inactivation-insensitive, ALDH1A1 and ALDH3A1 may be actively participating in the detoxification of these aldehydes in the cells.

Emerging Associations of the ALDH2*2 Polymorphism with Disease Susceptibility

“…Due to damage to the cardiac myocytes, excessive production of 4-HNE may ultimately impair cardiac contractility. ALDH2 has been shown to oxidize 4-HNE to a less reactive product and is hypothesized to be a protective factor [72]. Conversely, the ALDH2*2 genotype is thought to be associated with increased apoptosis and myocardial damage during ischemia [1,73].…”

ALDH2*2 Allele is a Negative Risk Factor for Cerebral Infarction in Chinese Women

“…Recent studies have indicated that ALDH2 is able to metabolize numerous other short-chain aliphatic aldehydes, as well as some aromatic and polycyclic aldehydes (Klyosov 1996). Other reactive aldehydes including 4-hydroxy-2-nonenal(4-HNE), malondialdehyde(MDA), and environmental aldehydes from lipid peroxidation under oxidative stress can also be metabolized by ALDH2 (Chen et al 2010;Yoval-Sanchez and Rodriguez-Zavala 2012). Therefore, ALDH2 plays an important role in preventing numerous pathologies, due to its detoxification effect of the above substrates.…”

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].…”