Alda‐1 modulates the kinetic properties of mitochondrial aldehyde dehydrogenase (ALDH2)

Abstract

Mitochondrial aldehyde dehydrogenase (ALDH2) has been proposed as a key enzyme in cardioprotection during ischemia-reperfusion processes. This proposal led to the search for activators of ALDH2 with the aim to develop cardioprotective drugs. Alda-1 was the first activator of ALDH2 identified and its cardioprotective effect has been extensively proven in vivo; however, the mechanism of activation is not fully understood. A crystallographic study showed that Alda-1 binds to the entrance of the aldehyde-binding site; therefore, Alda-1 should in essence be an inhibitor. In the present study, kinetic experiments were performed to characterize the effect of Alda-1 on the properties of ALDH2 (kinetic parameters, determination of the rate-limiting step, reactivity of the catalytic cysteine) and on the kinetic mechanism (type of kinetics, sequence of substrates entering, and products release). The results showed that Alda-1 dramatically modifies the properties of ALDH2, the K for NAD decreased by 2.4-fold, and the catalytic efficiency increased 4.4-fold; however, the K for the aldehyde increased 8.6-fold, thus, diminishing the catalytic efficiency. The alterations in these parameters resulted in a complex behavior, where Alda-1 acts as inhibitor at low concentrations of aldehyde and as an activator at high concentrations. Additionally, the binding of Alda-1 to ALDH2 made the deacylation less limiting and diminished the pK of the catalytic cysteine. Finally, NADH inhibition patterns indicated that Alda-1 induced a change in the sequence of substrates entry and products release, in agreement with the proposal of both substrates entering ALDH2 by the NAD entrance site.

Alpha-lipoic acid protects against pressure overload-induced heart failure via ALDH2-dependent Nrf1-FUNDC1 signaling

“…The indispensable role of ALDH2 in the pathogenesis of heart failure reveals that targeting ALDH2 might be a potential therapeutic option for heart failure and other cardiovascular diseases. Although many studies are performed to explore the efficacy of drugs capable of activating ALDH2, such as Alda-1, clinical promotion is limited due to cytotoxicity or other reasons of applied drugs 9 .…”

Alda-1 Ameliorates Liver Ischemia-Reperfusion Injury by Activating Aldehyde Dehydrogenase 2 and Enhancing Autophagy in Mice

“…Previous studies have indicated that ALDH2 activity is significantly decreased parallel with the remarkable accumulation of reactive aldehydes during liver IRI [15], suggesting that ALDH2 activation may play a protective role in liver IRI through cleaning up toxic aldehydes. Alda-1, a well-characterized ALDH2 activator, serves to activate or restore ALDH2 catalytic activity by modifying the kinetic properties of ALDH2 and increasing the substrate-enzyme interaction [16–18]. Previous studies have demonstrated that Alda-1 treatment significantly improves IRI in various types of organs including the heart, brain, lung, kidney, and intestine [16, 19–22].…”

Mitochondrial aldehyde dehydrogenase-2 deficiency compromises therapeutic effect of ALDH bright cell on peripheral ischemia

“…However, the improved NAD binding for Alda-1 stimulation was needed to establish ALDH2 activity, the functions of ALDH2 exhibited reductase, dehydrogenase and esterase activities, not all of the activities could be activated by Alda-1 [55]. Despite the presence of Alda-1, the catalytic process upon activation took place under saturated conditions [52], the rate of catalysis of ALDH2 was decreased at the low concentrations of aldehyde, the beneficial effects of Alda-1 were only observed under high oxidative stress conditions [56]. In summary, although the beneficial effects of Alda-1 have been elaborated in various disease models, the function of ALDH2 could not be completely restored.…”