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Alda-1 Modulates the Kinetic Properties of Mitochondrial Aldehyde Dehydrogenase (ALDH2)

Alda-1 Modulates the Kinetic Properties of Mitochondrial Aldehyde Dehydrogenase (ALDH2)

Javier A Belmont-Díaz, Belem Yoval-Sánchez, Luis F Calleja-Castañeda, Juan P Pardo Vázquez, José S Rodríguez-Zavala

FEBS J. 2016 Oct;283(19):3637-3650.

PMID: 27521998

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 Km for NAD+ decreased by 2.4-fold, and the catalytic efficiency increased 4.4-fold; however, the Km 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 pKa 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP349438386	Alda-1		349438-38-6	Price

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