Mitochondrial aldehyde dehydrogenase 1B1 enzyme variants and their clinical implications

Abstract

Aldehydes are highly reactive molecules in biological systems, where they bind to biomolecules such as DNA and proteins, resulting in functional jeopardy. Aldehydic attack may have an exogenous source, when directly absorbed from the environment, or be generated endogenously, after ethanol metabolism (generating acetaldehyde) or during mitochondrial lipid peroxidation (forming 4-hydroxynonenal). The main biological defense line against the attack from these molecules relies on the oxidation of aldehydes to carboxylic acids, catalyzed by enzymes from the Aldehyde Dehydrogenase superfamily (ALDH). Among the 17 proteins belonging to this group, two of them reside in the mitochondrial compartment, namely ALDH2 and ALDH1B1. The first, principal enzyme on acetaldehyde metabolism, harbors an inactive mutation with high prevalence in the east Asian population, responsible for aggressive adverse reactions after alcohol consumption and to a higher susceptibility to cardiovascular diseases (due to mitochondrial metabolism impairment). The second is still target of an incipient research. Its levels were reported elevated on some types of tumors. Besides, the gene of ALDH1B1 is characterized by the presence of several variants with high ethnic-specific frequencies, suggesting likely adaptations on genotype-environment relations. However, little is known about the impact of these mutations on ALDH1B1's biochemical features, and its physiological roles. One of these variants (R107L) was recently linked to a higher chance of suffering a heart attack among Chinese hypertense patients, likewise the mutation E504K on the ALDH2 gene. Our preliminary data (in collaboration with Prof. Daria Mochly-Rosen's lab, from Stanford University) suggests an association between the variant ALDH1B1 R107L and alcohol aversion, in a healthy Mexican population. Considering 1) the elevated populational frequency of some ALDH1B1 variants; 2) their association with deleterious phenotypes such as cardiovascular diseases and alcohol intolerance; and 3) the lack of information on scientific literature, we decided to investigate the biochemical, cellular and physiological context of these ALDH1B1 variants, as well as to characterize their frequency on a Brazilian population, both healthy and mouth Cancer patients (disease modulated by both alcohol consumption and aldehydic imbalance). For such, we will study the seven globally more frequent ALDH1B1 variants (R107L, A86V, V253FS, V176I, G193FS, G388FS and V470A). Our bioinformatic preliminary results suggest that some of these variants negatively affect the enzyme's stability and function. From there, we'll perform a functional and physiological characterization of these variants in three distinct levels of biological complexity: isolated recombinant protein, cell culture and transgenic mice under basal and stress conditions. Moreover, we'll analyze each variant's frequency in 240 healthy Brazilians and in 60 mouth Cancer patients, in collaboration with ICESP. This work will be of great value for planning and developing future clinical and pre-clinical studies focusing on aldehyde metabolizing enzymes as markers or targets for personalized treatment against infirmities such as Cancer or cardiovascular diseases (characterized by a high aldehydic load). It is worth mentioning that this proposal is linked to Redoxoma project, a Research, Innovation and Diffusion Center supported by FAPESP. This project will count on the collaboration of professors Che-Hong Chen, Ph.D., Daria Mochly-Rosen, Ph.D., from Stanford university, Professor Marisa Gennari de Medeiros, Ph.D., from IQ-USP, and Professor Gilberto de Castro, Ph.D., from ICESP-FMUSP. (AU)