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Studies of structure and function of aldehyde dehydrogenases involved in cellular signaling pathways and detoxification

Grant number: 13/12008-6
Support type:Scholarships in Brazil - Doctorate (Direct)
Effective date (Start): November 01, 2013
Effective date (End): October 31, 2017
Field of knowledge:Biological Sciences - Biology
Principal Investigator:José Xavier Neto
Grantee:Fábio Neves do Amaral
Home Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia, Inovações e Comunicações (Brasil). Campinas , SP, Brazil

Abstract

This project represents an extension of the paradigms that we created from our molecular simulation studies to understand the frequent structure and function changes of Aldehyde Dehydrogenases (ALDH) during evolution. The ALDHs form a superfamily of proteins that catalyze the oxidation of several aldehydes, but the evolutionary origins of their substrate preference are unknown. Despite having a high sequence identity, two of these ALDHs, the ADLH1 and ALDH2, exhibit distinct functional roles of cellular signaling and detoxification, respectively. Through previous computational and phylogenetic analysis, we found that, interestingly, the ALDH1s of invertebrate organisms (Branchiostoma floridae and Ciona intestinalis) show structural features more similar to their ALDH2s than the typical ALDH1. It suggests that these divergent ALDH1s evolved to provide small aldehydes detoxification pattern, what seems to represent the ancestral eukaryotic ALDH2s function. Our analysis also identified three aminoacid signatures, located internally in the Substrate Entry Channel (SEC), that distinguishes the ALDH1 from ALDH2. Thus, we find that ALDH1s have a wide, open and unobstructed SEC, consistent with the fact that these enzymes catalyze bulky long chain aldehydes, like retinaldehyde, a precursor of important signaling pathways. In contrast, the ALDH2s have a small and constricted SEC, consistent with the degradation function of small aldehydes, like the toxic metabolite acetaldehyde. In this project our objective is to understand the functional and structural correlation between ALDH1 and ALDH2 found in B. floridae and C. intestinalis to discover and comprehend their functional and evolutionary roles in chordates. Specifically, we will test the hypothesis that the three signatures described above are the fundamental core of the substrate preference, based on the signature origin. If confirmed experimentally, this will be a pioneer example of evolutionary molecular reversion, impacting directly in the current interpretations of the controversial Dollo's Law of Irreversibility. (AU)

Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
XAVIER-NETO, JOSE; SOUSA COSTA, ANGELA M.; FIGUEIRA, ANA CAROLINA M.; CAIAFFA, CARLO DONATO; DO AMARAL, FABIO NEVES; CERQUEIRA PERES, LARA MALDANIS; PIRES DA SILVA, BARBARA SANTOS; SANTOS, LUANA NUNES; MOISE, ALEXANDER R.; CASTILO, HOZANA ANDRADE. Signaling through retinoic acid receptors in cardiac development: Doing the right things at the right times. BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS, v. 1849, n. 2, SI, p. 94-111, FEB 2015. Web of Science Citations: 22.

Please report errors in scientific publications list by writing to: cdi@fapesp.br.