title: Structural shifts of aldehyde dehydrogenase enzymes were instrumental for the early evolution of retinoid-dependent axial patterning in metazoans.
abstract: Aldehyde dehydrogenases (ALDHs) catabolize toxic aldehydes and process the vitamin A-derived retinaldehyde into retinoic acid (RA), a small diffusible molecule and a pivotal chordate morphogen. In this study, we combine phylogenetic, structural, genomic, and developmental gene expression analyses to examine the evolutionary origins of ALDH substrate preference. Structural modeling reveals that processing of small aldehydes, such as acetaldehyde, by ALDH2, versus large aldehydes, including retinaldehyde, by ALDH1A is associated with small versus large substrate entry channels (SECs), respectively. Moreover, we show that metazoan ALDH1s and ALDH2s are members of a single ALDH1/2 clade and that during evolution, eukaryote ALDH1/2s often switched between large and small SECs after gene duplication, transforming constricted channels into wide opened ones and vice versa. Ancestral sequence reconstructions suggest that during the evolutionary emergence of RA signaling, the ancestral, narrow-channeled metazoan ALDH1/2 gave rise to large ALDH1 channels capable of accommodating bulky aldehydes, such as retinaldehyde, supporting the view that retinoid-dependent signaling arose from ancestral cellular detoxification mechanisms. Our analyses also indicate that, on a more restricted evolutionary scale, ALDH1 duplicates from invertebrate chordates (amphioxus and ascidian tunicates) underwent switches to smaller and narrower SECs. When combined with alterations in gene expression, these switches led to neofunctionalization from ALDH1-like roles in embryonic patterning to systemic, ALDH2-like roles, suggesting functional shifts from signaling to detoxification.
authors.affiliation: Laboratório de Genética e Cardiologia Molecular, Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, 05403-000, São Paulo-SP, Brazil.
authors.forename: Tiago J P
authors.initials: TJ
authors.lastname: Sobreira
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Marlétaz
authors.forename: Marcos
authors.initials: M
authors.lastname: Simões-Costa
authors.forename: Deborah
authors.initials: D
authors.lastname: Schechtman
authors.forename: Alexandre C
authors.initials: AC
authors.lastname: Pereira
authors.forename: Frédéric
authors.initials: F
authors.lastname: Brunet
authors.forename: Sarah
authors.initials: S
authors.lastname: Sweeney
authors.forename: Ariel
authors.initials: A
authors.lastname: Pani
authors.forename: Jochanan
authors.initials: J
authors.lastname: Aronowicz
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lowe
authors.forename: Bradley
authors.initials: B
authors.lastname: Davidson
authors.forename: Vincent
authors.initials: V
authors.lastname: Laudet
authors.forename: Marianne
authors.initials: M
authors.lastname: Bronner
authors.forename: Paulo S L
authors.initials: PS
authors.lastname: de Oliveira
authors.forename: Michael
authors.initials: M
authors.lastname: Schubert
authors.forename: José
authors.initials: J
authors.lastname: Xavier-Neto
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D001499:Bayes Theorem; D019521:Body Patterning / Q000502:physiology*; D016000:Cluster Analysis; D019295:Computational Biology; D019143:Evolution, Molecular; D020869:Gene Expression Profiling; D020131:Genes, Duplicate / Q000235:genetics; D017403:In Situ Hybridization; D016013:Likelihood Functions; D008957:Models, Genetic; D008958:Models, Molecular; D010802:Phylogeny; D011487:Protein Conformation; D016415:Sequence Alignment; D015398:Signal Transduction / Q000235:genetics*; D013045:Species Specificity; D014212:Tretinoin / Q000378:metabolism*
chemical_list: D014212:Tretinoin; D000444:Aldehyde Dehydrogenase