Comparative studies of vertebrate aldehyde dehydrogenase 3: Sequences, structures, phylogeny and evolution. Evidence for a mammalian origin for the ALDH3A1 gene

Abstract

Mammalian ALDH3 genes (ALDH3A1, ALDH3A2, ALDH3B1 and ALDH3B2) encode enzymes of peroxidic and fatty aldehyde metabolism. ALDH3A1 also plays a major role in anterior eye tissue UV-filtration. BLAT and BLAST analyses were undertaken of several vertebrate genomes using rat, chicken and zebrafish ALDH3-like amino acid sequences. Predicted vertebrate ALDH3 sequences and structures were highly conserved, including residues involved in catalysis, coenzyme binding and enzyme structure as reported by Liu et al. [27] for rat ALDH3A1. Phylogeny studies of human, rat, opossum, platypus, chicken, xenopus and zebrafish ALDH3-like sequences supported three hypotheses: (1) the mammalian ALDH3A1 gene was generated by a tandem duplication event of an ancestral vertebrate ALDH3A2 gene; (2) multiple mammalian and chicken ALDH3B-like genes were generated by tandem duplication events within genomes of related species; and (3) vertebrate ALDH3A and ALDH3B genes were generated prior to the appearance of bony fish more than 500 million years ago.

Aldehyde dehydrogenase 3 converts farnesal into farnesoic acid in the corpora allata of mosquitoes

“…1 and Supplemental Table 2). Amino acid sequence alignments of A. aegypti , D. melanogaster and human ALDH3s revealed conserved residues involved in chain folding, formation of the active site funnel, substrate binding, cofactor binding, stabilization of the transition state during catalysis and aldehyde oxidation (Liu et al, 1997; Hempel and Wang, 1997; Lloyd et al, 2007; Holmes and Hempel, 2011) (Supplemental Fig. 2).…”

Detection of ALDH3B2 in Human Placenta

“…[16] and the following sequences: NCBI sequence NP_001128640.1 of ALDH3A1, NCBI sequence NP_000373.1 of ALDH3A2, NCBI sequence NP_001154945.1 of ALDH3B1 and long ALDH3B2 isoform sequence, the product of translation of mRNA transcript number U37519.1 from NCBI obtained using ExPASy server [14], with alanine in the position encoded by premature stop codon. Orange indicates residues involved in substrate binding, red residues involved in cofactor binding, blue three proline residues contributing to the tertiary structure, violet residue 236, gray shading residues highly conserved: Cys-244 acting as a nucleophile; Glu-334 activating thiol group of Cys-244; Gly-241 positioning Cys-244; Glu-210 activating water molecule that hydrolyzes ester group, residues responsible for cofactor binding: Gly-188 and Gly-193 forming Rossmann fold; Lys-138, Glu-334, and Phe-336 responsible for nicotinamide ring positioning and hydrogen bond formation to the NAD(P) + adenine ribose; Ile-335 and Lys-214 ensuring appropriate geometry of cofactor binding domain; Asn-115 crucial for catalytic activity, transiently stabilizing oxygen of carboxyl group of tetrahedral intermediate; Asp-248 conserved in ALDHs belonging to the third subfamily, responsible for appropriate geometry of active site; Arg-26, Gly-106, Pro-117, Gly-132, Pro-338, Gly-384, Asn-389, and Gly-404 [1,17]. ALDH3B1 MDPLGDTLRRLREAFHAGRTRPAEFRAAQLQGLGRFLQENKQLLHDALAQDLHKSAFESE 60 ALDH3B2 MDPFEDTLRRLREAFNAGRTRPAEFRAAQLQGLGHFLQENKQLLRDVLAQDLHKPAFEAD 60 ALDH3A1 MSKISEAVKRARAAFSSGRTRPLQFRIQQLEALQRLIQEQEQELVGALAADLHKNEWNAY 60 ALDH3A2 ---MELEVRRVRQAFLSGRSRPLRFRLQQLEALRRMVQEREKDILTAIAADLCKSEFNVY 57 ALDH3B1 VSEVAISQGEVTLALRNLRAWMKDERVPKNLATQLDSAFIRKEPFGLVLIIAPWNYPLNL 120 ALDH3B2 ISELILCQNEVDYALKNLQAWMKDEPRSTNLFMKLDSVFIWKEPFGLVLIIAPWNYPLNL 120 ALDH3A1 YEEVVYVLEEIEYMIQKLPEWAADEPVEKTPQTQQDELYIHSEPLGVVLVIGTWNYPFNL 120 ALDH3A2 SQEVITVLGEIDFMLENLPEWVTAKPVKKNVLTMLDEAYIQPQPLGVVLIIGAWNYPFVL 117 : ..…”

“…However, attention should be paid to the residue 236, whose function was elucidated in the context of Sjögren-Larsson syndrome. In the case of ALDH3A2, Lys-236 is known to protonate the transient oxyanion formed during the catalysis [1]. Replacing it with cysteine present in this position in ALDH3B2 may affect enzyme activity.…”

“…Similar structures were observed including the three major domains: the catalytic domain, the NAD binding domain and an oligomerization domain, involved in the dimer formation ( Figure 10). The two first mentioned domains are separated by the active site cleft [1]. The quaternary structure shows the homo-dimer.…”

“…ALDH3B2 gene, also known as ALDH8, belongs to the aldehyde dehydrogenase (ALDH) gene superfamily [1]. This superfamily consists of 19 putatively functional genes [2] that encode enzymes catalyzing the NAD(P)+ -dependent irreversible oxidation of aldehydes to the corresponding carboxylic acids.…”