| The aldehyde dehydrogenase (ALDH) superfamily is a group of enzymes that catalyze the NAD(P)+-dependent oxidation of a wide variety of endogenous and exogenous aldehydes to their corresponding carboxylic acids. This family is present in all taxonomic lineages studied, including archaea, bacteria, and eukaryotes. As a torrent of new genomic data has become available over the past decade, there is now a need to organize and examine the evolution of this critical superfamily. To create a reference of the distribution and number of ALDHs in vertebrates, 11 representative species with completed genomes were examined and the full number of ALDHs was manually studied (Chapter 2). One recently investigated gene, ALDH1B1 appeared to have a limited distribution and high similarity to ALDH2. This gene has received increased attention recently as a mediator of alcohol metabolism, growth and development, and as a biomarker and possibly key mediator of colon cancer. The complete known distribution of ALDH1B1 was investigated, as well as its evolutionary origins as a retrotransposition of ALDH2. In addition, it was shown that although ALDH1B1 has a unique pattern of expression and substrate specificity from ALDH2, they retain enough similarity that heterotetramerization (and possibly cross-regulation) may be feasible (Chapter 3). From determining the distribution of ALDH1B1 and ALDH16A1 across phylogenies, in both cases frogs appeared to have unusual patterns of ALDH distributions. Since there was no frog representative in previous work, the full number of frog ALDHs was determined and full gene trees were created to examine the phylogenetic distribution of frog ALDHs. This also allowed deeper examination of the distribution and evolution of ALDHs. From this analysis it was determined rather than frogs being unusual, ALDH1B1 likely arose in the early vertebrate lineage and was subsequently lost in species other than frogs and mammals, and that a unique non-catalytic version of ALDH16A1 likely arose in fish, and was transferred to an early amniote ancestor (Chapter 4). This and other examples of evolution of 'dead-enzymes' within enzyme families led to the search for additional examples of non-catalytic ALDHs. 182 examples were found across all three kingdoms, which were divided into 19 groups based on protein sequence, with a large number of newly discovered records coming from bacteria and fungi (Chapter 4). Finally, the substrate specificity and effect of human polymorphisms of ALDH1B1 were investigated in depth, and it was found that ALDH1B1 likely plays a role in growth and development via retinaldehyde metabolism, and that this function may be disrupted by mutations prevalent in human populations, especially via the ALDH1B1*2 (A86V) mutation (Chapter 5). This work together enhances our understanding of the distribution and evolutionary origins of the ALDH superfamily as a whole, and increases the understanding of the mechanisms of action of ALDH1B1 in particular. |
