Evolution of ACDs

Evolutionary studies of the ACDs have been extremely helpful over the years in identifying new enzymes in this gene family and understanding their function. The gene family in humans now contains 11 members, however, the substrate specificities of two remain undetermined and the physiologic functions of at least four are unclear.

We have combined bioinformatic and phylogenetic approaches to investigate the evolutionary history of the ACDs with particular focus on prediction of substrate specificity for the human ACD10 and ACD11. Using BlastP (Altschul et al. 1990) we searched the non-redundant protein database of the National Center for Biotechnology Information (NCBI), the Institute for genomic Research (TIGR) and the UniProt/SwissProt protein databases for homologs of all 11 human ACADs (accession numbers: GCD [Q92947], IVD [AAA52711], SBCAD [NP_001600], MCAD [P11310], SCAD [AAH25963], ACDL [P28330], VLCAD [P49748], IBD [Q9UKU7], ACAD9 [Q9H845], ACAD10 [NP_079523], ACAD11 [AAH19607]). Homologs of human acyl-CoA oxidases (ACOX1 [Q15067], ACOX3 [NP_003492], ACOX2 [NP_003491]) were used as outgroup taxa.

To trace the evolution of the entire ACAD family we have searched for protein homologs from fully sequenced genomes of three archeal taxa (Archaeoglobus fulgidus, Halobacterium sp., and Thermoplasma acidophilum), four bacterial taxa (Bacillus cereus, Geobacillus kaustophilus, Clostridium tetani, Geobacter metallireducens), three fungal taxa (Cryptococcus neoformans, Aspergilus fumigatus, Yarrowia lipolytica), two plant taxa (Arabidopsis thaliana, Oryza sativa), two basal eukaryotic genomes (Trypanosoma cruzi, Dictyostelium discoideum), and other eukaryotic taxa (Caenorhabditis elegans, Drosophila melanogaster, Tetraodon nigroviridis, Danio rerio, Gallus galus, Mus musculus and Rattus novergicus). More species from each life domain were included in refined analyses of major clades.

The origin of the ACD family can be traced back more than 2 billion years to the origin of the Archaea, Bacteria and Eukaryota. At least two primordial ACDs were already present at this time, one of which was the ancestor of glutaryl-CoA dehydrogenase (GCD). The emergence of the ACD family is marked by several rounds of gene duplication at or early after the divergence of the three domains of life. The rise of the archaea domain is marked by gene duplication producing ACDs specific to the archaea lineage, followed by consecutive rounds of gene amplifications specific to extant archaea taxa. This pattern is not surprising due to the fact that there are significant differences in the membrane lipid composition of Archaea and of Bacteria/Eukaryota. Unlike Eukaryota and Bacteria that have ester-linked fatty acids in lipids, Archaea have ether-linked lipids with C20-C40 isoprenoid (multiply-branched) chains. Nevertheless, the long branched isoprenoid hydrocarbon fatty acids are not exclusive to Archaea but are also found in Bacteria and prominently in basal Metazoa, specifically in the Porifera.

Our phylogenetic analyses indicate that Bacteria and Eukaryota emerged already equipped with six to eight ACD homologs, and subsequently few lineage-specific duplications occurred. However, about 400-600 million years ago two additional duplications occurred in parallel before speciation of higher eukaryotes, particularly Coelomata, that gave rise to ACAD10/ACAD11 and ACAD9/VLCAD. The most parsimonious scenario suggests that the most ancestral ACD had branched-chain specificity and that ACDs with straight-chain specificity derived later at the root of Bacteria and Eukaryota. Previous functional studies have revealed that ACDs active against branched-chain such as IVD, SBCAD, and IBD always exhibit significant activity with straight substrates, while ACDs primarily active against straight-chain substrates usually have limited activity with branched-chain substrates. Together these observations imply that the ancestral ACDs were functional generalists that evolved towards specialization.

Interestingly, our analyses reveal that LCAD has retained the most general substrate specificity compared to its ACD ancestor through evolution, allowing it to develop different substrate utilization patterns in different organisms.

Principal Investigator
Gerard Vockley, MD, PhD

Last Update
August 13, 2010
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Last Update
August 13, 2010