Human ACD10 and 11

We originally identified the ACD portion of the human ACD10 and 11 genes through extended computer database searches. The coding region shared only 25 percent residues on average with the other ACDs but enough key motifs were present to make it of interest. These sequences were recently reported by another group as ACD10 and 11 without any functional studies. Of note, the residue in the position homologous to the catalytic base (a Glu in all other ACDs) is an Asp in ACD10 and 11. With additional analysis, it became obvious that the ACD portions of ACD10 and 11 were part of much more complex loci. Both contain an additional predicted aminoglycoside phosphotransferase (APH) domain at the N terminus along with a hydrolase whose functions in vivo are unknown.

Of note, while the ACD10 gene supports production of a transcript containing exclusively ACD sequences, at least six transcripts with differing domains were present in the EST databases and could be amplified from mRNA. ACD11 transcripts are similarly complex. Moreover, the ACD portions of these genes are expressed in a very different pattern from those ACDs involved primarily in energy metabolism. Both are found in high levels in neural tissue as well as a variety of other tissues important in physiologic barrier function. Thus we have postulated that ACD10 and 11 play a role in pathways other than energy metabolism.

When translated in vitro, the ACD-portion of ACD11 is imported efficiently into mitochondria and processed to a mature form. Our phylogenetic analysis suggests that long branched-chain fatty acids are the most likely substrates for ACD10. To examine this, ACD10 was expressed in E. coli and tested for activity with our usual panel of substrates. All were inactive. In contrast, activity was detected with 2-methyl-C15-CoA as substrate though the reaction was not robust, indicating that it was not the optimum substrate. Expression of the mature intra-mitochondrial form of human ACD11 in E. coli produces an enzyme with maximal ACD activity towards C22-CoA. It has relative activities towards C23-, C24-, and C26-CoA of 60 percent, 15 percent, and 15 percent respectively compared to C22-CoA.

As described above, C. elegans has only one gene homologous to human ACAD10/11 and was consistently recovered at the base of the Coelomates. Thus, the C. elegans enzyme is expected to reflect the ancestral function of the human enzymes. A review of the literature and expression data in WormBase, suggest that that the C. elegans ACD10/11 homolog is active in the metabolism of iso-branched-C15-17-CoAs. These are derivatives of epidermal membrane lipid components important in promoting normal barrier function. We therefore will use a C. elegans knock-out model of ACD10/11 in this National Institutes of Health-funded project to identity novel roles for this enzyme and provide valuable insight into possible metabolic phenotypes of ACD10 and 11 in humans. It is noteworthy that isovaleryl-CoA is a key starting compound in the synthesis of iso-branched lipids and thus they should be deficient in patients with maple syrup urine disease who are unable to synthesize isovaleryl-CoA and found in excess in patients with isovaleric acidemia.

Principal Investigator
Gerard Vockley, MD, PhD

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