Research

LCAD, VLCAD and ACAD9

Mitochondrial β-oxidation spiral starts with three enzymes that use long chain fatty acyl-CoAs as substrates: long chain acyl-CoA dehydrogenase (LCAD), very long chain acyl-CoA dehydrogenase (LCAD) and Acyl-CoA dehydrogenase family member 9 (ACAD9). While the former seem to be less specific and can accommodate bulkier substrates with branched chains or with acyl moiety containing heterocyclic groups, the latter two are more specific to very long (greater than 16 carbons chain length) saturated acyl-CoAs, and very long unsaturated acyl-CoAs, respectively. 

Another potential physiological role that is being investigated is the possible role of LCAD and ACAD9 in synthetic pathways. Evidence that ACAD9 and LCAD likely function in lipid recycling and synthesis in human brain and lung, respectively, supported by their unique substrate utilization and tissue distribution pattern. Furthermore, this study examines several fibroblast cell lines suspected of being ACAD9-deficient. Genetic analysis of patients’ ACAD9 gene at the genomic level and its RNA transcript have revealed an unusual complexity being investigated further.

Structure and function relationship investigation is also under way to identify specific regions of the VLCAD involved in interaction with other mitochondrial structures, including the inner mitochondrial membrane and CPT II. 

Using site directed mutagenesis researchers have identified amino acid residues that add significant stability to the VLCAD protein manifested in increased recombinant enzyme production, purification yield, and enzyme activity, expression. These are located at the C-terminus region, an area that has not been resolved by X-ray crystallography. It’s likely that the replaced residues either directly or indirectly contribute to wild type instability when they are not interacting with their physiological partner.

Principal Investigator
Al-Walid A. Mohsen, PhD

Last Update
August 14, 2010
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Last Update
August 14, 2010
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