Human Acyl-CoA dehydrogenase-9 plays a novel role in the mitochondrial β-oxidation of unsaturated fatty acids

Regina Ensenauer, Miao He, Jan Marie Willard, Eric S. Goetzman, Thomas J. Corydon, Brian B. Vandahl, Al Walid Mohsen, Grazia Isaya, Jerry Vockley

Research output: Contribution to journalArticle

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Abstract

Unsaturated fatty acids play an important role in the prevention of human diseases such as diabetes, obesity, cancer, and neurodegeneration. However, their oxidation in vivo by acyl-CoA dehydrogenases (ACADs) that catalyze the first step of each cycle of mitochondrial fatty acid β-oxidation is not entirely understood. Recently, a novel ACAD (ACAD-9) of unknown function that is highly homologous to human very-long-chain acyl-CoA dehydrogenase was identified by large-scale random sequencing. To characterize its enzymatic role, we have expressed ACAD-9 in Escherichia coli, purified it, and determined its pattern of substrate utilization. The N terminus of the mature form of the enzyme was identified by in vitro mitochondrial import studies of precursor protein. A 37-amino acid leader peptide was cleaved sequentially by two mitochondrial peptidases to yield a predicted molecular mass of 65 kDa for the mature subunit. Submitochondrial fractionation studies found native ACAD-9 to be associated with the mitochondrial membrane. Gel filtration analysis indicated that, like very-long-chain acyl-CoA dehydrogenase, ACAD-9 is a dimer, in contrast to the other known ACADs, which are tetramers. Purified mature ACAD-9 had maximal activity with long-chain unsaturated acyl-CoAs as substrates (C16:1-, C18:1-, C18:2-, C22:6-CoA). These results suggest a previously unrecognized role for ACAD-9 in the mitochondrial β-oxidation of long-chain unsaturated fatty acids. Because of the substrate specificity and abundance of ACAD-9 in brain, we speculate that it may play a role in the turnover of lipid membrane unsaturated fatty acids that are essential for membrane integrity and structure.

Original languageEnglish (US)
Pages (from-to)32309-32316
Number of pages8
JournalJournal of Biological Chemistry
Volume280
Issue number37
DOIs
StatePublished - Sep 16 2005

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Acyl-CoA Dehydrogenases
Unsaturated Fatty Acids
Oxidation
human ACADVL protein
Long-Chain Acyl-CoA Dehydrogenase
Substrates
human ACAD9 protein
Membranes
Protein Precursors
Mitochondrial Membranes
Molecular mass
Coenzyme A
Membrane Lipids
Fractionation
Medical problems
Protein Sorting Signals
Substrate Specificity
Dimers
Escherichia coli
Gel Chromatography

ASJC Scopus subject areas

  • Biochemistry

Cite this

Ensenauer, R., He, M., Willard, J. M., Goetzman, E. S., Corydon, T. J., Vandahl, B. B., ... Vockley, J. (2005). Human Acyl-CoA dehydrogenase-9 plays a novel role in the mitochondrial β-oxidation of unsaturated fatty acids. Journal of Biological Chemistry, 280(37), 32309-32316. https://doi.org/10.1074/jbc.M504460200

Human Acyl-CoA dehydrogenase-9 plays a novel role in the mitochondrial β-oxidation of unsaturated fatty acids. / Ensenauer, Regina; He, Miao; Willard, Jan Marie; Goetzman, Eric S.; Corydon, Thomas J.; Vandahl, Brian B.; Mohsen, Al Walid; Isaya, Grazia; Vockley, Jerry.

In: Journal of Biological Chemistry, Vol. 280, No. 37, 16.09.2005, p. 32309-32316.

Research output: Contribution to journalArticle

Ensenauer, R, He, M, Willard, JM, Goetzman, ES, Corydon, TJ, Vandahl, BB, Mohsen, AW, Isaya, G & Vockley, J 2005, 'Human Acyl-CoA dehydrogenase-9 plays a novel role in the mitochondrial β-oxidation of unsaturated fatty acids', Journal of Biological Chemistry, vol. 280, no. 37, pp. 32309-32316. https://doi.org/10.1074/jbc.M504460200
Ensenauer, Regina ; He, Miao ; Willard, Jan Marie ; Goetzman, Eric S. ; Corydon, Thomas J. ; Vandahl, Brian B. ; Mohsen, Al Walid ; Isaya, Grazia ; Vockley, Jerry. / Human Acyl-CoA dehydrogenase-9 plays a novel role in the mitochondrial β-oxidation of unsaturated fatty acids. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 37. pp. 32309-32316.
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