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Acyl-CoA Dehydrogenases: Dynamic History of Protein Family Evolution

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Abstract

The acyl-CoA dehydrogenases (ACADs) are enzymes that catalyze the α,β-dehydrogenation of acyl-CoA esters in fatty acid and amino acid catabolism. Eleven ACADs are now recognized in the sequenced human genome, and several homologs have been reported from bacteria, fungi, plants, and nematodes. We performed a systematic comparative genomic study, integrating homology searches with methods of phylogenetic reconstruction, to investigate the evolutionary history of this family. Sequence analyses indicate origin of the family in the common ancestor of Archaea, Bacteria, and Eukaryota, illustrating its essential role in the metabolism of early life. At least three ACADs were already present at that time: ancestral glutaryl-CoA dehydrogenase (GCD), isovaleryl-CoA dehydrogenase (IVD), and ACAD10/11. Two gene duplications were unique to the eukaryotic domain: one resulted in the VLCAD and ACAD9 paralogs and another in the ACAD10 and ACAD11 paralogs. The overall patchy distribution of specific ACADs across the tree of life is the result of dynamic evolution that includes numerous rounds of gene duplication and secondary losses, interdomain lateral gene transfer events, alteration of cellular localization, and evolution of novel proteins by domain acquisition. Our finding that eukaryotic ACAD species are more closely related to bacterial ACADs is consistent with endosymbiotic origin of ACADs in eukaryotes and further supported by the localization of all nine previously studied ACADs in mitochondria.

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Abbreviations

ACADs:

Acyl-CoA dehydrogenases

ACOX:

Acyl-CoA oxidase

GCD:

Glutaryl-CoA dehydrogenase

IBD:

Isobutyryl-CoA dehydrogenase

IVD:

Isovaleryl-CoA dehydrogenase

VLCAD:

Very long-chain acyl-CoA dehydrogenase

LCAD:

Long-chain acyl-CoA dehydrogenase

SCAD:

Short-chain acyl-CoA dehydrogenase

SBCAD:

Short/branched-chain acyl-CoA dehydrogenase, also known as 2-methyl branched chain acyl-CoA dehydrogenase

MCAD:

Medium-chain acyl-CoA dehydrogenase

LGT:

Lateral gene transfer

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Acknowledgments

This work was supported by PHS NIH Grant R01-DK54936 and the Pennsylvania Department of Health, Tobacco Formula Funding. We thank Eric Goetzman for discussion on physiological effects of ACAD deficiencies.

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Author notes

  1. Zuzana Swigoňová

    Present address: Department of Biological Sciences, University of Pittsburgh, 4249 Fifth Avenue, Pittsburgh, PA, 15260, USA

  2. Jerry Vockley

    Present address: Division of Medical Genetics, Children’s Hospital of Pittsburgh, UPMC, Children’s Hospital Drive, 45th Street and Penn Avenue, Pittsburgh, PA, 15201, USA

Authors and Affiliations

  1. Department of Pediatrics, University of Pittsburgh, Children’s Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA, 15213, USA

    Zuzana Swigoňová, Al-Walid Mohsen & Jerry Vockley

Authors
  1. Zuzana Swigoňová
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  2. Al-Walid Mohsen
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Corresponding authors

Correspondence to Zuzana Swigoňová or Jerry Vockley.

Electronic supplementary material

Below are the links to the electronic supplementary materials.

Supplementary material 1 (PDF 61 kb)

Supplementary material 2 (PDF 138 kb)

Supplementary material 3 (PDF 133 kb)

Data matrix of acyl-CoA dehydrogenases and outgroups (DOC 1337 kb)

Data matrix of glutary-CoA dehydrogenases (DOC 65 kb)

Data matrix of ACAD10 and ACAD11 homologs (DOC 260 kb)

Data matrix of isovalyryl-CoA dehydrogenases (DOC 105 kb)

Data matrix of very-long acyl-CoA dehydrogenase and ACAD9 homologs (DOC 111 kb)

Data matrix of long-chain acyl-CoA dehydrogenases and relatives (DOC 85 kb)

Data matrix of isobutyryl-CoA dehydrogenases (DOC 46 kb)

Data matrix of short/branched-chain acyl-CoA dehydrogenases (DOC 216 kb)

Data matrix of short-chain acyl-CoA dehydrogenases (DOC 175 kb)

Data matrix of medium-chain acyl-CoA dehydrogenases (DOC 121 kb)

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Swigoňová, Z., Mohsen, AW. & Vockley, J. Acyl-CoA Dehydrogenases: Dynamic History of Protein Family Evolution. J Mol Evol 69, 176–193 (2009). https://doi.org/10.1007/s00239-009-9263-0

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  • DOI: https://doi.org/10.1007/s00239-009-9263-0

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