Structural basis for expanded substrate specificities of human long chain acyl-CoA dehydrogenase and related acyl-CoA dehydrogenases

Narayanan, Beena; Xia, Chuanwu; McAndrew, Ryan; Shen, Anna L.; Kim, Jung-Ja P.

doi:10.1038/s41598-024-63027-6

Structural basis for expanded substrate specificities of human long chain acyl-CoA dehydrogenase and related acyl-CoA dehydrogenases

Journal Article · Wed Jun 05 00:00:00 EDT 2024 · Scientific Reports

DOI:https://doi.org/10.1038/s41598-024-63027-6· OSTI ID:2447409

Narayanan, Beena ^[1]; Xia, Chuanwu ^[2]; McAndrew, Ryan ^[3]; Shen, Anna L. ^[4]; Kim, Jung-Ja P. ^[1]

Medical College of Wisconsin, Milwaukee, WI (United States)
Univ. of North Florida, Jacksonville, FL (United States)
Medical College of Wisconsin, Milwaukee, WI (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Univ. of Wisconsin, Madison, WI (United States)

Crystal structures of human long-chain acyl-CoA dehydrogenase (LCAD) and the catalytically inactive Glu291Gln mutant, have been determined. These structures suggest that LCAD harbors functions beyond its historically defined role in mitochondrial β-oxidation of long and medium-chain fatty acids. LCAD is a homotetramer containing one FAD per 43 kDa subunit with Glu291 as the catalytic base. The substrate binding cavity of LCAD reveals key differences which makes it specific for longer and branched chain substrates. The presence of Pro132 near the start of the E helix leads to helix unwinding that, together with adjacent smaller residues, permits binding of bulky substrates such as 3α, 7α, l2α-trihydroxy-5β-cholestan-26-oyl-CoA. This structural element is also utilized by ACAD11, a eucaryotic ACAD of unknown function, as well as bacterial ACADs known to metabolize sterol substrates. Sequence comparison suggests that ACAD10, another ACAD of unknown function, may also share this substrate specificity. These results suggest that LCAD, ACAD10, ACAD11 constitute a distinct class of eucaryotic acyl CoA dehydrogenases.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States); Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF)

Grant/Contract Number:: AC02-05CH11231; AC02-06CH11357

OSTI ID:: 2447409

Journal Information:: Scientific Reports, Journal Name: Scientific Reports Vol. 14; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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