# Structural Basis for Expanded Substrate Specificities of Human Long Chain Acyl-CoA Dehydrogenase and Related Acyl- CoA Dehydrogenases

## TL;DR

This study reveals how human long-chain acyl-CoA dehydrogenase (LCAD) can bind bulky substrates, suggesting broader functions beyond fatty acid metabolism.

## Contribution

The paper identifies a structural basis for LCAD's expanded substrate specificity and links it to related enzymes with unknown functions.

## Key findings

- LCAD's substrate cavity allows binding of bulky and branched substrates due to Pro132-induced helix unwinding.
- ACAD11 and bacterial ACADs share this structural feature, suggesting similar substrate specificity.
- LCAD, ACAD10, and ACAD11 form a distinct class of eucaryotic acyl-CoA dehydrogenases.

## Abstract

Crystal structures of human long-chain acyl-CoA dehydrogenase (LCAD) and the E291Q 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 43kDa 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.