Crystal structures of apo- and FAD-bound human peroxisomal acyl-CoA oxidase provide mechanistic basis explaining clinical observations.

Ravi R Sonani, Artur Blat, Grzegorz Dubin

International journal of biological macromolecules 2022 Apr 30

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Peroxisomal acyl-CoA oxidase 1a (ACOX1a) catalyzes the first and rate-limiting step of fatty acid oxidation, the conversion of acyl-CoAs to 2-trans-enoyl-CoAs. The dysfunction of human ACOX1a (hACOX1a) leads to deterioration of the nervous system manifesting in myeloneuropathy, hypotonia and convulsions. Crystal structures of hACOX1a in apo- and cofactor (FAD)-bound forms were solved at 2.00 and 2.09 Å resolution, respectively. hACOX1a exists as a homo-dimer with solvation free energy gain (ΔGo) of -44.7 kcal mol-1. Two FAD molecules bind at the interface of protein monomers completing the active sites. The substrate binding cleft of hACOX1a is wider compared to human mitochondrial very-long chain specific acyl-CoA dehydrogenase. Mutations (p.G178C, p.M278V and p.N237S) reported to cause dysfunctionality of hACOX1a are analyzed on its 3D-structure to understand structure-function related perturbations and explain the associated phenotypes. Copyright © 2022 Elsevier B.V. All rights reserved.

Citation

Ravi R Sonani, Artur Blat, Grzegorz Dubin. Crystal structures of apo- and FAD-bound human peroxisomal acyl-CoA oxidase provide mechanistic basis explaining clinical observations. International journal of biological macromolecules. 2022 Apr 30;205:203-210