Faculty Collaboration Database

Acyl-CoA Oxidases Fine-Tune the Production of Ascaroside Pheromones with Specific Side Chain Lengths. ACS Chem Biol 2018 Apr 20;13(4):1048-1056

Date

03/15/2018

Pubmed ID

29537254

DOI

10.1021/acschembio.7b01021

Scopus ID

2-s2.0-85045932344 (requires institutional sign-in at Scopus site)   21 Citations

Abstract

Caenorhabditis elegans produces a complex mixture of ascaroside pheromones to control its development and behavior. Acyl-CoA oxidases, which participate in β-oxidation cycles that shorten the side chains of the ascarosides, regulate the mixture of pheromones produced. Here, we use CRISPR-Cas9 to make specific nonsense and missense mutations in acox genes and determine the effect of these mutations on ascaroside production in vivo. Ascaroside production in acox-1.1 deletion and nonsense strains, as well as a strain with a missense mutation in a catalytic residue, confirms the central importance of ACOX-1.1 in ascaroside biosynthesis and suggests that ACOX-1.1 functions in part by facilitating the activity of other acyl-CoA oxidases. Ascaroside production in an acox-1.1 strain with a missense mutation in an ATP-binding site at the ACOX-1.1 dimer interface suggests that ATP binding is important for the enzyme to function in ascaroside biosynthesis in vivo. Ascaroside production in strains with deletion, nonsense, and missense mutations in other acox genes demonstrates that ACOX-1.1 works with ACOX-1.3 in processing ascarosides with 7-carbon side chains, ACOX-1.4 in processing ascarosides with 9- and 11-carbon side chains, and ACOX-3 in processing ascarosides with 13- and 15-carbon side chains. It also shows that ACOX-1.2, but not ACOX-1.1, processes ascarosides with 5-carbon ω-side chains. By modeling the ACOX structures, we uncover characteristics of the enzyme active sites that govern substrate preferences. Our work demonstrates the role of specific acyl-CoA oxidases in controlling the length of ascaroside side chains and thus in determining the mixture of pheromones produced by C. elegans.

Author List

Zhang X, Wang Y, Perez DH, Jones Lipinski RA, Butcher RA

Author

Rachel Jones Lipinski Research Scientist I in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Acyl-CoA Oxidase
Adenosine Triphosphate
Animals
Caenorhabditis elegans
Catalytic Domain
Gene Editing
Glycolipids
Models, Molecular
Mutation
Oxidation-Reduction
Pheromones