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Proc Natl Acad Sci U S A

Title:		Structural characterization of acyl-CoA oxidases reveals a direct link between pheromone biosynthesis and metabolic state in Caenorhabditis elegans
Author(s):		Zhang X; Li K; Jones RA; Bruner SD; Butcher RA;
Address:		"Department of Chemistry, University of Florida, Gainesville, FL 32611. Department of Chemistry, University of Florida, Gainesville, FL 32611 butcher@chem.ufl.edu"
Journal Title:		Proc Natl Acad Sci U S A
Year:		2016
Volume:		20160822
Issue:		36
Page Number:		10055 - 10060
DOI:		10.1073/pnas.1608262113
ISSN/ISBN:		1091-6490 (Electronic) 0027-8424 (Print) 0027-8424 (Linking)
Abstract:		"Caenorhabditis elegans secretes ascarosides as pheromones to communicate with other worms and to coordinate the development and behavior of the population. Peroxisomal beta-oxidation cycles shorten the side chains of ascaroside precursors to produce the short-chain ascaroside pheromones. Acyl-CoA oxidases, which catalyze the first step in these beta-oxidation cycles, have different side chain-length specificities and enable C. elegans to regulate the production of specific ascaroside pheromones. Here, we determine the crystal structure of the acyl-CoA oxidase 1 (ACOX-1) homodimer and the ACOX-2 homodimer bound to its substrate. Our results provide a molecular basis for the substrate specificities of the acyl-CoA oxidases and reveal why some of these enzymes have a very broad substrate range, whereas others are quite specific. Our results also enable predictions to be made for the roles of uncharacterized acyl-CoA oxidases in C. elegans and in other nematode species. Remarkably, we show that most of the C. elegans acyl-CoA oxidases that participate in ascaroside biosynthesis contain a conserved ATP-binding pocket that lies at the dimer interface, and we identify key residues in this binding pocket. ATP binding induces a structural change that is associated with tighter binding of the FAD cofactor. Mutations that disrupt ATP binding reduce FAD binding and reduce enzyme activity. Thus, ATP may serve as a regulator of acyl-CoA oxidase activity, thereby directly linking ascaroside biosynthesis to ATP concentration and metabolic state"
Keywords:		Acyl-CoA Oxidase/*chemistry/genetics/metabolism Adenosine Triphosphate/chemistry/metabolism Amino Acid Sequence Animals Binding Sites Caenorhabditis elegans/*chemistry/enzymology Caenorhabditis elegans Proteins/*chemistry/genetics/metabolism Crystallograp;
Notes:		"MedlineZhang, Xinxing Li, Kunhua Jones, Rachel A Bruner, Steven D Butcher, Rebecca A eng Research Support, Non-U.S. Gov't 2016/08/24 Proc Natl Acad Sci U S A. 2016 Sep 6; 113(36):10055-60. doi: 10.1073/pnas.1608262113. Epub 2016 Aug 22"