title: Elucidating a chemical defense mechanism of Antarctic sponges: A computational study.
abstract: In 2000, a novel secondary metabolite (erebusinone, Ereb) was isolated from the Antarctic sea sponge, Isodictya erinacea. The bioactivity of Ereb was investigated, and it was found to inhibit molting when fed to the arthropod species Orchomene plebs. Xanthurenic acid (XA) is a known endogenous molt regulator present in arthropods. Experimental studies have confirmed that XA inhibits molting by binding to either (or both) of two P450 enzymes (CYP315a1 or CYP314a1) that are responsible for the final two hydroxylations in the production of the molt-inducing hormone, 20-hydroxyecdysone (20E). The lack of crystal structures and biochemical assays for CYP315a1 or CYP314a1, has prevented further experimental exploration of XA and Ereb's molt inhibition mechanisms. Herein, a wide array of computational techniques - homology modeling, molecular dynamics simulations, binding site bioinformatics, flexible receptor-flexible ligand docking, and molecular mechanics-generalized Born surface area calculations - have been employed to elucidate the structure-function relationships between the aforementioned P450s and the two described small molecule inhibitors (Ereb and XA). Results indicate that Ereb likely targets CYP315a1 by interacting with a network of aromatic residues in the binding site, while XA may inhibit both CYP315a1 and CYP314a1 because of its aromatic, as well as charged nature.
authors.affiliation: Department of Chemistry, University of South Florida, 4202 E. Fowler Ave., CHE205, Tampa, FL 33620, USA.
authors.forename: Sai Lakshmana
authors.initials: SL
authors.lastname: Vankayala
authors.affiliation: Department of Chemistry, University of South Florida, 4202 E. Fowler Ave., CHE205, Tampa, FL 33620, USA.
authors.forename: Fiona L
authors.initials: FL
authors.lastname: Kearns
authors.affiliation: Department of Chemistry, University of South Florida, 4202 E. Fowler Ave., CHE205, Tampa, FL 33620, USA.
authors.forename: Bill J
authors.initials: BJ
authors.lastname: Baker
authors.affiliation: Department of Chemistry, Eckerd College, 4200 54th Avenue South, St. Petersburg, FL 33711, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Larkin
authors.affiliation: Department of Chemistry, University of South Florida, 4202 E. Fowler Ave., CHE205, Tampa, FL 33620, USA. Electronic address: hlw@usf.edu.
authors.forename: H
authors.initials: H
authors.lastname: Lee Woodcock
mesh_terms: D000470:Alkaloids / Q000737:chemistry*; D000595:Amino Acid Sequence / Q000187:drug effects; D000818:Animals; D000864:Antarctic Regions; D059001:Aquatic Organisms / Q000737:chemistry* / Q000378:metabolism; D001181:Arthropods / Q000187:drug effects; D001665:Binding Sites; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D056004:Molecular Dynamics Simulation; D018978:Molting / Q000187:drug effects*; D011161:Porifera / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D014977:Xanthurenates / Q000737:chemistry*
chemical_list: D000470:Alkaloids; D014977:Xanthurenates; C000626198:erebusinone; C028330:xanthurenic acid; D003577:Cytochrome P-450 Enzyme System
keywords: Aromatic interactions; Erebusinone; Homology modeling; Molecular dynamics simulations; P450 enzyme; Xanthurenic acid