Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form
D-Scholarship @ Pitt Banner and Links to Homepage

Terminal alkene formation by the thioesterase of curacin A biosynthesis: Structure of a decarboxylating thioesterase

Gehret, JJ and Gu, L and Gerwick, WH and Wipf, P and Sherman, DH and Smith, JL (2011) Terminal alkene formation by the thioesterase of curacin A biosynthesis: Structure of a decarboxylating thioesterase. Journal of Biological Chemistry, 286 (16). 14445 - 14454. ISSN 0021-9258

[img] Plain Text (licence)
Available under License : See the attached license file.
Download (1kB)

Abstract

Curacin A is a polyketide synthase (PKS)-non-ribosomal peptide synthetase-derived natural product with potent anticancer properties generated by the marine cyanobacterium Lyngbya majuscula. Type I modular PKS assembly lines typically employ a thioesterase (TE) domain to off-load carboxylic acid or macrolactone products from an adjacent acyl carrier protein (ACP) domain. In a striking departure from this scheme the curacin A PKS employs tandem sulfotransferase and TE domains to form a terminal alkene moiety. Sulfotransferase sulfonation of β-hydroxy-acyl-ACP is followed by TE hydrolysis, decarboxylation, and sulfate elimination (Gu, L., Wang, B., Kulkarni, A., Gehret, J. J., Lloyd, K. R., Gerwick, L., Gerwick, W. H., Wipf, P., Håkansson, K., Smith, J. L., and Sherman, D. H. (2009) J. Am. Chem. Soc. 131, 16033-16035). With low sequence identity to other PKS TEs (<15%), the curacin TE represents a new thioesterase subfamily. The 1.7-Å curacin TE crystal structure reveals how the familiar α/β-hydrolase architecture is adapted to specificity for β-sulfated substrates. A Ser-His-Glu catalytic triad is centered in an open active site cleft between the core domain and a lid subdomain. Unlike TEs from other PKSs, the lid is fixed in an open conformation on one side by dimer contacts of a protruding helix and on the other side by an arginine anchor from the lid into the core. Adjacent to the catalytic triad, another arginine residue is positioned to recognize the substrate β-sulfate group. The essential features of the curacin TE are conserved in sequences of five other putative bacterial ACP-ST-TE tridomains. Formation of a sulfate leaving group as a biosynthetic strategy to facilitate acyl chain decarboxylation is of potential value as a route to hydrocarbon biofuels. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

Share

Citation/Export:
Social Networking:
Share |

Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Gehret, JJ
Gu, L
Gerwick, WH
Wipf, Ppwipf@pitt.eduPWIPF
Sherman, DH
Smith, JL
Date: 22 April 2011
Date Type: Publication
Journal or Publication Title: Journal of Biological Chemistry
Volume: 286
Number: 16
Page Range: 14445 - 14454
DOI or Unique Handle: 10.1074/jbc.m110.214635
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0021-9258
MeSH Headings: Amino Acid Sequence; Biofuels; Carboxylic Acids--chemistry; Crystallography, X-Ray--methods; Cyanobacteria--metabolism; Cyclopropanes--chemistry; Models, Chemical; Molecular Sequence Data; Mutagenesis, Site-Directed; Palmitoyl-CoA Hydrolase--chemistry; Polyketide Synthases--chemistry; Protein Conformation; Protein Structure, Secondary; Protein Structure, Tertiary; Proteins--chemistry; Sequence Homology, Amino Acid; Thiazoles--chemistry
Other ID: NLM PMC3077644
PubMed Central ID: PMC3077644
PubMed ID: 21357626
Date Deposited: 28 May 2013 15:21
Last Modified: 02 Feb 2019 15:57
URI: http://d-scholarship-dev.library.pitt.edu/id/eprint/18746

Metrics

Monthly Views for the past 3 years

Plum Analytics

Altmetric.com

Actions (login required)

View Item View Item