Enzymatic Logic of Anthrax Stealth Siderophore Biosynthesis:  AsbA Catalyzes ATP-Dependent Condensation of Citric Acid and Spermidine

Daniel Oves-Costales,† Nadia Kadi,† Mark J. Fogg,‡ Lijiang Song,† Keith S. Wilson,‡ and Gregory L. Challis*†
Department of Chemistry, University of Warwick, Coventry CV4 7AL, U.K., and Structural Biology Laboratory, Department of Chemistry, University of York, Heslington, York YO10 5YW, U.K.
J. Am. Chem. Soc., 2007, 129 (27), pp 8416–8417
DOI: 10.1021/ja072391o
Publication Date (Web): June 19, 2007
Copyright © 2007 American Chemical Society
†

 University of Warwick.

,
‡

 University of York.

,
*

In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

, g.l.challis@warwick.ac.uk

Abstract

Abstract Image

Petrobactin is an iron-chelating siderophore originally isolated from Marinobacter hydrocarbonoclasticus that has been shown to play an important role in growth under iron-deficient conditions and virulence of the deadly bioterrorism agent Bacillus anthracis. It has recently been shown not to bind to siderocalin, leading it to be designated as a “stealth siderophore” that can avoid the mammalian immune system. A unique combination of nonribosomal peptide synthetase (NRPS) and NRPS-independent siderophore (NIS) synthetase enzymes is known to be required for petrobactin biosynthesis in B. anthracis. Here it is shown that AsbA from B. anthracis, the first type A NIS synthetase to be biochemically characterized, catalyzes ATP-dependent regioselective condensation of citric acid with N8 of spermidine, but not with N1-(3,4-dihydroxybenzoyl)-spermidine. These results rule out a recently proposed pathway for petrobactin biosynthesis involving AsbA-catalyzed condensation of N1-(3,4-dihydroxybenzoyl)-spermidine with citric acid and show that acylation of N1 of spermidine with the 3,4-dihydroxybenzoyl group must occur after acylation of N8 of spermidine with citrate. They also provide the fundamental knowledge needed to establish a high throughput screen for inhibitors of AsbA that may provide the basis for development of new antibiotics for the treatment of deadly anthrax infections.

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History

  • Published In Issue July 11, 2007
  • Received April 5, 2007

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