Article abstract
Nature Chemical Biology 4, 69 - 74 (2008)
Published online: 2 December 2007 | doi:10.1038/nchembio.2007.56
Discovery and characterization of a marine bacterial SAM-dependent chlorinase
Alessandra S Eustáquio1,4, Florence Pojer2,4, Joseph P Noel2 & Bradley S Moore1,3
Abstract
Halogen atom incorporation into a scaffold of bioactive compounds often amplifies biological activity, as is the case for the anticancer agent salinosporamide A (1), a chlorinated natural product from the marine bacterium Salinispora tropica. Significant effort in understanding enzymatic chlorination shows that oxidative routes predominate to form reactive electrophilic or radical chlorine species. Here we report the genetic, biochemical and structural characterization of the chlorinase SalL, which halogenates S-adenosyl-L-methionine (2) with chloride to generate 5'-chloro-5'-deoxyadenosine (3) and L-methionine (4) in a rarely observed nucleophilic substitution strategy analogous to that of Streptomyces cattleya fluorinase. Further metabolic tailoring produces a halogenated polyketide synthase substrate specific for salinosporamide A biosynthesis. SalL also accepts bromide and iodide as substrates, but not fluoride. High-resolution crystal structures of SalL and active site mutants complexed with substrates and products support the SN2 nucleophilic substitution mechanism and further illuminate halide specificity in this newly discovered halogenase family.
- Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
- Howard Hughes Medical Institute, Jack H. Skirball Center for Chemical Biology and Proteomics, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.
- These authors contributed equally to this work.
Correspondence to: Bradley S Moore1,3 e-mail: bsmoore@ucsd.edu
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
RESEARCH
Arsenic Trioxide Induces Apoptosis of Cutaneous T Cell Lymphoma Cells: Evidence for a Partially Caspase-Independent Pathway and Potentiation by Ascorbic Acid (Vitamin C)Journal of Investigative Dermatology Original Article
Biochemistry Biosynthesis of an organofluorine moleculeNature Brief Communication (21 Mar 2002)
Crystal structure and mechanism of a bacterial fluorinating enzymeNature Letters to Editor (05 Feb 2004)
Crystal structure of human osteoclast cathepsin K complex with E-64Nature Structural Biology Correspondence (01 Feb 1997)
