New Biological Chlorination Pathway Found

A new biological chlorination pathway has been found that is distinctly different from previously known routes. Bradley S. Moore of the University of California, San Diego, and coworkers have discovered and characterized chlorinase SalL, an enzyme that catalyzes the addition of chlorine to a precursor of salinosporamide A (Nat. Chem. Biol., DOI: 10.1038/nchembio.2007.56). This chlorinated natural product from a marine bacterium has anticancer activity and is currently in Phase I clinical trials.

Removing chlorine reduces salinosporamide A's activity by a factor of 500. Investigating how chlorine is added to the precursor, Moore and coworkers unexpectedly found that SalL catalyzes a nonoxidative reaction in which chloride acts as a nucleophile. All four previously known biological chlorination routes use oxidative mechanisms.

The findings opened the way for the researchers to genetically manipulate the bacterium so it would generate new salinosporamides. Moore believes the work could also lead to the ability to produce bioengineered natural products with reactive chlorine ???handles??? that could be modified synthetically.