1. Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA
2. †Present address: Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA (S.E.O.); Department of Chemistry, Harvey Mudd College, Claremont, California 91711, USA (D.A.V.)
3. *These authors contributed equally to this work

Correspondence to: Christopher T. Walsh¹ Correspondence and requests for materials should be addressed to C.T.W. (Email: christopher_walsh@hms.harvard.edu).

Abstract

Enzymatic incorporation of chlorine, bromine or iodine atoms occurs during the biosynthesis of more than 4,000 natural products¹. Halogenation can have significant consequences for the bioactivity of these products so there is great interest in understanding the biological catalysts that perform these reactions. Enzymes that halogenate unactivated aliphatic groups have not previously been characterized. Here we report the activity of five proteins—CmaA, CmaB, CmaC, CmaD and CmaE—in the construction of coronamic acid (CMA; 1-amino-1-carboxy-2-ethylcyclopropane), a constituent of the phytotoxin coronatine synthesized by the phytopathogenic bacterium Pseudomonas syringae². CMA derives from l-allo-isoleucine, which is covalently attached to CmaD through the actions of CmaA, a non-ribosomal peptide synthetase module, and CmaE, an unusual acyltransferase. We show that CmaB, a member of the non-haem Fe²⁺, -ketoglutarate-dependent enzyme superfamily, is the first of its class to show halogenase activity, chlorinating the -position of l-allo-isoleucine. Another previously undescribed enzyme, CmaC, catalyses the formation of the cyclopropyl ring from the -Cl-l-allo-isoleucine product of the CmaB reaction. Together, CmaB and CmaC execute -halogenation followed by intramolecular -elimination, in which biological chlorination is a cryptic strategy for cyclopropyl ring formation.

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