HIGHLIGHT www.rsc.org/npr | Natural Product Reports Biological formation of pyrroles: Nature’s logic and enzymatic machinery Christopher T. Walsh,* Sylvie Garneau-Tsodikova† and Annaleise R. Howard-Jones Received (in Cambridge, UK) 2 May 2006 First published as an Advance Article on the web 15th June 2006 DOI: 10.1039/b605245m Covering: up to May 2006. This Highlight provides an overview of the molecular logic employed in the formation and elaboration of pyrroles during natural product biosyntheses. The pyrrole ring, either in its unadorned form or as the pyrrole-2-carboxylate moiety commonly encountered in natural products, possesses many useful chemical and electronic features that are readily exploited in biological contexts. The ring itself is planar and electron rich, highly susceptible to electrophilic attack, capable of oxidation and able to participate in both p–p stacking and hydrogen-bonding interactions; the 2-carboxylate moiety provides a nucleophilic center for derivatization, hydrogen bonding and reaction with biological targets. The focus of this Highlight is primarily on the construction of pyrrole rings during secondary metabolite formation, and on their derivatization and incorporation into natural products. Overall biosynthetic strategies are discussed as well as relevant enzymology and mechanistic details. Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA, 02115 † Current address: Department of Medicinal Chemistry, College of Phar- macy & Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109. Christopher T. Walsh, born in 1944, majored in biology at Harvard and completed his PhD in biochemistry in the lab of Fritz Lipmann at the Rockefeller Institute of Medical Research. He was on the MIT faculty (1972–1987), and since 1987 has been at Harvard Medical School. He served as Chair of the Department of Chemistry at MIT (1982–1987) and of the Department of Biological Chemistry and Molecular Pharmacology at Harvard Medical School (1987–1995). His research interests lie in enzyme and inhibitor mechanisms and in the biosynthesis of nonribosomal peptide antibiotics. Sylvie Garneau-Tsodikova, born in Qu´ ebec, Canada, received her BSc (1995) and MSc (1997) in chemistry from the Universit´ e Laval, where she worked under the supervision of Robert Chˆ enevert and Pers´ ephone Canonne. She completed her PhD in chemistry in January 2003 at the University of Alberta with John C. Vederas on the studies of new antimicrobial agents acting on bacterial cell walls. As a postdoctoral fellow with Christopher T. Walsh at Harvard Medical School, she studied halogenation and pyrrole formation of various natural products. She is currently an Assistant Professor of Medicinal Chemistry at the College of Pharmacy and the Life Sciences Institute at the University of Michigan, where she studies the mechanisms of enzymes involved in the biosynthesis of anticancer agents. Annaleise R. Howard-Jones was born in Queensland, Australia, and received her BSc (2000) and MSc (2001) in chemistry from the University of Sydney, working under the direction of Margaret M. Harding. She completed her DPhil at the University of Oxford (2004) with Sir Jack E. Baldwin, working on mechanistic and structural studies of the non-haem iron oxidase, isopenicillin N synthase. She is currently a postdoctoral fellow in the laboratory of Christopher T. Walsh at the Harvard Medical School, where her research focuses on biosynthetic routes to indolocarbazole natural products. Christopher T. Walsh Sylvie Garneau-Tsodikova Annaleise R. Howard-Jones 1 Introduction The five-membered heteroaromatic pyrrole ring, planar and electron rich, is a useful recognition element in many biological contexts—forming hydrogen bonds, coordinating metals, and This journal is © The Royal Society of Chemistry 2006 Nat. Prod. Rep., 2006, 23, 517–531 | 517