Fungal cyclooligomer depsipeptides: From classical biochemistry to combinatorial biosynthesis Roderich S€ ussmuth, a Jane M€ uller, a Hans von D€ ohren b and Istv an Moln ar * cd Received 14th July 2010 DOI: 10.1039/c001463j Covering: up to the end of August 2010 This review surveys the biological activities and the iterative and recursive biosynthetic mechanisms of fungal cyclooligomer depsipeptides, and their structural diversification by various combinatorial biosynthetic methods. 1 Introduction 2 Cyclooligomer depsipeptides in fungi: Structure, distribution, biological activities 2.1 Cyclohexadepsipeptides: Beauvericin 2.2 Cyclohexadepsipeptides: Enniatins 2.3 Cyclohexadepsipeptides: Hirsutellide A 2.4 Cyclooctadepsipeptides: Bassianolide 2.5 Cyclooctadepsipeptides: The PF1022 congeners 2.6 Cyclooctadepsipeptides: Verticilide 2.7 Diketomorpholines: Bassiatin and lateritin 2.8 CODs in bacteria 3 Survey of COD biosynthetic systems in fungi 3.1 Enzyme isolation and stability 3.2 Reconstitution of COD biosynthesis in vitro with purified CODS enzymes (‘‘total biosynthesis’’) 3.3 Cloning of CODS genes 4 Functional anatomy of fungal CODSs 4.1 Overall structures 4.2 Adenylation domains 4.2.1 Hydroxycarboxylic acid-activating domains (A 1 ) 4.2.2 Amino acid activating domains (A 2 ) 4.3 Carrier domains 4.4 Methyltransferase domains (M 2 ) 4.5 Condensation domains (C) 4.6 Iterative and recursive processes during cylooligo- merisation 4.7 Cyclooligomerization and the phylogeny of CODSs 4.8 Cyclooligomerization during fungal and bacterial COD biosynthesis 4.9 Pseudo-cyclodimeric fungal natural products 5 Precursor supply, regulation and export 5.1 Biosynthesis of 2-hydroxycarboxylic acids in COD- producing fungi 5.2 Hydroxycarboxylic acid incorporation in bacterial vs. fungal NRPS systems 5.3 Regulation and export 6 Heterologous expression of CODSs 6.1 Enniatin synthetase gene fragments 6.2 Heterologous production of beauvericin 7 Structural diversification of CODs 7.1 Natural COD congeners 7.2 Unnatural CODs from precursor-directed biosyn- thesis 7.3 Mutasynthesis and combinatorial mutasynthesis 7.4 In vitro biosynthesis (‘‘total biosynthesis’’) of COD analogs using purified enzymes 7.5 Combinatorial biosynthesis by precursor supply pathway engineering 8 Conclusions 9 Abbreviations 10 References 1 Introduction Nonribosomal peptides represent an extensive family of small- molecule natural products, including antibiotics, anticancer agents, immunosuppressants, enzyme inhibitors, siderophores, herbicides, antifungals, insecticides, and anthelminthics. Non- ribosomal peptides are biosynthesized on giant multi-domain enzymes called nonribosomal peptide synthetases (NRPSs). 1–4 The core domains of NRPSs include those that are responsible a Technische Universit € at Berlin, Institut f € ur Chemie, Strasse des 17. Juni 124, 10623 Berlin, Germany. E-mail: suessmuth@chem.tu-berlin.de; Fax: (+49) 030-314-79651 b Technische Universit € at Berlin, AG Biochemie und Molekulare Biologie, Franklinstrasse 29, 10587 Berlin, Germany c SW Center for Natural Products Research and Commercialization, Office of Arid Lands Studies, School of Natural Resources and the Environment, The University of Arizona, 250 E. Valencia Rd., Tucson, AZ, 85706, USA. E-mail: imolnar@cals.arizona.edu d Bio5 Institute, The University of Arizona, 1657 E. Helen Str., Tucson, AZ, 85721, USA This journal is ª The Royal Society of Chemistry 2011 Nat. Prod. Rep., 2011, 28, 99–124 | 99 Dynamic Article Links C < NPR Cite this: Nat. Prod. Rep., 2011, 28, 99 www.rsc.org/npr REVIEW Downloaded by University of Arizona on 25 January 2011 Published on 20 October 2010 on http://pubs.rsc.org | doi:10.1039/C001463J View Online