Metagenomic Approaches for Exploiting Uncultivated Bacteria as a Resource for Novel Biosynthetic Enzymology Micheal C. Wilson, Jörn Piel Chemistry &

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Metagenomic Approaches for Exploiting Uncultivated Bacteria as a Resource for Novel Biosynthetic Enzymology Micheal C. Wilson, Jörn Piel Chemistry & Biology Volume 20, Issue 5, Pages 636-647 (May 2013) DOI: 10.1016/j.chembiol.2013.04.011 Copyright © 2013 Elsevier Ltd Terms and Conditions

Figure 1 General Metagenomic Workflow Graphical schematic summarizing the steps involved in a typical metagenomic workflow. Chemistry & Biology 2013 20, 636-647DOI: (10.1016/j.chembiol.2013.04.011) Copyright © 2013 Elsevier Ltd Terms and Conditions

Figure 2 Natural Products Whose Biosynthetic Pathways Were Identified through Metagenomics or Single-Cell Isolation from a Metagenomic Sample The turbomycins (1 and 2) and terragine A (3) pathways were discovered from soil metagenomes, the patellazole A (4) and bryostatin 1 (5) pathways are from symbiotic bacteria associated with marine invertebrates, and the apratoxin A (6) pathway was identified by single-cell analysis of a cyanobacterium. Chemistry & Biology 2013 20, 636-647DOI: (10.1016/j.chembiol.2013.04.011) Copyright © 2013 Elsevier Ltd Terms and Conditions

Figure 3 Small Molecules and Proposed Biosynthesis Determined through Functional Screening and Heterologous Expression of Metagenomic eDNA (A) Proposed biosynthesis of long-chain N-acyltyrosines ([7] and [8]) and their enol ester derivatives (9). (B) Proposed biosynthesis of isocyanide-functionalized indoles (10). (C) Structure of paerucumarin (11). (D) Representative aromatic polyketides isolated from heterologous expression of eDNA from soil metagenomes. Chemistry & Biology 2013 20, 636-647DOI: (10.1016/j.chembiol.2013.04.011) Copyright © 2013 Elsevier Ltd Terms and Conditions

Figure 4 Polyketides Derived from Trans-AT PKS Pathways With the exception of leinamcyin (17), these trans-AT PKS products were derived from pathways discovered through homology-based metagenomic library screening/sequencing. Chemistry & Biology 2013 20, 636-647DOI: (10.1016/j.chembiol.2013.04.011) Copyright © 2013 Elsevier Ltd Terms and Conditions

Figure 5 RiPPs from Pathways Elucidated through Metagenomic Studies Posttranslational modifications are indicated by color: heterocyclization (pink); prenylation (green); C-methylation (orange); N-methylation (violet); epimerization (red); and hydroxylation (blue). Polytheonamides differ in the stereochemistry of the sulfoxide moiety. Chemistry & Biology 2013 20, 636-647DOI: (10.1016/j.chembiol.2013.04.011) Copyright © 2013 Elsevier Ltd Terms and Conditions

Figure 6 Modifications of Cyanobactin Ribosomal Peptides Enzymatic reactions for (A) heterocyclization, (B) macrocyclization, and (C) prenylation as determined through in vitro experiments. Chemistry & Biology 2013 20, 636-647DOI: (10.1016/j.chembiol.2013.04.011) Copyright © 2013 Elsevier Ltd Terms and Conditions