Biosynthesis of Colabomycin E, a New Manumycin-Family Metabolite, Involves an Unusual Chain-Length Factor

• Published in: Chembiochem : a European journal of chemical biology 2014-06, Vol.15 (9), p.1334-1345
• Main Authors: Petříčková, Kateřina, Pospíšil, Stanislav, Kuzma, Marek, Tylová, Tereza, Jágr, Michal, Tomek, Petr, Chroňáková, Alica, Brabcová, Eva, Anděra, Ladislav, Krištůfek, Václav, Petříček, Miroslav
• Format: Article
• Language: English
• Subjects: Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - metabolism; Anti-Inflammatory Agents - pharmacology; Bacteriology; Biosynthesis; Bridged Bicyclo Compounds, Heterocyclic - chemistry; Bridged Bicyclo Compounds, Heterocyclic - metabolism; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Cell Line; chain-length factors; Dose-Response Relationship, Drug; Humans; Interleukin-1beta - secretion; manumycins; Metabolites; Molecular Structure; polyketides; Polyunsaturated Alkamides - chemistry; Polyunsaturated Alkamides - metabolism; Polyunsaturated Alkamides - pharmacology; secondary metabolites; Streptomyces; Streptomyces - chemistry; Streptomyces - metabolism; Structure-Activity Relationship
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.201400068

Colabomycin E is a new member of the manumycin‐type metabolites produced by the strain Streptomyces aureus SOK1/5‐04 and identified by genetic screening from a library of streptomycete strains. The structures of colabomycin E and accompanying congeners were resolved. The entire biosynthetic gene cluster was cloned and expressed in Streptomyces lividans. Bioinformatic analysis and mutagenic studies identified components of the biosynthetic pathway that are involved in the formation of both polyketide chains. Recombinant polyketide synthases (PKSs) assembled from the components of colabomycin E and asukamycin biosynthetic routes catalyzing the biosynthesis of “lower” carbon chains were constructed and expressed in S. aureus SOK1/5‐04 ΔcolC11–14 deletion mutant. Analysis of the metabolites produced by recombinant strains provided evidence that in both biosynthetic pathways the length of the lower carbon chain is controlled by an unusual chain‐length factor supporting biosynthesis either of a triketide in asukamycin or of a tetraketide in colabomycin E. Biological activity assays indicated that colabomycin E significantly inhibited IL‐1β release from THP‐1 cells and might thus potentially act as an anti‐inflammatory agent. Working on the chain: A gene cluster encoding for the antibiotic colabomycin E was isolated and characterized from a strain selected by genetic screening. A PKS involved in the formation of one carbon chain was identified. Recombination with a homologous enzyme indicated a new class of short‐chain chain‐length factors involved in the synthesis of tri‐ or tetraketides.