Coronavirus Information for the UC San Diego Community

Our leaders are working closely with federal and state officials to ensure your ongoing safety at the university. Stay up to date with the latest developments. Learn more.

Ketoreductase domain dysfunction expands chemodiversity: Malyngamide biosynthesis in the cyanobacterium Okeania hirsuta

TitleKetoreductase domain dysfunction expands chemodiversity: Malyngamide biosynthesis in the cyanobacterium Okeania hirsuta
Publication TypeJournal Article
Year of Publication2018
AuthorsMoss N.A, Leao T., Rankin M.R, McCullough T.M, Qu P.P, Korobeynikov A., Smith J.L, Gerwick L, Gerwick WH
JournalAcs Chemical Biology
Date Published2018/12
Type of ArticleArticle
ISBN Number1554-8929
Accession NumberWOS:000454568000020
KeywordsBiochemistry & Molecular Biology; collection; discovery; gene-cluster; identification; inhibitor; lipoic acid; lyngbya-majuscula; mechanism; natural-products; Skeleton

Dozens of type A malyngamides, principally identified by a decorated six-membered cyclohexanone head group and methoxylated lyngbic acid tail, have been isolated over several decades. Their environmental sources include macro- and microbiotic organisms, including sea hares, red alga, and cyanobacterial assemblages, but the true producing organism has remained enigmatic. Many type A analogues display potent bioactivity in human-health related assays, spurring an interest in this molecular class and its biosynthetic pathway. Here, we present the discovery of the type A malyngamide biosynthetic pathway in the first sequenced genome of the cyanobacterial genus Okeania. Bioinformatic analysis of two cultured Okeania genome assemblies identified 62 and 68 kb polyketide synthase/nonribosomal peptide synthetase (PKS/NRPS) pathways with unusual loading and termination genes. NMR data of malyngamide C acetate derived from C-13-substrate-fed cultures provided evidence that an intact octanoate moiety is transferred to the first KS module via a LipM homologue originally associated with lipoic acid metabolism and implicated an inactive ketoreductase (KR0) as critical for six-membered ring formation, a hallmark of the malyngamide family. Phylogenetic analysis and homology modeling of the penultimate KR0 domain inferred structural cofactor binding and active site alterations as contributory to domain dysfunction, which was confirmed by recombinant protein expression and NADPH binding assay. The carbonyl retained from this KR0 ultimately enables an intramolecular Knoevenagel condensation to form the characteristic cyclohexanone ring. Understanding this critical step allows assignment of a biosynthetic model for all type A malyngamides, whereby well-characterized tailoring modifications explain the surprising proliferation and diversity of analogues.

Short TitleACS Chem. Biol.
Student Publication: 
Research Topics: