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J Biol Chem. 2018 Dec 28;293(52):19982-19995. doi: 10.1074/jbc.RA118.005314. Epub 2018 Oct 16.

Discovery of the actinoplanic acid pathway in Streptomyces rapamycinicus reveals a genetically conserved synergism with rapamycin.

Author information

1
From the Novartis Technical Operations, Antiinfectives, SI-1234 Mengeš, Slovenia, peter.mrak@novartis.com.
2
University of Ljubljana, 1000 Ljubljana, Slovenia.
3
Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel, Switzerland.
4
From the Novartis Technical Operations, Antiinfectives, SI-1234 Mengeš, Slovenia.
5
Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, and.
6
Novartis Institutes for BioMedical Research, Novartis Campus, 4056 Basel, Switzerland, charles-1.moore@novartis.com.

Abstract

Actinobacteria possess a great wealth of pathways for production of bioactive compounds. Following advances in genome mining, dozens of natural product (NP) gene clusters are routinely found in each actinobacterial genome; however, the modus operandi of this large arsenal is poorly understood. During investigations of the secondary metabolome of Streptomyces rapamycinicus, the producer of rapamycin, we observed accumulation of two compounds never before reported from this organism. Structural elucidation revealed actinoplanic acid A and its demethyl analogue. Actinoplanic acids (APLs) are potent inhibitors of Ras farnesyltransferase and therefore represent bioactive compounds of medicinal interest. Supported with the unique structure of these polyketides and using genome mining, we identified a gene cluster responsible for their biosynthesis in S. rapamycinicus Based on experimental evidence and genetic organization of the cluster, we propose a stepwise biosynthesis of APL, the first bacterial example of a pathway incorporating the rare tricarballylic moiety into an NP. Although phylogenetically distant, the pathway shares some of the biosynthetic principles with the mycotoxins fumonisins. Namely, the core polyketide is acylated with the tricarballylate by an atypical nonribosomal peptide synthetase-catalyzed ester formation. Finally, motivated by the conserved colocalization of the rapamycin and APL pathway clusters in S. rapamycinicus and all other rapamycin-producing actinobacteria, we confirmed a strong synergism of these compounds in antifungal assays. Mining for such evolutionarily conserved coharboring of pathways would likely reveal further examples of NP sets, attacking multiple targets on the same foe. These could then serve as a guide for development of new combination therapies.

KEYWORDS:

actinobacteria; actinoplanic acid; genomics; natural product biosynthesis; pathway; peptide biosynthesis; polyketide; protein farnesylation; rapamycin; synergy; target of rapamycin (TOR); tricarboxylic acid cycle (TCA cycle) (Krebs cycle)

Conflict of interest statement

The authors declare that they have no conflicts of interest with the contents of this article.

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