A Novel Biosynthetic Pathway for the Production of Isoquinolines in Streptomyces albus

• Applicant: Professor Dr. Andriy Luzhetskyy
• Subject Area: Metabolism, Biochemistry and Genetics of Microorganisms ; Pharmacy
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 461750128

The isoquinoline skeleton is a part of more than 2500 alkaloids some of which such as codeine or morphine have a remarkable pharmaceutical value. Currently, plants are the major source of isoquinolines thus limiting their biosynthetic engineering and generation of new derivatives. Few years ago, several new isoquinoline derivatives (Mansouramycins A, B, C, and D) have been isolated from marine strain Streptomyces sp. Mei37. The biological activity assays with the purified mansouramycins revealed their broad activity against gram-positive bacteria Staphylococcus aureus and Bacillus subtilis and the gram-negative bacterium Escherichia coli. Mansouramycins also exhibit growth inhibition of the green algae Chlorella vulgaris, Chlorella sorokiniana, and Scenedesmus subspicatus. In addition they also demonstrated high activity against 36 human tumor cell lines, comprising 14 different solid tumor types. Recently we have discovered a family of various masouramycins in S. albus Del14 a cluster-free derivative of S. albus J1074. Numerous feeding experiments with C13-labelled amino acids could unambiguously establish L-tryptophane as a precursor for isoquinoline moiety. This was extremely surprising since all isoquinoline alkaloids known to date are synthesized from L-tyrosine. In this proposal we aim to decipher the novel intriguing biosynthetic route leading to production of an isoquinoline scaffold. Mansouramycins are produced by the S. albus Del14 in which all secondary metabolite gene clusters detected by AntiSMASH were deleted. Using bioinformatics and transcriptomics tools we could identify a set of genes responsible for the biosynthesis of mansouramycins, which is not assigned by any published software. Within this project we are going to study the novel mansouramycin biosynthetic pathway in great details, which will enable generation of new active isoquinoline derivatives via biosynthetic engineering.

• DFG Programme: Research Grants