Issue 18, 2020

Towards a sustainable generation of pseudopterosin-type bioactives

Abstract

Pseudopterosins (Ps), marine diterpene glycosides derived from the marine octocoral Antillogorgia elisabethae, have potent anti-inflammatory activity demonstrated in phase II clinical trials. As multi-step total chemical synthesis is not economical, Ps applications are limited to anti-irritant cosmeceuticals, which are exclusively sourced by unsustainable coral extraction. While chemical intermediates in Ps biosynthesis have been resolved, the underlying biochemical processes remain elusive. Therefore, a coral independent route to enable sustainable access to Ps and respective bioactive precusors is required. Here, in silico guided mutagenesis of the hydropyrene synthase (HpS) from Streptomyces clavuligerus reveals five unique, catalytically relevant methionine residues, and affords selective formation of biosynthetic Ps precursors isoelisabethatriene A and B in an Escherichia coli host with total terpene yield of HpS M75L of 41.91 ± 1.87 mg L−1. This is the first experimental precedence of methionine residues being involved in terpene synthase catalysis, indicating that HpS may belong to a new subfamily. Further, lipase catalysed chemo-enzymatic oxidation differentially transforms the isomers isoelisabethatriene A and B to the advanced Ps precursor erogorgiaene (yield: 69%) and the new compound 1R-epoxy-elisabetha-5,14-diene (EED) (yield: 41%), respectively. As erogorgiaene has significant activity against multi-drug resistant Mycobacterium tuberculosis, the process provides a consolidated and scalable access to erogorgiaene, which allows further clinical development of this compound. Moreover, erogorgiaene access also provides a consolidated route for Ps synthesis. Synergistically EED generation affords a new scaffold for Ps-type drug development. These technologies assist in preserving fragile coral reef ecosystem biodiversity and open a fast track for clinical Ps development.

Graphical abstract: Towards a sustainable generation of pseudopterosin-type bioactives

Supplementary files

Article information

Article type
Paper
Submitted
19 May 2020
Accepted
20 Jul 2020
First published
20 Jul 2020

Green Chem., 2020,22, 6033-6046

Towards a sustainable generation of pseudopterosin-type bioactives

M. Ringel, M. Reinbold, M. Hirte, M. Haack, C. Huber, W. Eisenreich, M. A. Masri, G. Schenk, L. W. Guddat, B. Loll, R. Kerr, D. Garbe and T. Brück, Green Chem., 2020, 22, 6033 DOI: 10.1039/D0GC01697G

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements