Chemical and Genetic Studies on the Formation of Pyrrolones During the Biosynthesis of Cytochalasans. Issue 9 (14th January 2021)

• Record Type: Journal Article
• Authors: Zhang, Haili; Hantke, Verena; Bruhnke, Pia; Skellam, Elizabeth J.; Cox, Russell J.
• Is Part Of: Chemistry. Volume 27:Issue 9(2021)
• Page Start: 3106
• Page End: 3113
• Publication Date: 2021-01-14
• Subjects: biosynthesis -- cytochalasan -- hydrolase -- Knoevenagel -- pyrrolone; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.202004444
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: A key step during the biosynthesis of cytochalasans is a proposed Knoevenagel condensation to form the pyrrolone core, enabling the subsequent 4+2 cycloaddition reaction that results in the characteristic octahydroisoindolone motif of all cytochalasans. In this work, we investigate the role of the highly conserved α, β‐hydrolase enzymes PyiE and ORFZ during the biosynthesis of pyrichalasin H and the ACE1 metabolite, respectively, using gene knockout and complementation techniques. Using synthetic aldehyde models we demonstrate that the Knoevenagel condensation proceeds spontaneously but results in the 1, 3‐dihydro‐2 H ‐pyrrol‐2‐one tautomer, rather than the required 1, 5‐dihydro‐2 H ‐pyrrol‐2‐one tautomer. Taken together our results suggest that the α, β‐hydrolase enzymes are essential for first ring cyclisation, but the precise nature of the intermediates remains to be determined. Abstract : Curiouser and curiouser : The long‐proposed intermediacy of 1, 5‐dihydro pyrrol‐2‐ones, which are required during cytochlasan biosynthesis, is called into question. An enzyme involved in this formal Knoevenagel step (PyiE) is identified and a potential mechanism suggested.