Structural basis for olivetolic acid formation by a polyketide cyclase from Cannabis sativa

The FEBS Journal
Xinmei YangHiroyuki Morita

Abstract

In polyketide biosynthesis, ring formation is one of the key diversification steps. Olivetolic acid cyclase (OAC) from Cannabis sativa, involved in cannabinoid biosynthesis, is the only known plant polyketide cyclase. In addition, it is the only functionally characterized plant α+β barrel (DABB) protein that catalyzes the C2-C7 aldol cyclization of the linear pentyl tetra-β-ketide CoA as the substrate, to generate olivetolic acid (OA). Herein, we solved the OAC apo and OAC-OA complex binary crystal structures at 1.32 and 1.70 Å resolutions, respectively. The crystal structures revealed that the enzyme indeed belongs to the DABB superfamily, as previously proposed, and possesses a unique active-site cavity containing the pentyl-binding hydrophobic pocket and the polyketide binding site, which have never been observed among the functionally and structurally characterized bacterial polyketide cyclases. Furthermore, site-directed mutagenesis studies indicated that Tyr72 and His78 function as acid/base catalysts at the catalytic center. Structural and/or functional studies of OAC suggested that the enzyme lacks thioesterase and aromatase activities. These observations demonstrated that OAC employs unique catalytic machinery utilizin...Continue Reading

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Citations

Oct 11, 2016·Natural Product Reports·Lumír Ondřej HanušGiovanni Appendino
Jul 24, 2018·PloS One·Richard D RichinsMary A O'Connell
Mar 11, 2020·Annual Review of Plant Biology·I KovalchukT F Sharbel
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Mar 17, 2021·Journal of Cannabis Research·M Nazir TahirJohn F Trant
Jun 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Kevin J H LimWen Shan Yew
Jul 1, 2021·Applied Microbiology and Biotechnology·Sophie MoureuRuben Christiaan Hartkoorn
Jul 29, 2021·The Plant Journal : for Cell and Molecular Biology·Mehran Dastmalchi
Jan 29, 2019·ACS Chemical Neuroscience·Samuel D BanisterIain S McGregor

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