Enzymatic Formation of a Skipped Methyl-Substituted Octaprenyl Side Chain of Longestin (KS-505a): Involvement of Homo-IPP as a Common Extender Unit

Taro Ozaki; Sandip S Shinde; Lei Gao; Ryo Okuizumi; Chengwei Liu; Yasushi Ogasawara; Xiaoguang Lei; Tohru Dairi; Atsushi Minami; Hideaki Oikawa

doi:10.1002/anie.201802116

Enzymatic Formation of a Skipped Methyl-Substituted Octaprenyl Side Chain of Longestin (KS-505a): Involvement of Homo-IPP as a Common Extender Unit

Angew Chem Int Ed Engl. 2018 May 28;57(22):6629-6632. doi: 10.1002/anie.201802116. Epub 2018 Apr 26.

Authors

Taro Ozaki¹, Sandip S Shinde^{1

2}, Lei Gao^{1

3}, Ryo Okuizumi¹, Chengwei Liu¹, Yasushi Ogasawara⁴, Xiaoguang Lei³, Tohru Dairi⁴, Atsushi Minami¹, Hideaki Oikawa¹

Affiliations

¹ Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo, Hokkaido, 060-0810, Japan.
² Organic Chemistry Division, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pashan, Pune-, 411008, India.
³ College of Chemistry and Molecular Engineering, Peking University, Haidian District, Beijing, 100871, China.
⁴ Graduate School of Engineering, Hokkaido University, Sapporo, Hokkaido, 060-8628, Japan.

PMID: 29603559
DOI: 10.1002/anie.201802116

Abstract

Longestin (KS-505a), a specific inhibitor of phosphodiesterase, is a meroterpenoid that consists of a unique octacyclic terpene skeleton with branched methyl groups at unusual positions (C1 and C12). Biochemical analysis of Lon23, a methyltransferase involved in the biosynthesis of longestin, demonstrated that it methylates homoisopentenyl diphosphate (homo-IPP) to afford (3Z)-3-methyl IPP. This compound, along with IPP, is selectively accepted as extender units by Lon22, a geranylgeranyl diphosphate (GGPP) synthase homologue, to yield dimethylated GGPP (dmGGPP). The absolute configuration of dmGGPP was determined to be (4R,12R) by degradation and chiral GC analysis. These findings allowed us to propose an enzymatic sequence for key steps of the biosynthetic pathway of the unusual homoterpenoid longestin.

Keywords: biosynthesis; longestin; methyltransferases; prenyltransferases; terpenoids.

Publication types

Research Support, Non-U.S. Gov't