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Enzymatic Formation of a Skipped Methyl‐Substituted Octaprenyl Side Chain of Longestin (KS‐505a): Involvement of Homo‐IPP as a Common Extender Unit
Author(s) -
Ozaki Taro,
Shinde Sandip S.,
Gao Lei,
Okuizumi Ryo,
Liu Chengwei,
Ogasawara Yasushi,
Lei Xiaoguang,
Dairi Tohru,
Minami Atsushi,
Oikawa Hideaki
Publication year - 2018
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201802116
Subject(s) - stereochemistry , biosynthesis , chemistry , enzyme , absolute configuration , atp synthase , side chain , terpene , methyltransferase , extender , yield (engineering) , methyl group , biochemistry , methylation , group (periodic table) , organic chemistry , polyurethane , gene , polymer , materials science , metallurgy
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 (3 Z )‐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 (4 R ,12 R ) 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.