title: Lanosterol biosynthesis: the critical role of the methyl-29 group of 2,3-oxidosqualene for the correct folding of this substrate and for the construction of the five-membered D ring.
abstract: Lanosterol synthase catalyzes the polycyclization reaction of (3S)-2,3-oxidosqualene (1) into tetracyclic lanosterol 2 by folding 1 in a chair-boat-chair-chair conformation. 27-Nor- and 29-noroxidosqaulenes (7 and 8, respectively) were incubated with this enzyme to investigate the role of the methyl groups on 1 for the polycyclization cascade. Compound 7 afforded two enzymatic products, namely, 30-norlanosterol (12) and 26-normalabaricatriene (13; 12/13 9:1), which were produced through the normal chair-boat-chair-chair conformation and an atypical chair-chair-boat conformation, respectively. Compound 8 gave two products 14 and 15 (14/15 4:5), which were generated by the normal and the unusual polycyclization pathways through a chair-chair-boat-chair conformation, respectively. It is remarkable that the twist-boat structure for the B-ring formation was changed to an energetically favored chair structure for the generation of 15. Surprisingly, 14 and 15 consisted of a novel 6,6,6,6-fused tetracyclic ring system, thus differing from the 6,6,6,5-fused lanosterol skeleton. Together with previous results, we conclude that the methyl-29 group is critical to the correct folding of 1, with lesser contributions from the other branched methyl groups, such as methyl-26, -27, and -28. Furthermore, we demonstrate that the methyl-29 group has a crucial role in the formation of the five-membered D ring of the lanosterol scaffold.
authors.affiliation: Department of Applied Biological Chemistry, Faculty of Agriculture and Graduate School of Science and Technology, Niigata University, Ikarashi 2-8050, Nishi-ku, Niigata, 950-2181, Japan. hoshitsu@agr.niigata-u.ac.jp
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Hoshino
authors.forename: Akifumi
authors.initials: A
authors.lastname: Chiba
authors.forename: Naomi
authors.initials: N
authors.lastname: Abe
mesh_terms: D000475:Alkenes / Q000737:chemistry*; D002384:Catalysis; D003500:Cyclization; D019751:Intramolecular Transferases / Q000737:chemistry* / Q000378:metabolism*; D007810:Lanosterol / Q000737:chemistry* / Q000378:metabolism*; D008968:Molecular Conformation; D015394:Molecular Structure; D011083:Polycyclic Compounds / Q000737:chemistry* / Q000378:metabolism*; D013185:Squalene / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D013729:Terpenes / Q000737:chemistry*
chemical_list: C002821:2,3-oxidosqualene; D000475:Alkenes; D011083:Polycyclic Compounds; D013729:Terpenes; D007810:Lanosterol; D013185:Squalene; D019751:Intramolecular Transferases; C021924:lanosterol synthase