Structural elucidation of cisoid and transoid cyclization pathways of a sesquiterpene synthase using 2-fluorofarnesyl diphosphates

  • Noel J
  • Dellas N
  • Faraldos J
 et al. 
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Sesquiterpene skeletal complexity in nature originates from the enzyme-catalyzed ionization of (trans,trans)-farnesyl diphosphate (FPP) and subsequent cyclization along either 2,3-transoid or 2,3-cisoid farnesyl cation pathways. Tobacco 5-epi-aristolochene synthase (TEAS), a transoid synthase, produces cisoid products as a component of its minor product spectrum. To investigate the cryptic cisoid cyclization pathway in TEAS, (cis,trans)-FPP was employed as an alternative substrate. Strikingly, TEAS was catalytically robust in the enzymic conversion of (cis,trans)-FPP to exclusively (≥99.5%) cisoid products. Further, crystallog. characterization of wild-type TEAS and a catalytically promiscuous mutant (M4 TEAS) with 2-fluoro analogs of both all-trans FPP and (cis,trans)-FPP revealed binding modes consistent with pre-organization of the farnesyl chain. These results provide a structural glimpse into both cisoid and transoid cyclization pathways efficiently templated by a single enzyme active site, consistent with the recently elucidated stereochem. of the cisoid products. Further, computational studies using d. functional theory calcns. reveal concerted, highly asynchronous cyclization pathways leading to the major cisoid cyclization products. The implications of these discoveries for expanded sesquiterpene diversity in nature are discussed. [on SciFinder(R)]

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  • Joseph P. Noel

  • Nikki Dellas

  • Juan A. Faraldos

  • Marylin Zhao

  • B. Andes Hess

  • Lidia Smentek

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