Structural Basis of Catalysis in the Bacterial Monoterpene
Synthases Linalool Synthase and 1,8-Cineole Synthase
Version 2 2017-09-21, 04:30
Version 1 2017-08-21, 20:31
Posted on 2017-09-21 - 04:30
Terpenoids form the
largest and stereochemically most diverse class
of natural products, and there is considerable interest in producing
these by biocatalysis with whole cells or purified enzymes, and by
metabolic engineering. The monoterpenes are an important class of
terpenes and are industrially important as flavors and fragrances.
We report here structures for the recently discovered Streptomyces clavuligerus monoterpene synthases linalool
synthase (bLinS) and 1,8-cineole synthase (bCinS), and we show that
these are active biocatalysts for monoterpene production using biocatalysis
and metabolic engineering platforms. In metabolically engineered monoterpene-producing E. coli strains, use of bLinS leads to 300-fold higher
linalool production compared with the corresponding plant monoterpene
synthase. With bCinS, 1,8-cineole is produced with 96% purity compared
to 67% from plant species. Structures of bLinS and bCinS, and their
complexes with fluorinated substrate analogues, show that these bacterial
monoterpene synthases are similar to previously characterized sesquiterpene
synthases. Molecular dynamics simulations suggest that these monoterpene
synthases do not undergo large-scale conformational changes during
the reaction cycle, making them attractive targets for structured-based
protein engineering to expand the catalytic scope of these enzymes
toward alternative monoterpene scaffolds. Comparison of the bLinS
and bCinS structures indicates how their active sites steer reactive
carbocation intermediates to the desired acyclic linalool (bLinS)
or bicyclic 1,8-cineole (bCinS) products. The work reported here provides
the analysis of structures for this important class of monoterpene
synthase. This should now guide exploitation of the bacterial enzymes
as gateway biocatalysts for the production of other monoterpenes and
monoterpenoids.
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Karuppiah, Vijaykumar; Ranaghan, Kara E.; G. H. Leferink, Nicole; Johannissen, Linus O.; Shanmugam, Muralidharan; Ní Cheallaigh, Aisling; et al. (2017). Structural Basis of Catalysis in the Bacterial Monoterpene
Synthases Linalool Synthase and 1,8-Cineole Synthase. ACS Publications. Collection. https://doi.org/10.1021/acscatal.7b01924
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AUTHORS (15)
VK
Vijaykumar Karuppiah
KR
Kara E. Ranaghan
NG
Nicole G. H. Leferink
LJ
Linus O. Johannissen
MS
Muralidharan Shanmugam
AN
Aisling Ní Cheallaigh
NB
Nathan J. Bennett
LK
Lewis J. Kearsey
ET
Eriko Takano
JG
John M. Gardiner
MW
Marc W. van der Kamp
SH
Sam Hay
AM
Adrian J. Mulholland
DL
David Leys
NS
Nigel S. Scrutton
KEYWORDS
bCinSmonoterpene synthasesMolecular dynamics simulationsplant monoterpene synthasestructured-based protein engineeringreactive carbocation intermediatesStreptomyces clavuligerus monoterpene synthases linalool synthaseBacterial Monoterpene Synthases Linalool SynthasebLinSalternative monoterpene scaffolds