Modeling enzyme catalysis: The CotB2 cyclase mechanism

Terpene cyclases are responsible for the initial cyclization cascade in the multistep synthesis of more than 80,000 known natural products. This abundance of compounds is generated using a very limited pool of substrates based on linear isoprenoids [i]. The chemodiversity obtained by terpene cyclases suggests a catalytic challenge to these enzymes. CotB2 is a di-terpene cyclase from Streptomyces melanosporofaciens, which synthesizes the formation of cyclooctat-9-en-7-ol, a precursor to cyclooctatin. Cyclooctatin is a next-generation anti-inflammatory drug [ii]-[iii]. In this work, we present a detailed mechanistic study of the biosynthesis of cyclooctat-9-en-7-ol by CotB2 cyclase, using theoretical tools (such as, quantum mechanics and molecular dynamics calculations [iv]-[vi]. A detailed understanding of the CotB2 mechanism can provide important information towards a synthetic strategy for cyclooctatin and related terpene manufacturing.

[i] Degenhardt, J., T.G. Köllner, and J. Gershenzon, Monoterpene and sesquiterpene synthases and the origin of terpene skeletal diversity in plants. Phytochemistry, 2009. 70(15-16): p. 1621-1637

[ii]AOYAGI, T., et al., CYCLOOCTATIN, A NEW INHIBITOR OF LYSOPHOSPHOLIPASE, PRODUCED BY Streptomyces melanosporofaciens MI614-43F2. The Journal of antibiotics, 1992. 45(10): p. 1587-1591

[iii] AOYAMA, T., et al., The structure of cyclooctatin, a new inhibitor of lysophospholipase. The Journal of antibiotics, 1992. 45(10): p. 1703-1704.

[iv] Hill, J.-R., L. Subramanian, and A. Maiti, Molecular modeling techniques in material sciences. 2005: CRC press

[v] Lennard-Jones, J.E., Cohesion. Proceedings of the Physical Society, 1931. 43(5): p. 461.

[vi] Cramer, C.J., Essentials of computational chemistry: theories and models. 2013: John Wiley & Sons.