QM/MM study of the taxadiene synthase mechanism. Issue 21 (6th May 2019)

• Record Type: Journal Article
• Authors: van Rijn, Jeaphianne P. M.; Escorcia, Andrés M.; Thiel, Walter
• Is Part Of: Journal of computational chemistry. Volume 40:Issue 21(2019)
• Page Start: 1902
• Page End: 1910
• Publication Date: 2019-05-06
• Subjects: enzyme catalysis -- enzyme promiscuity -- QM/MM -- terpene synthase -- taxadiene; Chemistry -- Data processing -- Periodicals; 542.85
• DOI: 10.1002/jcc.25846
• Languages: English
• ISSNs: 0192-8651

Abstract

Abstract : Combined quantum mechanics/molecular mechanics (QM/MM) calculations were used to investigate the reaction mechanism of taxadiene synthase (TXS). TXS catalyzes the cyclization of geranylgeranyl diphosphate (GGPP) to taxadiene (T) and four minor cyclic products. All these products originate from the deprotonation of carbocation intermediates. The reaction profiles for the conversion of GGPP to T as well as to minor products were calculated for different configurations of relevant TXS carbocation complexes. The QM region was treated at the M06‐2X/TZVP level, while the CHARMM27 force field was used to describe the MM region. The QM/MM calculations suggest a reaction pathway for the conversion of GGPP to T, which slightly differs from previous proposals regarding the number of reaction steps and the conformation of the carbocations. The QM/MM results also indicate that the formation of minor products via water‐assisted deprotonation of the carbocations is highly exothermic, by about −7 to −23 kcal/mol. Curiously, however, the computed barriers and reaction energies indicate that the formation of some of the minor products is more facile than the formation of T. Thus, the present QM/MM calculations provide detailed insights into possible reaction pathways and into the origin of the promiscuity of TXS, but they do not reproduce the product distribution observed experimentally. © 2019 Wiley Periodicals, Inc. Abstract : Taxadiene synthase catalyzes the cyclization of geranylgeranyl diphosphate (GGPP) to taxadiene and four minor cyclic products. Taxadiene is a biosynthetic precursor to the potent anticancer drug taxol. Getting molecular insights into taxadiene synthase catalysis may help to improve the industrial processes currently employed to produce taxol. The authors present QM/MM calculations of potential reaction pathways from GGPP to taxadiene and a possible explanation for why taxadiene synthase not only produces taxadiene, but also generates side products.