Enhancing the High-spin Reactivity in C-H Bond Activation by Iron (IV)-Oxo Species: Insights from Paclitaxel Hydroxylation by CYP2C8

Overview

Journal Front Chem

Specialty Chemistry

Date 2024 Sep 30

PMID 39345859

Authors

Dongxiao Yue

Hajime Hirao

Affiliations

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Abstract

Previous theoretical studies have revealed that high-spin states possess flatter potential energy surfaces than low-spin states in reactions involving iron(IV)-oxo species of cytochrome P450 enzymes (P450s), nonheme enzymes, or biomimetic complexes. Therefore, actively utilizing high-spin states to enhance challenging chemical transformations, such as C-H bond activation, represents an intriguing research avenue. However, the inherent instability of high-spin states relative to low-spin states in pre-reaction complexes often hinders their accessibility around the transition state, especially in heme systems with strong ligand fields. Counterintuitively, our investigation of the metabolic hydroxylation of paclitaxel by human CYP2C8 using a hybrid quantum mechanics and molecular mechanics (QM/MM) approach showed that the high-spin sextet state exhibits unusually high stability, when the reaction follows a secondary reaction pathway leading to 6β-hydroxypaclitaxel. We thoroughly analyzed the factors contributing to the enhanced stabilization of the high-spin state, and the knowledge obtained could be instrumental in designing competent biomimetic catalysts and biocatalysts for C-H bond activation.

Citing Articles

Hydrogen-Bond-Assisted Catalysis: Hydroxylation of Paclitaxel by Human CYP2C8.

Yue D, Ng E, Hirao H J Am Chem Soc. 2024; 146(44):30117-30125.

PMID: 39441858 PMC: 11544615. DOI: 10.1021/jacs.4c07937.

References

Yue D, Hirao H . Mechanism of Selective Aromatic Hydroxylation in the Metabolic Transformation of Paclitaxel Catalyzed by Human CYP3A4. J Chem Inf Model. 2023; 63(24):7826-7836. DOI: 10.1021/acs.jcim.3c01630. View

Becke A, Johnson E . A density-functional model of the dispersion interaction. J Chem Phys. 2005; 123(15):154101. DOI: 10.1063/1.2065267. View

Gandeepan P, Muller T, Zell D, Cera G, Warratz S, Ackermann L . 3d Transition Metals for C-H Activation. Chem Rev. 2018; 119(4):2192-2452. DOI: 10.1021/acs.chemrev.8b00507. View

Grimme S, Ehrlich S, Goerigk L . Effect of the damping function in dispersion corrected density functional theory. J Comput Chem. 2011; 32(7):1456-65. DOI: 10.1002/jcc.21759. View

Shaik S, Kumar D, de Visser S, Altun A, Thiel W . Theoretical perspective on the structure and mechanism of cytochrome P450 enzymes. Chem Rev. 2005; 105(6):2279-328. DOI: 10.1021/cr030722j. View

Li Z, Jiang Y, Guengerich F, Ma L, Li S, Zhang W . Engineering cytochrome P450 enzyme systems for biomedical and biotechnological applications. J Biol Chem. 2019; 295(3):833-849. PMC: 6970918. DOI: 10.1074/jbc.REV119.008758. View

Anastas P, Eghbali N . Green chemistry: principles and practice. Chem Soc Rev. 2009; 39(1):301-12. DOI: 10.1039/b918763b. View

Kumar S . Engineering cytochrome P450 biocatalysts for biotechnology, medicine and bioremediation. Expert Opin Drug Metab Toxicol. 2010; 6(2):115-31. PMC: 2811222. DOI: 10.1517/17425250903431040. View

Bigi J, Harman W, Lassalle-Kaiser B, Robles D, Stich T, Yano J . A high-spin iron(IV)-oxo complex supported by a trigonal nonheme pyrrolide platform. J Am Chem Soc. 2012; 134(3):1536-42. DOI: 10.1021/ja207048h. View

10.

England J, Guo Y, Farquhar E, Young Jr V, Munck E, Que Jr L . The crystal structure of a high-spin oxoiron(IV) complex and characterization of its self-decay pathway. J Am Chem Soc. 2010; 132(25):8635-44. PMC: 2903234. DOI: 10.1021/ja100366c. View

11.

Yamaguchi J, Yamaguchi A, Itami K . C-H bond functionalization: emerging synthetic tools for natural products and pharmaceuticals. Angew Chem Int Ed Engl. 2012; 51(36):8960-9009. DOI: 10.1002/anie.201201666. View

12.

England J, Guo Y, Van Heuvelen K, Cranswick M, Rohde G, Bominaar E . A more reactive trigonal-bipyramidal high-spin oxoiron(IV) complex with a cis-labile site. J Am Chem Soc. 2011; 133(31):11880-3. PMC: 3150404. DOI: 10.1021/ja2040909. View

13.

Sono M, Roach M, Coulter E, Dawson J . Heme-Containing Oxygenases. Chem Rev. 1996; 96(7):2841-2888. DOI: 10.1021/cr9500500. View

14.

Kumar G, Oatis Jr J, Thornburg K, Heldrich F, Hazard 3rd E, Walle T . 6 alpha-Hydroxytaxol: isolation and identification of the major metabolite of taxol in human liver microsomes. Drug Metab Dispos. 1994; 22(1):177-9. View

15.

Balcells D, Clot E, Eisenstein O . C-H bond activation in transition metal species from a computational perspective. Chem Rev. 2010; 110(2):749-823. DOI: 10.1021/cr900315k. View

16.

Sastri C, Lee J, Oh K, Lee Y, Lee J, Jackson T . Axial ligand tuning of a nonheme iron(IV)-oxo unit for hydrogen atom abstraction. Proc Natl Acad Sci U S A. 2007; 104(49):19181-6. PMC: 2148264. DOI: 10.1073/pnas.0709471104. View

17.

Weaver B . How Taxol/paclitaxel kills cancer cells. Mol Biol Cell. 2014; 25(18):2677-81. PMC: 4161504. DOI: 10.1091/mbc.E14-04-0916. View

18.

de Visser S, Ogliaro F, Harris N, Shaik S . Multi-state epoxidation of ethene by cytochrome P450: a quantum chemical study. J Am Chem Soc. 2001; 123(13):3037-47. DOI: 10.1021/ja003544+. View

19.

Denisov I, Makris T, Sligar S, Schlichting I . Structure and chemistry of cytochrome P450. Chem Rev. 2005; 105(6):2253-77. DOI: 10.1021/cr0307143. View

20.

Shaik S, Cohen S, Wang Y, Chen H, Kumar D, Thiel W . P450 enzymes: their structure, reactivity, and selectivity-modeled by QM/MM calculations. Chem Rev. 2009; 110(2):949-1017. DOI: 10.1021/cr900121s. View