QM/MM Study of the Reaction Mechanism of L-Tyrosine Hydroxylation Catalyzed by the Enzyme CYP76AD1

J Phys Chem B. 2024 Oct 3;128(39):9447-9454. doi: 10.1021/acs.jpcb.4c05209. Epub 2024 Aug 26.

Abstract

We have studied the hydroxylation mechanism of l-Tyr by the heme-dependent enzyme CYP76AD1 from the sugar beet (Beta vulgaris). This enzyme has a promising biotechnological application in modified yeast strains to produce medicinal alkaloids, an alternative to the traditional opium poppy harvest. A generative machine learning software based on AlphaFold was used to build the structure of CYP76AD1 since there are no structural data for this specific enzyme. After model validation, l-Tyr was docked in the active site of CYP76AD1 to assemble the reactive complex, whose catalytic distances remained stable throughout the 100 ns of MD simulation. Subsequent QM/MM calculations elucidated that l-Tyr hydroxylation occurs in two steps: hydrogen abstraction from l-Tyr by CpdI, forming an l-Tyr radical, and subsequent radical rebound, corresponding to a rate-limiting step of 16.0 kcal·mol-1. Our calculations suggest that the hydrogen abstraction step should occur in the doublet state, while the radical rebound should happen in the quartet state. The clarification of the reaction mechanism of CYP76AD1 provides insights into the rational optimization of the biosynthesis of alkaloids to eliminate the use of opium poppy.

MeSH terms

  • Beta vulgaris / chemistry
  • Beta vulgaris / metabolism
  • Biocatalysis
  • Catalytic Domain
  • Cytochrome P-450 Enzyme System* / chemistry
  • Cytochrome P-450 Enzyme System* / metabolism
  • Hydroxylation
  • Molecular Dynamics Simulation
  • Quantum Theory*
  • Tyrosine* / chemistry
  • Tyrosine* / metabolism

Substances

  • Tyrosine
  • Cytochrome P-450 Enzyme System