On the engineering of reductase-based-monooxygenase activity in CYP450 peroxygenases

Yadav, Shalini; Shaik, Sason; Dubey, Kshatresh Dutta

doi:10.1039/d3sc06538c

Chem. Sci.

2024

DOI: 10.1039/d3sc06538c

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On the engineering of reductase-based-monooxygenase activity in CYP450 peroxygenases

Shalini Yadav,

Sason Shaik,

Kshatresh Dutta Dubey

Abstract: Recent bioengineering of CYP450OleT shows that peroxide-based CYP450OleT can be converted to a reductase-based self-sufficient enzyme, which is capable of efficient hydroxylation and decarboxylation activity for a wide range of...

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Cited by 3 publications

References 55 publications

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A possible origin of life in nonpolar environments

Vitas,

Dobovišek

2025

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A possible origin of life in nonpolar environments

Vitas,

Dobovišek

2025

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Structural and mechanistic insights into oxidative biaryl coupling to form the arylomycin core by an engineered CYP450

Kardam,

Bhatt,

Dubey

2025

Dalton Trans.

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Mechanism of the Oxidative Ring-Closure Reaction during Gliotoxin Biosynthesis by Cytochrome P450 GliF

Qureshi,

Mokkawes,

Cao

et al. 2024

IJMS

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During gliotoxin biosynthesis in fungi, the cytochrome P450 GliF enzyme catalyzes an unusual C–N ring-closure step while also an aromatic ring is hydroxylated in the same reaction cycle, which may have relevance to drug synthesis reactions in biotechnology. However, as the details of the reaction mechanism are still controversial, no applications have been developed yet. To resolve the mechanism of gliotoxin biosynthesis and gain insight into the steps leading to ring-closure, we ran a combination of molecular dynamics and density functional theory calculations on the structure and reactivity of P450 GliF and tested a range of possible reaction mechanisms, pathways and models. The calculations show that, rather than hydrogen atom transfer from the substrate to Compound I, an initial proton transfer transition state is followed by a fast electron transfer en route to the radical intermediate, and hence a non-synchronous hydrogen atom abstraction takes place. The radical intermediate then reacts by OH rebound to the aromatic ring to form a biradical in the substrate that, through ring-closure between the radical centers, gives gliotoxin products. Interestingly, the structure and energetics of the reaction mechanisms appear little affected by the addition of polar groups to the model and hence we predict that the reaction can be catalyzed by other P450 isozymes that also bind the same substrate. Alternative pathways, such as a pathway starting with an electrophilic attack on the arene to form an epoxide, are high in energy and are ruled out.

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On the engineering of reductase-based-monooxygenase activity in CYP450 peroxygenases

Abstract: Recent bioengineering of CYP450OleT shows that peroxide-based CYP450OleT can be converted to a reductase-based self-sufficient enzyme, which is capable of efficient hydroxylation and decarboxylation activity for a wide range of...

Cited by 3 publications

References 55 publications

A possible origin of life in nonpolar environments

A possible origin of life in nonpolar environments

Structural and mechanistic insights into oxidative biaryl coupling to form the arylomycin core by an engineered CYP450

Mechanism of the Oxidative Ring-Closure Reaction during Gliotoxin Biosynthesis by Cytochrome P450 GliF

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