Engineering cytochrome P450 enzyme systems for biomedical and biotechnological applications

Enzymatic Hydroxylations of sp3-Carbons

The selective oxygenation of non-activated carbon atoms is an ongoing synthetic challenge and biocatalysts, particularly hemoprotein oxygenases, continue to be investigated for their potential, given both their sustainable chemistry credentials and also their superior selectivity. However, issues of stability, activity and complex reaction requirements often render these biocatalytic oxygenations problematic with respect to scalable industrial processes. A continuing focus on Cyto-chromes P450 (P450s), which require a reduced nicotinamide cofactor and redox protein partners for electron transport, has now led to better catalysts and processes with a greater understanding of process requirements and limitations for both in vitro and whole-cell systems. However, the discovery and development of unspecific peroxygenases (UPOs) has also recently provided valuable complementary technology to P450-catalyzed reactions. UPOs need only hydrogen peroxide to effect ox-ygenations but are hampered by their sensitivity to peroxide and also by limited selectivity. In this perspective we survey recent developments in the engineering of proteins, cells and processes for oxygenations by these two groups of hemopro-teins and evaluate their potential and relative merits for scalable reactions.

Hemoprotein Catalyzed Oxygenations: P450s, UPOs, and Progress toward Scalable Reactions.

This review outlines recent developments in protein engineering of stereo‐ and regioselective enzymes, which are of prime interest in organic and pharmaceutical chemistry as well as biotechnology. The widespread application of enzymes was hampered for decades due to limited enantio‐, diastereo‐ and regioselectivity, which was the reason why most organic chemists were not interested in biocatalysis. This attitude began to change with the advent of semi‐rational directed evolution methods based on focused saturation mutagenesis at sites lining the binding pocket. Screening constitutes the labor‐intensive step (bottleneck), which is the reason why various research groups are continuing to develop techniques for the generation of small and smart mutant libraries. Rational enzyme design, traditionally an alternative to directed evolution, provides small collections of mutants which require minimal screening. This approach first focused on thermostabilization, and did not enter the field of stereoselectivity until later. Computational guides such as the Rosetta algorithms, HotSpot Wizard metric, and machine learning (ML) contribute significantly to decision making. The newest advancements show that semi‐rational directed evolution such as CAST/ISM and rational enzyme design no longer develop on separate tracks, instead, they have started to merge. Indeed, researchers utilizing the two approaches have learned from each other. Today, the toolbox of organic chemists includes enzymes, primarily because the possibility of controlling stereoselectivity by protein engineering has ensured reliability when facing synthetic challenges. This review was also written with the hope that undergraduate and graduate education will include enzymes more so than in the past.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1002/cbic.202200049

Making Enzymes Suitable for Organic Chemistry by Rational Protein Design

Regioselective aromatic O-demethylation with an artificial P450BM3 peroxygenase system

Switching an Artificial P450 Peroxygenase into Peroxidase via Mechanism-Guided Protein Engineering.

We report the selective hydroxylation of small alkanes with H2O2 catalyzed by an artificial P450 peroxygenase system generated from engineered cytochrome P450BM3 variants in assistance with dual-fu...

Peroxide-Driven Hydroxylation of Small Alkanes Catalyzedby an Artificial P450BM3 Peroxygenase System

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Switching an Artificial P450 Peroxygenase into Peroxidase via Mechanism-Guided Protein Engineering.

Peroxide-Driven Hydroxylation of Small Alkanes Catalyzedby an Artificial P450BM3 Peroxygenase System