The Red Color of Life Transformed – Synthetic Advances and Emerging Applications of Protoporphyrin IX in Chemical Biology

European Journal of Organic Chemistry, Journal Year: 2020, Volume and Issue: 2020(22), P. 3171 - 3191

Published: Feb. 26, 2020

Protoporphyrin IX (PPIX) is the porphyrin scaffold of heme b, a ubiquitous prosthetic group proteins responsible for oxygen binding (hemoglobin, myoglobin), electron transfer (cytochrome c) and catalysis P450, catalases, peroxidases). PPIX its metallated derivatives frequently find application as therapeutic agents, imaging tools, catalysts, sensors in light harvesting. The vast toolkit accessible functionalization reactions enables easy synthetic modification to meet requirements multiple uses. In past few years, particular interest has arisen exploiting interaction with biomolecules such DNA heme-binding evolve molecular devices new functions well uncover potential toeholds. This review strives shine on most recent developments chemistry uses selected fields chemical biology.

Language: Английский

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Cofactor Binding Dynamics Influence the Catalytic Activity and Selectivity of an Artificial Metalloenzyme

ACS Catalysis, Journal Year: 2020, Volume and Issue: 10(20), P. 11783 - 11790

Published: Sept. 18, 2020

We present an artificial metalloenzyme based on the transcriptional regulator LmrR that exhibits dynamics involving positioning of its abiological metal cofactor. The position cofactor, in turn, was found to be related preferred catalytic reactivity, which is either enantioselective Friedel-Crafts alkylation indoles with β-substituted enones or tandem alkylation/enantioselective protonation α-substituted enones. could specialized for one these reactions introducing a single mutation protein. relation between cofactor and activity selectivity catalysis has not been described natural enzymes and, date, appears particular metalloenzymes.

Language: Английский

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Myoglobins engineered with artificial cofactors serve as artificial metalloenzymes and models of natural enzymes

Dalton Transactions, Journal Year: 2020, Volume and Issue: 50(6), P. 1940 - 1949

Published: Dec. 22, 2020

Replacement of heme in an oxygen-binding hemoprotein with artificial cofactors provides metalloenzymes as well enzyme models.

Language: Английский

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C–N Bond Forming Radical Rebound Is the Enantioselectivity-Determining Step in P411-Catalyzed Enantioselective C(sp³)–H Amination: A Combined Computational and Experimental Investigation

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(25), P. 11215 - 11225

Published: May 18, 2022

Engineered metalloenzymes represent promising catalysts for stereoselective C-H functionalization reactions. Recently, P450 enzymes have been evolved to allow new-to-nature intramolecular C(sp3)-H amination reactions via a nitrene transfer mechanism, giving rise diamine derivatives with excellent enantiocontrol. To shed light on the origin of enantioselectivity, combined computational and experimental study was carried out. Hybrid quantum mechanics/molecular mechanics calculations were performed investigate activation energies enantioselectivities both hydrogen atom (HAT) subsequent C-N bond forming radical rebound steps. Contrary previously hypothesized enantioinduction mechanisms, our show that step is enantioselectivity-determining, whereas preceding HAT only moderately stereoselective. Furthermore, selectivity in initial ablated by rapid conformational change intermediate prior formation. This finding corroborated using set enantiomerically pure, monodeuterated substrates. classical ab initio molecular dynamics simulations out flexibility carbon-centered intermediate. key species undergoes facile enzyme active site from pro-(R) pro-(S) configuration, slower due spin-state ring strain cyclization process, thereby allowing stereoablative Together, these studies revealed an underappreciated mechanism biocatalytic functionalizations involving intermediates, opening up new avenues development other challenging asymmetric functionalizations.

Language: Английский

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Enantio- and Diastereodivergent Cyclopropanation of Allenes by Directed Evolution of an Iridium-Containing Cytochrome

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(3), P. 1819 - 1824

Published: Jan. 8, 2024

Alkylidene cyclopropanes (ACPs) are valuable synthetic intermediates because of their constrained structure and opportunities for further diversification. Although routes to ACPs known, preparations with control both the configuration cyclopropyl (R vs S) group geometry alkene (E Z) unknown. We describe enzymatic cyclopropanation allenes ethyl diazoacetate (EDA) catalyzed by an iridium-containing cytochrome (Ir(Me)-CYP119) that controls stereochemical elements. Two mutants Ir(Me)-CYP119 identified 6-codon (6c, VILAFG) saturation mutagenesis catalyze formation (E)-ACPs −93% >99% ee >99:1 E/Z ratio just three rounds 96 mutants. By four additional mutagenesis, enzyme variant was forms (Z)-ACPs up 94% a 28:72 ratio. Computational studies show orientation carbene unit dictated mutated positions accounts stereoselectivity.

Language: Английский

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