Iron Porphyrin Carbenes as Catalytic Intermediates: Structures, Mössbauer and NMR Spectroscopic Properties, and Bonding

Khade, Rahul L.; Fan, Wenbing; Ling, Yan; Liu, Yang; Oldfield, Eric; Zhang, Yong

doi:10.1002/anie.201402472

Cited by 70 publications

(98 citation statements)

References 46 publications

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“…In addition to the possibility that structural plasticity accounts for the distance of the alkylated sites from the iron center, recent computational studies by Khade et al . 14a also invoked a dative bond from the carbene moiety to Fe, which could implicate a diffusible carbene species in the active site and might account for the observed alkylation pattern.…”

Section: Resultsmentioning

confidence: 99%

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Identification of Mechanism-Based Inactivation in P450-Catalyzed Cyclopropanation Facilitates Engineering of Improved Enzymes

et al. 2016

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Following the recent discovery that heme proteins can catalyze the cyclopropanation of styrenyl olefins with high efficiency and selectivity, interest in developing new enzymes for a variety of non-natural carbene transfer reactions has burgeoned. The fact that diazo compounds and other carbene precursors are known mechanism-based inhibitors of P450s, however, led us to investigate if they also interfere with this new enzyme function. We present evidence for two inactivation pathways that are operative during cytochrome P450-catalyzed cyclopropanation. Using a combination of UV-Vis, mass spectrometry, and proteomic analyses, we show that the heme cofactor and several nucleophilic side chains undergo covalent modification by ethyl diazoacetate (EDA). Substitution of two of the affected residues with less-nucleophilic amino acids led to a more than two-fold improvement in cyclopropanation performance (total TTN). Elucidating the inactivation pathways of heme protein-based carbene transfer catalysts should aid in the optimization of this new biocatalytic function.

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Section: Resultsmentioning

confidence: 99%

“…That the affected residues are all nucleophilic in nature is consistent with the proposed electrophilic character of the carbenoid species. 14 Modifications presumably occur by way of O–, N–, and S– alkylation by the carbene fragment.…”

Section: Resultsmentioning

confidence: 99%

Identification of Mechanism-Based Inactivation in P450-Catalyzed Cyclopropanation Facilitates Engineering of Improved Enzymes

et al. 2016

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“…Using model systems, recent DFT studies have investigated the nature of the putative iron carbenoid intermediate, shedding light on factors governing its formation and reactivity [50–52]. In particular, work by Sharon et al .…”

Section: Outlook - Future Opportunities For Hemoprotein Engineeringmentioning

confidence: 99%

Exploiting and engineering hemoproteins for abiological carbene and nitrene transfer reactions

Brandenberg

Fasan

Arnold

2017

Current Opinion in Biotechnology

292

221

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The surge in reports of heme-dependent proteins as catalysts for abiotic, synthetically valuable carbene and nitrene transfer reactions dramatically illustrates the evolvability of the protein world and our nascent ability to exploit that for new enzyme chemistry. We highlight the latest additions to the hemoprotein-catalyzed reaction repertoire (including carbene Si–H and C–H insertions, Doyle-Kirmse reactions, aldehyde olefinations, azide-to-aldehyde conversions, and intermolecular nitrene C–H insertion) and show how different hemoprotein scaffolds offer varied reactivity and selectivity. Preparative-scale syntheses of pharmaceutically relevant compounds accomplished with these new catalysts are beginning to demonstrate their biotechnological relevance. Insights into the determinants of enzyme lifetime and product yield are providing generalizable cues for engineering heme-dependent proteins to further broaden the scope and utility of these non-natural activities.

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“…This is consistent with its improved performance compared to mPW1PW91 as reported in a recent NMR chemical shielding study. 57 In addition, the impact of the choice of the basis set on the NMR calculation was investigated. Using the all electron Huzinaga basis set 50 14s10p5d, calculations with ωB97XD resulted in an isotropic chemical shift of 299 ppm.…”

Section: Resultsmentioning

confidence: 99%

⁷⁷Se Chemical Shift Tensor of l-Selenocystine: Experimental NMR Measurements and Quantum Chemical Investigations of Structural Effects

2015

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The genetically encoded amino acid selenocysteine and its dimeric form, selenocystine, are both utilized by nature. They are found in active sites of selenoproteins, enzymes that facilitate a diverse range of reactions, including the detoxification of reactive oxygen species and regulation of redox pathways. Due to selenocysteine and selenocystine’s specialized biological roles, it is of interest to examine their 77Se NMR properties and how those can in turn be employed to study biological systems. We report the solid-state 77Se NMR measurements of the L-selenocystine chemical shift tensor, which provides the first experimental chemical shift tensor information of selenocysteine-containing systems. Quantum chemical calculations of L-selenocystine models were performed to help understand various structural effects on 77Se L-selenocystine’s chemical shift tensor. The effects of protonation state, protein environment, and substituent of selenium-bonded carbon on the isotropic chemical shift were found to be in a range of ca. 10–20 ppm. However, the conformational effect was found to be much larger, spanning ca. 600 ppm for the C-Se-Se-C dihedral angle range of −180° to +180°. Our calculations show that around the minimum energy structure with a C-Se-Se-C dihedral angle of ca. −90°, the energy costs to alter the dihedral angle in the range from −120° to −60° are within only 2.5 kcal/mol. This makes it possible to realize these conformations in a protein or crystal environment. 77Se NMR was found to be a sensitive probe to such changes and has an isotropic chemical shift range of 272±30 ppm for this energetically favorable conformation range. The energy-minimized structures exhibited calculated isotropic shifts that lay within 3–9% of those reported in previous solution NMR studies. The experimental solid-state NMR isotropic chemical shift is near the lower bound of this calculated range for these readily accessible conformations. These results suggest that, the dihedral information may be deduced for a protein with appropriate structural models. These first-time experimental and theoretical results will facilitate future NMR studies of selenium-containing compounds and proteins.

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Iron Porphyrin Carbenes as Catalytic Intermediates: Structures, Mössbauer and NMR Spectroscopic Properties, and Bonding

Cited by 70 publications

References 46 publications

Identification of Mechanism-Based Inactivation in P450-Catalyzed Cyclopropanation Facilitates Engineering of Improved Enzymes

Identification of Mechanism-Based Inactivation in P450-Catalyzed Cyclopropanation Facilitates Engineering of Improved Enzymes

Exploiting and engineering hemoproteins for abiological carbene and nitrene transfer reactions

⁷⁷Se Chemical Shift Tensor of l-Selenocystine: Experimental NMR Measurements and Quantum Chemical Investigations of Structural Effects

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Iron Porphyrin Carbenes as Catalytic Intermediates: Structures, Mössbauer and NMR Spectroscopic Properties, and Bonding

Cited by 70 publications

References 46 publications

Identification of Mechanism-Based Inactivation in P450-Catalyzed Cyclopropanation Facilitates Engineering of Improved Enzymes

Identification of Mechanism-Based Inactivation in P450-Catalyzed Cyclopropanation Facilitates Engineering of Improved Enzymes

Exploiting and engineering hemoproteins for abiological carbene and nitrene transfer reactions

77Se Chemical Shift Tensor of l-Selenocystine: Experimental NMR Measurements and Quantum Chemical Investigations of Structural Effects

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Product

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⁷⁷Se Chemical Shift Tensor of l-Selenocystine: Experimental NMR Measurements and Quantum Chemical Investigations of Structural Effects