YEN-TING LIN
@manchester.ac.uk
Department of Chemical Engineering and Analytical Science
University of Manchester
RESEARCH INTERESTS
Oxidative properties of heme and nonheme enzymes. Nature contains many enzymes that utilize molecular oxygen on an iron center, namely there a large group of enzymes with a heme central ligand but also many enzymes with non-heme ligands.
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Sam P. de Visser, Yen-Ting Lin, Hafiz Saqib Ali, Umesh Kumar Bagha, Gourab Mukherjee, and Chivukula V. Sastri
Elsevier BV
Abstract There are many examples in bioinorganic chemistry, where metalloenzymes produce different reaction products than analogous biomimetic model complexes despite them having the same transition metal and first-coordination sphere environment. As a result, a lot of research has been devoted to the understanding of the effect of the first- and second coordination sphere of catalytic reaction centers. Thermodynamically, catalysis should follow the Bell-Evans-Polanyi principle, where the product with the largest driving force gives the lowest reaction barrier and consequently highest reaction rate and dominant reaction products. However, there are many examples in the literature, where the dominant products of an enzymatic reaction do not correspond to the reaction process with the largest exothermicity. In general, catalysis that follows the Bell-Evans-Polanyi principle is designated positive catalysis, whereas when products are obtained from non-Bell-Evans-Polanyi reactivity, it is defined as negative catalysis. In enzymes; however, the first- and second-coordination sphere determines whether positive or negative catalysis happens but many intricate details on how selectivities are reversed are still unknown. In this review paper, we cover recent advances on enzyme understanding where negative catalysis is dominant over positive catalysis. We show that the enzyme can achieve this feat, e.g., through the positioning of substrate and oxidant that then gives the desired product distributions. In particular, often the substrate is positioned such that the desired group of the substrate is placed as close as possible to the oxidant, while unwanted activation channels are blocked by electrostatic perturbations or shielded by protein residues. Furthermore, recent work has shown that reactivity patterns in enzymes can also be influenced by long-range electrostatic interactions like an electric dipole field that can weaken or strengthen chemical bonds through long-range polarization effects. As a result of these electric field effects and long-range electrostatic interactions, enzymes can react through negative catalysis, where a thermodynamically less likely process gives the dominant products. In this review paper, we define and describe positive and negative catalysis in enzymes and compare structure and reactivity with biomimetic and homogeneous catalysts for a number of mononuclear iron-type enzymes including the cytochromes P450 and non-heme iron dioxygenases.
Yen-Ting Lin and Sam P. de Visser
MDPI AG
There are two types of cytochrome P450 enzymes in nature, namely, the monooxygenases and the peroxygenases. Both enzyme classes participate in substrate biodegradation or biosynthesis reactions in nature, but the P450 monooxygenases use dioxygen, while the peroxygenases take H2O2 in their catalytic cycle instead. By contrast to the P450 monooxygenases, the P450 peroxygenases do not require an external redox partner to deliver electrons during the catalytic cycle, and also no external proton source is needed. Therefore, they are fully self-sufficient, which affords them opportunities in biotechnological applications. One specific P450 peroxygenase, namely, P450 OleTJE, reacts with long-chain linear fatty acids through oxidative decarboxylation to form hydrocarbons and, as such, has been implicated as a suitable source for the biosynthesis of biofuels. Unfortunately, the reactions were shown to produce a considerable amount of side products originating from Cα and Cβ hydroxylation and desaturation. These product distributions were found to be strongly dependent on whether the substrate had substituents on the Cα and/or Cβ atoms. To understand the bifurcation pathways of substrate activation by P450 OleTJE leading to decarboxylation, Cα hydroxylation, Cβ hydroxylation and Cα−Cβ desaturation, we performed a computational study using 3-phenylpropionate and 2-phenylbutyrate as substrates. We set up large cluster models containing the heme, the substrate and the key features of the substrate binding pocket and calculated (using density functional theory) the pathways leading to the four possible products. This work predicts that the two substrates will react with different reaction rates due to accessibility differences of the substrates to the active oxidant, and, as a consequence, these two substrates will also generate different products. This work explains how the substrate binding pocket of P450 OleTJE guides a reaction to a chemoselectivity.
Yen‐Ting Lin, Hafiz Saqib Ali, and Sam P. Visser
Wiley
The nonheme iron dioxygenase 2-(trimethylammonio)-ethylphosphonate dioxygenase (TmpA) is an enzyme involved in the regio- and chemoselective hydroxylation at the C 1 -position of the substrate as part of the biosynthesis of glycine betaine in bacteria and carnitine in humans. To understand how the enzyme avoids breaking the weak C 2 -H bond in favor of C 1 -hydroxylation, we set up a cluster model of 242 atoms representing the first and second-coordination sphere of the metal center and substrate binding pocket and investigated possible reaction mechanisms of substrate activation by an iron(IV)-oxo species by density functional theory methods. In agreement with experimental product distributions, the calculations predict a favorable C 1 -hydroxylation pathway. The calculations show that the selectivity is guided through electrostatic perturbations inside the protein from charged residues, external electric fields and electric dipole moments. In particular, charged residues influence and perturb the homolytic bond strength of the C 1 -H and C 2 -H bonds of the substrate, and strongly strengthens the C 2 -H bond in the substrate-bound orientation.
Yen‐Ting Lin, Hafiz S. Ali, and Sam P. Visser
Wiley
Aryloxyalkanoate dioxygenases are unique herbicide biodegrading nonheme iron enzymes found in plants and hence, from environmental and agricultural point of view they are important and valuable. However, they often are substrate specific and little is known on the details of the mechanism and the substrate scope. To this end, we created enzyme models and calculate the mechanism for 2,4-dichlorophenoxyacetic acid biodegradation and 2-methyl substituted analogs by density functional theory. The work shows that the substrate binding is tight and positions the aliphatic group close to the metal center to enable a chemoselective reaction mechanism to form the C 2 -hydroxy products, whereas the aromatic hydroxylation barriers are well higher in energy. Subsequently, we investigated the metabolism of R - and S -methyl substituted inhibitors and show that these do not react as efficiently as 2,4-dichlorophenoxyacetic acid substrate due to stereochemical clashes in the active site and particularly for the R -isomer give high rebound barriers.
Daniel C. Cummins, Jessica G. Alvarado, Jan Paulo T. Zaragoza, Muhammad Qadri Effendy Mubarak, Yen-Ting Lin, Sam P. de Visser, and David P. Goldberg
American Chemical Society (ACS)
The transfer of •OH from metal-hydroxo species to carbon radicals (R•) to give hydroxylated products (ROH) is a fundamental process in metal-mediated heme and nonheme C-H bond oxidations. This step, often referred to as the hydroxyl "rebound" step, is typically very fast, making direct study of this process challenging if not impossible. In this report, we describe the reactions of the synthetic models M(OH)(ttppc) (M = Fe (1), Mn (3); ttppc = 5,10,15-tris(2,4,6-triphenyl)phenyl corrolato3-) with a series of triphenylmethyl carbon radical (R•) derivatives ((4-X-C6H4)3C•; X = OMe, tBu, Ph, Cl, CN) to give the one-electron reduced MIII(ttppc) complexes and ROH products. Rate constants for 3 for the different radicals ranged from 11.4(1) to 58.4(2) M-1 s-1, as compared to those for 1, which fall between 0.74(2) and 357(4) M-1 s-1. Linear correlations for Hammett and Marcus plots for both Mn and Fe were observed, and the small magnitudes of the slopes for both correlations imply a concerted •OH transfer reaction for both metals. Eyring analyses of reactions for 1 and 3 with (4-X-C6H4)3C• (X = tBu, CN) also give good linear correlations, and a comparison of the resulting activation parameters highlight the importance of entropy in these •OH transfer reactions. Density functional theory calculations of the reaction profiles show a concerted process with one transition state for all radicals investigated and help to explain the electronic features of the OH rebound process.
Fabián G. Cantú Reinhard, Yen-Ting Lin, Agnieszka Stańczak, and Sam P. de Visser
MDPI AG
The cytochromes P450 are versatile enzymes found in all forms of life. Most P450s use dioxygen on a heme center to activate substrates, but one class of P450s utilizes hydrogen peroxide instead. Within the class of P450 peroxygenases, the P450 OleTJE isozyme binds fatty acid substrates and converts them into a range of products through the α-hydroxylation, β-hydroxylation and decarboxylation of the substrate. The latter produces hydrocarbon products and hence can be used as biofuels. The origin of these product distributions is unclear, and, as such, we decided to investigate substrate positioning in the active site and find out what the effect is on the chemoselectivity of the reaction. In this work we present a detailed computational study on the wild-type and engineered structures of P450 OleTJE using a combination of density functional theory and quantum mechanics/molecular mechanics methods. We initially explore the wild-type structure with a variety of methods and models and show that various substrate activation transition states are close in energy and hence small perturbations as through the protein may affect product distributions. We then engineered the protein by generating an in silico model of the double mutant Asn242Arg/Arg245Asn that moves the position of an active site Arg residue in the substrate-binding pocket that is known to form a salt-bridge with the substrate. The substrate activation by the iron(IV)-oxo heme cation radical species (Compound I) was again studied using quantum mechanics/molecular mechanics (QM/MM) methods. Dramatic differences in reactivity patterns, barrier heights and structure are seen, which shows the importance of correct substrate positioning in the protein and the effect of the second-coordination sphere on the selectivity and activity of enzymes.
Yen‐Ting Lin, Agnieszka Stańczak, Yulian Manchev, Grit D. Straganz, and Sam P. Visser
Wiley
Decarboxylation of fatty acids is an important reaction in cell metabolism, but also has potential in biotechnology for the biosynthesis of hydrocarbons as biofuels. The recently discovered nonheme iron decarboxylase UndA is involved in the biosynthesis of 1-undecene from dodecanoic acid and using X-ray crystallography was assigned to be a mononuclear iron species. However, the work was contradicted by spectroscopic studies that suggested UndA to be more likely a dinuclear iron system. To resolve this controversy we decided to pursue a computational study on the reaction mechanism of fatty acid decarboxylation by UndA using iron(III)-superoxo and diiron(IV)-dioxo models. We tested several models with different protonation states of active site residues. Overall, however, the calculations imply that mononuclear iron(III)-superoxo is a sluggish oxidant of hydrogen atom abstraction reactions in UndA and will not be able to activate fatty acid residues by decarboxylation at room temperature. By contrast, a diiron-dioxo complex reacts with much lower hydrogen atom abstraction barriers and hence is a more likely oxidant in UndA.
Thomas M. Pangia, Vishal Yadav, Emilie F. Gérard, Yen-Ting Lin, Sam P. de Visser, Guy N. L. Jameson, and David P. Goldberg
American Chemical Society (ACS)
An iron(III) methoxide complex reacts with para-substituted triarylmethyl radicals to give iron(II) and methoxyether products. Second-order rate constants for the radical derivatives were obtained. Hammett and Marcus plots suggest the radical transfer reactions proceed via a concerted process. Calculations support the concerted nature of these reactions involving a single transition state with no initial charge transfer. These findings have implications for the radical "rebound" step invoked in nonheme iron oxygenases, halogenases, and related synthetic catalysts.