Lanthanides are an example of nonbiogenic metal species and have been widely used in crystallographic and spectroscopic studies to probe Mg /Ca binding sites in metalloproteins by replacing the native cofactor. Recently, a methanol dehydrogenase (MDH) enzyme containing cerium ion in the active site has been isolated from Methylacidiphilum fumariolicum bacterium. With the aim to highlight as metal ion substitution can be reflected in catalytic mechanism, a comparative DFT study between Ca- and Ce-MDH has been undertaken. The obtained potential energy surfaces (PES), for two considered reaction mechanisms (named A and B), indicate mechanism A (addition-elimination and protonation processes) as the favored for both the enzymes and show as the barrier for the rate-determining step of Ce-MDH requires 19.4 kcal mol .

Oxidative conditions are frequently enhanced by the presence of redox metal ions. In this study, the role of capsaicin (8-methyl-N-vanillyl-6-nonenamide, CAP) in copper-induced oxidative stress was investigated using density functional theory simulations. It was found that CAP has the capability to chelate Cu(II), leading to complexes that are harder to reduce than free Cu(II). CAP fully turns off the Cu(II) reduction by Asc−, and slows down the reduction in this cation by O2•−. Therefore, CAP is proposed as an •OH-inactivating ligand by impeding the reduction in metal ions (OIL-1), hindering the production of •OH via Fenton-like reactions, at physiological pH. CAP is also predicted to be an excellent antioxidant as a scavenger of •OH, yielded through Fenton-like reactions (OIL-2). The reactions between CAP-Cu(II) chelates and •OH were estimated to be diffusion-limited. Thus, these chelates are capable of deactivating this dangerous radical immediately after being formed by Fenton-like reactions.

We have computationally determined the catalytic mechanism of human transketolase (hTK) using a cluster model approach and density functional theory calculations. We were able to determine all the relevant structures, bringing solid evidences to the proposed experimental mechanism, and to add important detail to the structure of the transition states and the energy profile associated with catalysis. Furthermore, we have established the existence of a crucial intermediate of the catalytic cycle, in agreement with experiments. The calculated data brought new insights to hTK's catalytic mechanism, providing free-energy values for the chemical reaction, as well as adding atomistic detail to the experimental mechanism.[a] Dr.

To elucidate the catalytic mechanism of cobalt(III)-benzonitrile and iron(III)--pivalonitrile hydratases, we have performed at density functional level a study using the cluster model approach. Computations were made in a protein framework. Following the suggestions given in a recent work on the analogous enzyme Fe(III)-NHase, we have explored the feasibility of a new working mechanism of examined enzymes. According to our results, after the formation of enzyme substrate complex, the reaction evolves toward product in only three steps. The first one is the nucleophilic attack, led by the -OH group of the αCys113-S-OH on the nitrile carbon atom, followed by the amide formation and by the enzyme restoring phase that our computations indicate as the most expensive step from the energetic point of view in both catalytic processes.

The exact chemical structure of non–crystallising natural products is still one of the main challenges in Natural Sciences. Despite tremendous advances in total synthesis, the absolute structural determination of a myriad of natural products with very sensitive chemical functionalities remains undone. Here, we show that a metal–organic framework (MOF) with alcohol–containing arms and adsorbed water, enables selective hydrolysis of glycosyl bonds, supramolecular order with the so–formed chiral fragments and absolute determination of the organic structure by single–crystal X–ray crystallography in a single operation. This combined strategy based on a biomimetic, cheap, robust and multigram available solid catalyst opens the door to determine the absolute configuration of ketal compounds regardless degradation sensitiveness, and also to design extremely–mild metal–free solid–catalysed processes without formal acid protons.

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A large number of enzymes need a metal ion to express their catalytic activity. Among the different roles that metal ions can play in the catalytic event, the most common are their ability to orient the substrate correctly for the reaction, to exchange electrons in redox reactions, to stabilize negative charges. In many reactions catalyzed by metal ions, they behave like the proton, essentially as Lewis acids but are often more effective than the proton because they can be present at high concentrations at neutral pH. In an attempt to adapt to drastic environmental conditions, enzymes can take advantage of the presence of many metal species in addition to those defined as native and still be active. In fact, today we know enzymes that contain essential bulk, trace, and ultra-trace elements. In this work, we report theoretical results obtained for three different enzymes each of which contains different metal ions, trying to highlight any differences in their working mechanism as a function of the replacement of the metal center at the active site.

Atomic resolution X-ray crystallography has shown that an intermediate (the X5P-ThDP adduct) of the catalytic cycle of transketolase (TK) displays a significant, putatively highly energetic, out-of-plane distortion in a sp 2 carbon adjacent to a lytic bond, suggested to lower the barrier of the subsequent step, and thus was postulated to embody a clear-cut demonstration of the intermediate destabilization effect. The lytic bond of the subsequent rate-limiting step was very elongated in the X-ray structure (1.61 Å), which was proposed to be a consequence of the out-of-plane distortion. Here we use high-level QM and QM/MM calculations to study the intermediate destabilization effect. We show that the intrinsic energy penalty for the observed distortion is small (0.2 kcal·mol –1 ) and that the establishment of a favorable hydrogen bond within X5P-ThDP, instead of enzyme steric strain, was found to be the main cause for the distortion. As the net energetic effect of the distortion is small, the establishment of the internal hydrogen bond (−0.6 kcal·mol –1 ) offsets the associated penalty. This makes the distorted structure more stable than the nondistorted one. Even though the energy contributions determined here are close to the accuracy of the computational methods in estimating penalties for geometric distortions, our data show that the intermediate destabilization effect provides a small contribution to the observed reaction rate and does not represent a catalytic effect that justifies the many orders of magnitude which enzymes accelerate reaction rates. The results help to understand the intrinsic enzymatic machinery behind enzyme’s amazing proficiency.