Redox‐Active Ligands in Catalysis

Nature’s use of redox‐active moieties combined with 3d transition‐metal ions is a powerful strategy to promote multi‐electron catalytic reactions. The ability of these moieties to store redox equivalents aids metalloenzymes in promoting multi‐electron reactions, avoiding high‐energy intermediates. In a biomimetic spirit, chemists have recently developed approaches relying on redox‐active moieties in the vicinity of metal centers to catalyze challenging transformations. This approach enables chemists to impart noble‐metal character to less toxic, and cost effective 3d transitional metals, such as Fe or Cu, in multi‐electron catalytic reactions.     

Recent Progress of Single-Atom Alloys in Heterogeneous Catalytic Reactions

In decades, heterogeneous catalysis has played a more significant role in social progress. However, the exorbitant price and low reserves vastly limit the application of noble metal catalysts, which are extensively used in heterogeneous catalysis. The single-atom-alloy catalysts (SAAs) have been regarded as a crucial way to improve the dispersion ratio of noble metal while maintaining great heterogeneous catalytic performance by dispersing noble metal single atoms on the surface of another metal. Besides the benefit from the metal bonds between noble metals and support metals, SAAs is also a unique method to construct metallic metal single atoms and obtain its characteristic catalytic performance, which is not possessed by other single atoms catalysts with positive electricity metal atoms. Most recently, SAAs have been demonstrated to catalyze a lot of significant heterogeneous reactions. This review will introduce the synthesis methods of SAAs and then summarize their applications in heterogeneous catalysis.     

Generation and Stabilization of a Dinickel Catalyst in a Metal-Organic Framework for Selective Hydrogenation Reactions

Although many monometallic active sites have been installed in metal–organic frameworks (MOFs) for catalytic reactions, there are no effective strategies to generate bimetallic catalysts in MOFs. Here we report the synthesis of a robust, efficient, and reusable MOF catalyst, MOF-NiH, by adaptively generating and stabilizing dinickel active sites using the bipyridine groups in MOF-253 with the formula of Al(OH)(2,2′-bipyridine-5,5′-dicarboxylate) for Z-selective semihydrogenation of alkynes and selective hydrogenation of C=C bonds in α,β-unsaturated aldehydes and ketones. Spectroscopic studies established the dinickel complex (bpy⋅⁻)Ni^II(μ₂-H)₂Ni^II(bpy⋅⁻) as the active catalyst. MOF-NiH efficiently catalyzed selective hydrogenation reactions with turnover numbers of up to 192 and could be used in five cycles of hydrogenation reactions without catalyst leaching or significant decrease of catalytic activities. The present work uncovers a synthetic strategy toward solution-inaccessible Earth-abundant bimetallic MOF catalysts for sustainable catalysis.     

The Role of Pyridoxal Phosphate in the Catalysis of Glycogen Phosphorylases

Glycogen phosphorylases catalyze the degradation of glycogen by phosphate (or arsenate) to glucose 1-phosphate (or glucose + arsenate). All glycogen phosphorylases that have been studied so far contain pyridoxal 5′-phosphate, a vitamin B₆-derivative, as cofactor. Removal of the cofactor results in an inactive apoenzyme. However, reduction of the azomethine bond linking pyridoxal phosphate to an ?-aminolysyl side chain of the enzyme with NaBH₄ does not inactivate glycogen phosphorylase. If therefore the cofactor should be involved in catalysis in glycogen phosphorylase it must function differently from all other classical pyridoxal phosphate dependent enzymes, for these are inactivated by reduction. ³¹P-NMR spectroscopy has revealed that the 5′-phosphate group of pyridoxal phosphate is present in catalytically active forms of glycogen phosphorylases as dianion in a hydrophobic environment shielded from aqueous solvent. Covalent and/or allosteric activation of muscle glycogen phosphorylases is accompanied by a transition of the monoprotonated form to the dianionic form of the phosphate group of the cofactor. We now report on such ionization changes in unregulated active potato- and E. coli maltodextrin phosphorylases on binding of glucose and oligosaccharides and following catalytic turnover, i.e. arsenolysis of α-1,4-glycosidic bonds. (Like glycogen phosphorylases, maltodextrin phosphorylases belong to the class of α-glucan phosphorylases.) The results of experiments carried out by our group together with recent findings on the three dimensional structure of crystalline muscle glycogen phosphorylases indicate a participation of the dianionic phosphate group as proton acceptor for the glucosyl transfer to and from the glucosyl acceptor. Although other interpretations are not excluded, at present little doubt remains that in the case of glycogen phosphorylases the dianionic phosphate group of the cofactor functions in catalysis.     

胍类催化剂

胍类化合物是一种有机强碱，在生理条件下处于完全质子化状态，在催化有机酸碱反应时，催化性能明显优于无机碱和其它有机碱催化剂。此外，经修饰后的胍类化合物可以用于不对称催化；如果对其进行生理模拟，又可以用于酶催化反应。本文主要对胍类化合物所催化的反应进行介绍。     

Asymmetric Syntheses with the Aid of Homogeneous Transition Metal Catalysts

The progress made in the field of homogeneous catalysis during the last five to six years has led, inter alia, to the development of highly selective catalysts for asymmetric syntheses. Homogeneous asymmetric hydrogenation, using well defined transition metal catalysts, may be achieved with optical yields of 85 to 90% or more. Catalytic reactions, in which the chiral centers are generated by C? C bond formation, can result in optical yields of 70 to 80%. The hydrogenation catalysts consist primarily of rhodium(I) complexes containing “Homer phosphanes”, phosphanes with chiral C atoms, or optically active amides. Catalysts which induce optical activity through the formation of C? C bonds have been developed from π-allylnickel halides, Lewis acids, and phosphanes containing chiral C atoms. The results obtained signify a breakthrough in an area of catalysis previously restricted to syntheses involving enzymes.     

Alkaline phosphatase catalysis is ultrasensitive to charge sequestered between the active site zinc ions

Escherichia coli alkaline phosphatase (AP) is a prototypical bimetalloenzyme, facilitating catalysis of phosphate monoester hydrolysis with two Zn2+ metal ions that are only 4 A apart. In the reaction's transition state, one of the nonbridging oxygen atoms of the transferred group appears to interact directly with the Zn2+ ion metallocluster. To determine the importance and the energetic properties of this interaction, we systematically varied the charge on this oxygen atom, exploiting the ability of AP to catalyze reactions of different classes of substrates. We observed that the AP catalytic proficiency correlates very well (R2 = 0.98) with the charge on this oxygen atom, over 8 orders of magnitude of catalytic proficiency. The slope of this linear correlation (31 +/- 2 kcal/mol per unit charge) is extraordinarily steep, indicating that AP greatly discriminates between differentially charged substrates. We suggest that this discrimination arises via an electrostatic interaction with the bimetallocluster. The dependence of the AP catalytic proficiency on the nonbridging oxygen charge is much larger than charge perturbation effects observed previously for other proteins. We propose that AP uses folding energy to position the two Zn2+ metal ions in close proximity, thereby creating an active site with a high electrostatic potential that is extraordinarily sensitive to the charge that "solvates" the metallocluster. The sensitivity of enzyme energetics to systematic variation in electrostatic properties provides a powerful measure of the active site environment. Future work comparing the sensitivity of related enzymes that have been optimized to catalyze different reactions will help reveal how natural selection has tuned related active sites to favor different reactions.     

Towards the Evolution of Artificial Metalloenzymes—A Protein Engineer's Perspective

Incorporating artificial metal‐cofactors into protein scaffolds results in a new class of catalysts, termed biohybrid catalysts or artificial metalloenzymes. Biohybrid catalysts can be modified chemically at the first coordination sphere of the metal complex, as well as at the second coordination sphere provided by the protein scaffold. Protein‐scaffold reengineering by directed evolution exploits the full power of nature's diversity, but requires validated screening and sophisticated metal cofactor conjugation to evolve biohybrid catalysts. In this Minireview, we summarize the recent efforts in this field to establish high‐throughput screening methods for biohybrid catalysts and we show how non‐chiral catalysts catalyze reactions enantioselectively by highlighting the first successes in this emerging field. Furthermore, we shed light on the potential of this field and challenges that need to be overcome to advance from biohybrid catalysts to true artificial metalloenzymes.     

Recent advances in tuning redox properties of electron transfer centers in metalloenzymes catalyzing the oxygen reduction reaction and H2 oxidation important for fuel cell design

Current fuel cell catalysts for the oxygen reduction reaction (ORR) and H₂ oxidation use precious metals and, for ORR, require high overpotentials. In contrast, metalloenzymes perform their respective reactions at low overpotentials using earth-abundant metals, making metalloenzymes ideal candidates for inspiring electrocatalytic design. Critical to the success of these enzymes are redox-active metal centers surrounding the active site of the enzyme. These electron transfer (ET) centers not only ensure fast ET to or away from the active site, but also tune the catalytic potential of the reaction as observed in multicopper oxidases as well as playing a role in dictating the catalytic bias of the reaction as realized in hydrogenases. This review summarizes recent advances in studying these ET centers in multicopper oxidases and heme-copper oxidases that perform ORR and in hydrogenases carrying out H₂ oxidation. Insights gained from understanding how the reduction potential of the ET centers affects reactivity at the active site in both the enzymes and their models are provided.     

Early Main Group Metal Catalysis: How Important is the Metal?

Organocalcium compounds have been reported as efficient catalysts for various alkene transformations. In contrast to transition metal catalysis, the alkenes are not activated by metal–alkene orbital interactions. Instead it is proposed that alkene activation proceeds through an electrostatic interaction with a Lewis acidic Ca²⁺. The role of the metal was evaluated by a study using the metal‐free catalysts: [Ph₂N^?][Me₄N⁺] and [Ph₃C^?][Me₄N⁺]. These “naked” amides and carbanions can act as catalysts in the conversion of activated double bonds (C?O and C?N) in the hydroamination of Ar? N?C?O and R? N?C?N? R (R=alkyl) by Ph₂NH. For the intramolecular hydroamination of unactivated C?C bonds in H₂C?CHCH₂CPh₂CH₂NH₂ the presence of a metal cation is crucial. A new type of hybrid catalyst consisting of a strong organic Schwesinger base and a simple metal salt can act as catalyst for the intramolecular alkene hydroamination. The influence of the cation in catalysis is further evaluated by a DFT study.     

An unusual pH-independent and metal-ion-independent mechanism for hairpin ribozyme catalysis

Background: Hairpin ribozymes (RNA enzymes) catalyze the same chemical reaction as ribonuclease A and yet RNAs do not usually have functional groups analogous to the catalytically essential histidine and lysine sidechains of protein ribonucleases. Some RNA enzymes appear to recruit metal ions to act as Lewis acids in charge stabilization and metal-bound hydroxide for general base catalysis, but it has been reported that the hairpin ribozyme functions in the presence of metal ion chelators. This led us to investigate whether the hairpin ribozyme exploits a metal-ion-independent catalytic strategy.Results: Substitution of sulfur for nonbridging oxygens of the reactive phosphate of the hairpin ribozyme has small, stereospecific and metal-ionindependent effects on cleavage and ligation mediated by this ribozyme. Cobalt hexammine, an exchange-inert metal complex, supports full hairpin ribozyme activity, and the ribozyme's catalytic rate constants display only a shallow dependence on pH.Conclusions: Direct metal ion coordination to phosphate oxygens is not essential for hairpin ribozyme catalysis and metal-bound hydroxide does not serve as the general base in this catalysis. Several models might account for the unusual pH and metal ion independence: hairpin cleavage and ligation might be limited by a slow conformational change; a pH-independent or metalcation-independent chemical step, such as breaking the 5′ oxygen-phosphorus bond, might be rate determining; or finally, functional groups within the ribozyme might participate directly in catalytic chemistry. Whichever the case, the hairpin ribozyme appears to employ a unique strategy for RNA catalysis.     

稀土金属在不对称催化中的应用:从均相催化到异相催化

稀土金属的配位数较高,可通过容纳大型手性配体,构筑手性环境,催化不对称反应的定向发生,在工业生产特别是制药工程中具有重要应用价值.本文以Henry反应、Mannich反应和Strecker反应为例,总结回顾了稀土金属催化剂在此类反应中的设计思路、性能特点与应用前景,旨在展现稀土金属催化剂兼具融合均相催化与异相催化的优势...     

Impact of divalent metal cations on the catalysis of peptide bonds: a DFT study

Within the ATP-grasp family of enzymes, divalent alkaline earth metals are proposed to chelate terminal ATP phosphates and facilitate the formation of peptide bonds. Density functional theory methods are used to explore the impact of metal ions on peptide bond formation, providing an insight into experimental metal substitution studies. Calculations show that alkaline earth and transition metal cations coordinate with an acylphosphate reactant and aid in the separation of the phosphate leaving group. The critical biochemical reaction is proposed to proceed through the formation of a six-membered transition state in the relatively nonpolar active site of human glutathione synthetase, an ATP-grasp enzyme. While the identity of the metal ion has a moderate impact on the thermodynamics of peptide bond formation, kinetic differences are much sharper. Simulations indicate that several transition metal ions, most notably Cu²⁺, may be particularly advantageous for catalysis. The detailed mechanistic study serves to elucidate the vital role of coordination chemistry in the formation of peptide bonds.     

Enzymatic radical catalysis: coenzyme B12-dependent diol dehydratase

A peculiar function resides in a peculiar structure. Coenzyme B₁₂ or adenosylcobalamin, a naturally occurring organometallic compound, serves as a cofactor for enzymatic radical reactions. How do the enzymes form catalytic radicals at the active sites? How do the enzymes utilize and control the high reactivity of the radicals for catalysis? Recently, three‐dimensional structures of several radical‐containing or radical‐forming enzymes including B₁₂ enzymes have been reported, enabling the analysis of the fine mechanisms of the action of these interesting enzymes. Our biochemical, mutational, and crystallographic studies as well as theoretical calculations on diol dehydratase, an adenosylcobalamin–dependent enzyme, revealed that its structure is adapted for its function—that is, activation of the Co? C bond toward homolysis, abstraction of a specific hydrogen atom from the substrate and its recombination to a particular product, and transition state stabilization in the hydroxyl group migration of a substrate‐derived radical. The functions of K⁺ and the active‐site amino acid residues in enzyme catalysis are also investigated. Based on the results, the fine mechanism of the enzyme and the energetic feasibility of enzymatic radical catalysis are described here. © 2002 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Chem Rec 2: 352–366, 2002: Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.10035     

Evidence for the metal-cofactor independence of an RNA phosphodiester-cleaving DNA enzyme

Background: RNA and DNA are polymers that lack the diversity of chemical functionalities that make proteins so suited to biological catalysis. All naturally occurring ribozymes (RNA catalysts) that catalyze the formation, transfer and hydrolysis of phosphodiesters require metal-ion cofactors for their catalytic activity. We wished to investigate whether, and to what extent, DNA molecules could catalyze the cleavage (by either hydrolysis or transesterification) of a ribonucleotide phosphodiester in the absence of divalent or higher-valent metal ions or, indeed, any other cofactors.Results: We performed in vitro selection and amplification experiments on a library of random-sequence DNA that incorporated a single ribonucleotide, a suitable site for cleavage. Following 12 cycles of selection and amplification, a ‘first generation’ of DNA enzymes (DNAzymes) cleaved their internal ribonucleotide phosphodiesters at rates ∼ 10⁷-fold faster than the spontaneous rate of cleavage of the dinucleotide ApA in the absence of divalent cations. Re-selection from a partially randomized DNA pool yielded ‘second generation’ DNAzymes that self-cleaved at rates of ∼ 0.01 min⁻¹ (a 10⁸-fold rate enhancement over the cleavage rate of ApA). The properties of these selected catalysts were different in key respects from those of metal-utilizing ribozymes and DNAzymes. The catalyzed cleavage took place in the presence of different chelators and ribonuclease inhibitors. Trace-metal analysis of the reaction buffer (containing very high purity reagents) by inductively coupled plasma-optical emission spectrophotometry indicated that divalent or higher-valent metal ions do not mediate catalysis by the DNAzymes.Conclusions: Our results indicate that, although ribozymes are sometimes regarded generically to be metalloenzymes, the nucleic acid components of ribozymes may play a substantial role in the overall catalysis. Given that metal cofactors increase the rate of catalysis by ribozymes only ∼ 10²−10³-fold above that of the DNAzyme described in this paper, it is conceivable that substrate positioning, transition-state stabilization or general acid/base catalysis by the nucleic acid components of ribozymes and DNAzymes may contribute significantly to their overall catalytic performance.     

Electrochemical Kinetics Support a Second Coordination Sphere Mechanism in Metal-Based Formate Dehydrogenase

Metal-based formate dehydrogenases are molybdenum or tungsten-dependent enzymes that catalyze the interconversion between formate and CO₂. According to the current consensus, the metal ion of the catalytic center in its active form is coordinated by 6 S (or 5 S and 1 Se) atoms, leaving no free coordination sites to which formate could bind to the metal. Some authors have proposed that one of the active site ligands decoordinates during turnover to allow formate binding. Another proposal is that the oxidation of formate takes place in the second coordination sphere of the metal. Here, we have used electrochemical steady-state kinetics to elucidate the order of the steps in the catalytic cycle of two formate dehydrogenases. Our results strongly support the “second coordination sphere” hypothesis.     

Isolation of novel ribozymes that ligate AMP-activated RNA substrates

Background: The protein enzymes RNA ligase and DNA ligase catalyze the ligation of nucleic acids via an adenosine-5′-5′-pyrophosphate ‘capped’ RNA or DNA intermediate. The activation of nucleic acid substrates by adenosine 5′-monophosphate (AMP) may be a vestige of ‘RNA world’ catalysis. AMP-activated ligation seems ideally suited for catalysis by ribozymes (RNA enzymes), because an RNA motif capable of tightly and specifically binding AMP has previously been isolated.Results: We used in vitro selection and directed evolution to explore the ability of ribozymes to catalyze the template-directed ligation of AMP-activated RNAs. We subjected a pool of 10¹⁵ RNA molecules, each consisting of long random sequences flanking a mutagenized adenosine triphosphate (ATP) aptamer, to ten rounds of in vitro selection, including three rounds involving mutagenic polymerase chain reaction. Selection was for the ligation of an oligonucleotide to the 5′-capped active pool RNA species. Many different ligase ribozymes were isolated; these ribozymes had rates of reaction up to 0.4 ligations per hour, corresponding to rate accelerations of ∼ 5 × 10⁵ over the templated, but otherwise uncatalyzed, background reaction rate. Three characterized ribozymes catalyzed the formation of 3′-5′-phosphodiester bonds and were highly specific for activation by AMP at the ligation site.Conclusions: The existence of a new class of ligase ribozymes is consistent with the hypothesis that the unusual mechanism of the biological ligases resulted from a conservation of mechanism during an evolutionary replacement of a primordial ribozyme ligase by a more modern protein enzyme. The newly isolated ligase ribozymes may also provide a starting point for the isolation of ribozymes that catalyze the polymerization of AMP-activated oligonucleotides or mononucleotides, which might have been the prebiotic analogs of nucleoside triphosphates.     

Thiamine models and perspectives on the mechanism of action of thiamine-dependent enzymes

Thiamine dependent enzymes catalyze ligase and lyase reactions near a carbonyl moiety. Chemical models for these reactions serve as useful tools to substantiate a detailed mechanism of action. This tutorial review covers all such studies performed thus far, emphasizing the role of each part around the active site and the conformation of the cofactor during catalysis.     

Regio- and Stereoselective Syntheses with Organocopper Reagents

Of all of the organometallic reagents currently used to form carbon–carbon bonds, organocopper reagents rank amongst the most important. Interest in these reagents centers not only on their regioselectivity, but also increasingly on their application in stereoselective transformations (principally Michael additions and S_N2′ reactions); the use of suitable substrates or chirally modified cuprates can lead to highly diastereo- and enantioselective reactions. Simultaneously, extensions of methods for the preparation and application of these reagents (for example functionalized organocopper species and Lewis acid catalysis, respectively) have opened up new horizons for organocopper reagents. Mechanistically, the reactions are well-documented and understood, but this aspect of the subject has not kept pace with the many rapid developments in preparative chemistry. Organocopper ragents have proved to be indispensable in the synthesis of complex natural products and pharmaceuticals, chiral auxiliaries, and molecules with interesting structural features. In this review we will discuss some of the more recent important developments in this area; the organization will follow the type of selectivity (regio-, diastereo-, and enantioselectivity).     

Factors determining the enzyme catalytic power caused by noncovalent interactions: Charge alterations in enzyme active sites

Understanding the origin of the enormous catalytic power of enzymes is very important. Electrostatic interactions and desolvation are the phenomena that are most proposed to explain the catalysis of enzymes; however, they also decelerate enzymatic reactions. How enzymes catalyze reactions through noncovalent interactions is still not well-understood. In this study, we explored how enzyme-substrate noncovalent interactions affect the free energy barriers (ΔG³s) of reactions by using a theoretical derivation approach. We found that enzymes reduce ΔG³s of reactions by decreasing positive charges and/or increasing negative charges in the electron-donating centers and by decreasing negative charges and/or increasing positive charges in the electron-accepting centers of reactions. Enzyme-substrate noncovalent interactions are essential approaches through which the charge alterations lead to ΔG³ reductions. Validations with reported experimental data demonstrated that this charge alteration mechanism can explain the catalyses caused by diverse types of noncovalent interactions. Electrostatic interactions and desolvation are the most observed noncovalent interactions essential for ΔG³ reductions. This mechanism does not contradict any specific enzymatic catalysis and overcomes the shortages of the electrostatic interaction and desolvation mechanisms. This study can provide useful guidance in exploring enzymatic catalysis and designing catalyst.