Accounts of Chemical Research最新文献

Selenocysteine (Sec), oftenreferred to as the21st amino acid,is a rare yet essential amino acid found in a small number of naturallyoccurring selenoproteins that play critical roles in redox regulation,antioxidant defence, and hormone metabolism. Owing to its distinctchemical properties, namely enhanced nucleophilicity, lower reductionpotential, and versatile redox behaviour of the side chain selenol/diselenidemoiety relative to the thiol/disulfide of Cys, Sec has recently beenleveraged for a range of applications in protein science.

Inthis account, we summarize our endeavors towards the developmentof selenium-mediated ligation methodologies for the rapid and highlyefficient assembly of proteins, including those bearing native post-translationalmodifications (PTMs) or “designer” modifications. Keyinnovations include the diselenide–selenoester ligation (DSL)and expressed protein selenoester ligation (EPSL). DSL enables therapid fusion of unprotected peptides through a chemoselective reactionbetween peptide selenoesters and selenopeptides. Notably, in the presenceof suitable additives, DSL can be performed at nanomolar concentrations,providing access to challenging classes of modified proteins, suchas lipoproteins, that are difficult to access via other techniques.We also discuss the extension of DSL chemistry to larger proteinsthrough the generation of protein selenoesters from recombinantlyexpressed intein fusion proteins. By combining the advantages of recombinantbacterial expression and the rapid kinetics of DSL at Sec, we highlightthe use of the EPSL technology for the generation of large, aggregation-proneproteins, including the lipidated GTPase YPT6 and mycobacterial lipoproteinsas novel vaccine antigens. Beyond protein synthesis and semi-synthesis,we have also demonstrated the utility of selenocysteine (Sec) as apowerful bioconjugation handle. Specifically, we highlight two novelSec-selective bioconjugation reaction manifolds in this account; thephotocatalytic diselenide contraction (PDC) and electrochemical selenoetherification(e-SE). These transformations enable dimerization and site-specificfunctionalization of peptide and protein diselenides with exceptionalregio- and chemoselectivity, offering significant advantages overother bioconjugation methods.

Overall, we believe that thesetechnologies represent a major advancein the generation of site-selectively modified peptides and proteins,unlocking new possibilities for applications in fundamental biologybut also the generation of next-generation diagnostics and therapeuticsbearing precise modifications at defined sites on proteins.

O-GlcNAcylationis a ubiquitous post-translationalmodification across the mammalian proteome, yet determining how individual O-GlcNAcylation events control specific protein functionsremains a central challenge. The O-GlcNAc cycle isgoverned by two enzymes: O-GlcNAc transferase (OGT),which installs O-GlcNAc, and O-GlcNAcase(OGA), which removes it. Because these enzymes act on thousands ofproteins, conventional methods, such as pharmacological inhibitionof OGT or OGA, produce broad cellular effects that are difficult toassign to individual substrates. This gap has motivated the developmentof targeted O-GlcNAcylation strategies, includinggenetically encoded and chemical biology tools, which have shown that O-GlcNAc can be selectively installed on defined proteinsto interrogate protein-specific O-GlcNAc functions.

This Account describes the development of O-GlcNAcTArgeting Chimeras, or OGTACs, as chemical tools for targeted O-GlcNAc installation. OGTACs are bifunctional moleculesthat can recruit OGT to a specific protein of interest. Specifically,an OGTAC consists of an OGT-engaging element, a linker, and a target-recognitionmotif, which together bring OGT into proximity with a selected substrate.

Our studies show that chemically induced proximity can redirectOGT toward selected proteins, thereby creating targeted O-GlcNAc writing that can partially bypass TPR-domain-mediated substraterecognition under engineered recruitment conditions. A central lessonis that productive O-GlcNAc writing requires notonly recruitment, but also proper ternary-complex formation and noninhibitoryOGT engagement. Moreover, the target-recognition motif determinesthe targetable protein space and achievable selectivity of the platform.By linking local O-GlcNAc installation to changesin protein turnover, signaling, and transcriptional output, OGTACsprovide a conceptual framework for using induced proximity to modulateprotein functions.

Electrochemical transition-metalcatalysis is an effective yetunderexplored platform for molecular construction. Combining the advantagesof electrochemically driven oxidation processes with the selectivitycontrol afforded by transition-metal catalysis, this field is characterizedby a rich variety of reaction types, mild conditions, and high controllability.However, it has long faced major scientific challenges: there is amismatch between electron transfer on the electrode surface and therate of catalyst-mediated reactant activation in solution, which complicatesprecise control over reaction selectivity, and metal catalysts (especiallyPd, Ag, and Cu) are prone to reductive deactivation, leading to prematuretermination of the reactions. To address these challenges, our grouphas developed three main strategies using oxidative cross-couplingreactions as a representative. First, in direct current (DC) electrosynthesis,we employed a divided cell to prevent the metal catalyst from migratingto the cathode. Second, under specific ligand and solvent combinations,we realized electro-oxidative metal-catalyzed reactions in an undividedcell by precisely controlling the redox potential. To this end, thesubstrates were equipped with directing groups (DGs) capable of chelatingwith the metal cation or an extra ligand was introduced into the reactionsystem, both of which effectively suppressed reductive deactivation.Through this approach, we successfully achieved a series of Pd-, Co-,and Mn-catalyzed oxidative C–H functionalization reactions.Third, we developed an unsymmetrical alternating current (AC)-drivenmetal catalysis strategy designed to accommodate a broader range ofreaction patterns. By precisely adjusting the duty ratio and currentof the AC waveform, we ensured smooth reactivation of the metal catalyst.This programmed waveform further enabled the maintenance of a highconcentration of the active metal species through a dynamic balance.Consequently, we successfully achieved Cu-, Ag-, and Pd-catalyzedoxidative C–H cross-coupling reactions. The synthetic utilityof AC was validated across a diverse set of mechanistic pathways,including C–H activation, radical relay, radical addition,and nucleophilic addition. We propose that AC can serve as a generaland robust platform to circumvent the persistent issue of metal catalystdeactivation in electrosynthesis. Overall, we have developed threestrategies from DC to AC electrosynthesis to address long-standingissues in electrochemical transition-metal catalysis. In contrastto the well-established DC electrosynthesis, the AC mode demonstratesa greater potential and diversity in transition-metal catalysis. Fullyexploiting the unique capabilities of AC to expand the applicationscenarios is of considerable scientific significance and practicalvalue.

Aromatic compounds are fundamentalto syntheticchemistry, biomedicine,and materials science. Among them, metallaaromatics─which incorporateat least one transition metal into an aromatic framework─representa distinctive class that has attracted substantial interest. The conceptof aromaticity, traditionally rooted in π-electrondelocalization, has been expanded by σ-aromaticity─firstproposed by Dewar in 1979 and subsequently established in all-metalclusters. Over the past decade, our group has developed a family ofmetal-centered conjugated polycyclic metallacycles termed carbolongcomplexes in which a carbon chain coordinates to a metal center viaa minimum of three metal–carbon bonds. These complexes exhibitremarkable stability towards water, oxygen, light, and heat, owingto polydentate chelation and aromatic stabilization.

This Accountsummarizes our systematic investigations into metallapentalene-fusedmetallacyclopropene derivatives─a unique subclass that integratesa highly strained three-membered ring into a robust aromatic scaffold.We describe our journey from the establishment of carbon-chain-basedframeworks via one-pot multiyne cyclizations to more elaborate carbolongskeletons through controlled [2+1] cycloadditions with isocyanidesand zinc carbenoids. Building on this carbon-rich platform, we extendedthe chemistry to peripheral p-block elements, incorporatingheteroatoms from groups 15, 16, and 17 into the metallacyclopropenecore to yield metalla-azirines, -phosphirenes, -chalcogenirenium,and -halirenium ions.

The fused metallacyclopropenes serve aspowerful synthetic intermediates,participating in formal [3+1], [3+2], and [3+3] cycloadditions toconstruct complex polycyclic architectures. The resulting materialsexhibit broad near-infrared absorption and high photothermal conversionefficiency and are promising for smart materials, drug delivery, andcancer phototherapy. Complementary computational studies have elucidatedtheir electronic structures. We established σ-aromaticity as a key stabilizing factor that counterbalances ringstrain─validating a long-debated concept and providing a designprinciple for stabilizing transient intermediates in transition-metalheterocycles. Systematic analyses of heteroatom-doped congeners revealclear periodic trends: the magnitude of σ-aromaticity─andconsequently the overall stability─is finely tuned by the electronicnature and size of the incorporated heteroatom. Ring strain energycalculations show that appropriate substitution can significantlyalleviate strain, reflecting the agreement between computation andexperiment.

Collectively, this work not only advances the fundamentalunderstandingof metallacyclic aromaticity but also paves the way for the rationaldesign of functional metallaaromatic materials with tailored properties.

Enzymes are powerful naturalcatalysts distinguishedby high efficiencyand selectivity. The use of enzymes in the chemical industry can theoreticallyenable numerous efficient and sustainable reaction pathways. Nevertheless,the application of enzymes is hindered by their narrow catalytic repertoire.Enzymes are readily deactivated under nonnatural environments, andtheir reaction types are limited. Developing enzymes with new catalyticfunctions has been a longstanding challenge in the field of biocatalysis.Strategies such as directed evolution and de novo protein design have been very successful in designing new enzymes.However, as both approaches rely on the engineering of amino acidsequences of proteins, they remain constrained and cannot fully meetthe growing demand for non-natural biocatalysis. Incorporating abioticcomponents with enzymes is a powerful tool for editing enzymes torender new catalytic capabilities. Metal-based components possessa broad catalytic repertoire, structural stability, and multifunctionality,making them promising building blocks for enzyme editing.

ThisAccount summarizes our contributions over the past decadein editing enzyme catalysts with metal-based components as a scale-dependentevolution, from nanoscale environmental modulation to atom-scale activesite redefinition, illustrating how enzyme editing with metal-basedcomponents can systematically address non-natural catalytic challenges.A conceptual framework in which enzymes are edited with metal-basedcomponents across scales from the nanometer to the atomic dimensionis introduced, establishing a logical basis for integrating biocatalysiswith abiotic reactivity. At the nanoscale, enzymes are encapsulatedin metal-based frameworks to improve the configuration stability,enabling catalysis under non-native and harsh conditions. The robustnessof enzymes under extreme pH, high temperature, and organic solventcan be largely enhanced through the regulation of metal-based frameworks.At the sub-nanoscale, metal clusters are embedded within enzyme scaffoldsto construct enzyme-metal hybrid catalysts. By integration of enzymaticand chemical catalysis, new non-natural catalytic processes can beestablished. At the atomic scale, metal atoms are incorporated intothe enzyme catalytic pocket, creating new hybrid active sites. Thehybrid active site endows an enzyme with capabilities to drive new-to-naturereactions, unlocking an expanded enzyme catalytic space. This workprovides a unifying conceptual framework that clarifies how metal-basedcomponents can be strategically employed to reprogram enzyme stability,functionality, and reactivity. We hope that the strategies and conceptsdiscussed herein offer comprehensive design principles for biohybridcatalysts and establish a foundation for reprogramming enzymatic functionbeyond evolutionary limitations.