Radical S-Adenosylmethionine Enzymes in Human Health and Disease.

Radical S-adenosylmethionine (SAM) enzymes catalyze an astonishing array of complex and chemically challenging reactions across all domains of life. Of approximately 114,000 of these enzymes, 8 are known to be present in humans: MOCS1, molybdenum cofactor biosynthesis; LIAS, lipoic acid biosynthesis; CDK5RAP1, 2-methylthio-N(6)-isopentenyladenosine biosynthesis; CDKAL1, methylthio-N(6)-threonylcarbamoyladenosine biosynthesis; TYW1, wybutosine biosynthesis; ELP3, 5-methoxycarbonylmethyl uridine; and RSAD1 and viperin, both of unknown function. Aberrations in the genes encoding these proteins result in a variety of diseases. In this review, we summarize the biochemical characterization of these 8 radical S-adenosylmethionine enzymes and, in the context of human health, describe the deleterious effects that result from such genetic mutations.

Protein-bound molybdenum cofactor is bioavailable and rescues molybdenum cofactor-deficient C. elegans.

The molybdenum cofactor (Moco) is a 520-Da prosthetic group that is synthesized in all domains of life. In animals, four oxidases (among them sulfite oxidase) use Moco as a prosthetic group. Moco is essential in animals; humans with mutations in genes that encode Moco biosynthetic enzymes display lethal neurological and developmental defects. Moco supplementation seems a logical therapy; however, the instability of Moco has precluded biochemical and cell biological studies of Moco transport and bioavailability. The nematode Caenorhabditis elegans can take up Moco from its bacterial diet and transport it to cells and tissues that express Moco-requiring enzymes, suggesting a system for Moco uptake and distribution. Here we show that protein-bound Moco is the stable, bioavailable species of Moco taken up by C. elegans from its diet and is an effective dietary supplement, rescuing a Celegans model of Moco deficiency. We demonstrate that diverse Moco:protein complexes are stable and bioavailable, suggesting a new strategy for the production and delivery of therapeutically active Moco to treat human Moco deficiency.

Learning from the worm: the effectiveness of protein-bound Moco to treat Moco deficiency.

Molybdenum cofactor (Moco) is synthesized endogenously in humans and is essential for human development. Supplementation of Moco or its precursors has been explored as a therapy to treat Moco-deficient patients but with significant limitations. By using the nematode C. elegans as a model, Warnhoff and colleagues (pp. 212-217) describe the beneficial impact of protein-bound Moco supplementation to treat Moco deficiency. If such an effect is conserved, this advance from basic research in worms may have significant clinical implications as a novel therapy for molybdenum cofactor deficiency.

Single-atom Mo-Co catalyst with low biotoxicity for sustainable degradation of high-ionization-potential organic pollutants.

Single-atom catalysts (SACs) are a promising area in environmental catalysis. We report on a bimetallic Co-Mo SAC that shows excellent performance in activating peroxymonosulfate (PMS) for sustainable degradation of organic pollutants with high ionization potential (IP > 8.5 eV). Density Functional Theory (DFT) calculations and experimental tests demonstrate that the Mo sites in Mo-Co SACs play a critical role in conducting electrons from organic pollutants to Co sites, leading to a 19.4-fold increase in the degradation rate of phenol compared to the CoCl2-PMS group. The bimetallic SACs exhibit excellent catalytic performance even under extreme conditions and show long-term activation in 10-d experiments, efficiently degrading 600 mg/L of phenol. Moreover, the catalyst has negligible toxicity toward MDA-MB-231, Hela, and MCF-7 cells, making it an environmentally friendly option for sustainable water treatment. Our findings have important implications for the design of efficient SACs for environmental remediation and other applications in biology and medicine.

Dynamic phase evolution of MoS3 accompanied by organodiselenide mediation enables enhanced performance rechargeable lithium battery.

Considerable efforts have been devoted to Li-S batteries, typically the soluble polysulfides shuttling effect. As a typical transition metal sulfide, MoS2 is a magic bullet for addressing the issues of Li-S batteries, drawing increasing attention. In this study, we introduce amorphous MoS3 as analogous sulfur cathode material and elucidate the dynamic phase evolution in the electrochemical reaction. The metallic 1T phase incorporated 2H phase MoS2 with sulfur vacancies (SVs-1T/2H-MoS2) decomposed from amorphous MoS3 achieves refined mixing with the "newborn" sulfur at the molecular level and supplies continuous conduction pathways and controllable physical confinement. Meanwhile, the in situ-generated SVs-1T/2H-MoS2 allows lithium intercalation in advance at high discharge voltage (≥1.8 V) and enables fast electron transfer. Moreover, aiming at the unbonded sulfur, diphenyl diselenide (PDSe), as a model redox mediator is applied, which can covalently bond sulfur atoms to form conversion-type organoselenosulfides, changing the original redox pathway of "newborn" sulfur in MoS3, and suppressing the polysulfides shuttling effect. It also significantly lowers the activation energy and thus accelerates the sulfur reduction kinetics. Thus, the in situ-formed intercalation-conversion hybrid electrode of SVs-1T/2H-MoS2 and organoselenosulfides realizes enhanced rate capability and superior cycling stability. This work provides a novel concept for designing high-energy-density electrode materials.

Bacterial stigmasterol degradation involving radical flavin delta-24 desaturase and molybdenum-dependent C26 hydroxylase.

Sterols are ubiquitous membrane constituents that persist to a large extent in the environment due to their water insolubility and chemical inertness. Recently, an oxygenase-independent sterol degradation pathway was discovered in a cholesterol-grown denitrifying bacterium Sterolibacterium (S.) denitrificans. It achieves hydroxylation of the unactivated primary C26 of the isoprenoid side chain to an allylic alcohol via a phosphorylated intermediate in a four-step ATP-dependent enzyme cascade. However, this pathway is incompatible with the degradation of widely distributed steroids containing a double bond at C22 in the isoprenoid side chain such as the plant sterol stigmasterol. Here, we have enriched a prototypical delta-24 desaturase from S. denitrificans, which catalyzes the electron acceptor-dependent oxidation of the intermediate stigmast-1,4-diene-3-one to a conjugated (22,24)-diene. We suggest an α4ß4 architecture of the 440 kDa enzyme, with each subunit covalently binding an flavin mononucleotide cofactor to a histidyl residue. As isolated, both flavins are present as red semiquinone radicals, which can be reduced by stigmast-1,4-diene-3-one but cannot be oxidized even with strong oxidizing agents. We propose a mechanism involving an allylic radical intermediate in which two flavin semiquinones each abstract one hydrogen atom from the substrate. The conjugated delta-22,24 moiety formed allows for the subsequent hydroxylation of the terminal C26 with water by a heterologously produced molybdenum-dependent steroid C26 dehydrogenase 2. In conclusion, the pathway elucidated for delta-22 steroids achieves oxygen-independent hydroxylation of the isoprenoid side chain by bypassing the ATP-dependent formation of a phosphorylated intermediate.

Intermediate-state imaging of electrical switching and quantum coupling of molybdenum disulfide monolayer.

SignificanceThin transparent semiconductors of two-dimensional materials are attractive for the practical applications in next-generation nanoelectronic and optoelectronic devices. Probing the electron states and electrical switching mechanisms of a molybdenum disulphide monolayer with atomic-scale thickness (6.5 Å) allows us to unlock the full technological potential of this nanomaterial. We introduced a plasmonic phase imaging method to uncover the underlying mechanism and detailed switching dynamics of an electrical-state switching event. This dramatic phase change can be attributed to the reversible switching of classical electromagnetic coupling and quantum coupling effects interplaying between a single metal nanoparticle and molybdenum disulphide monolayer, and the transient intermediate states during the switching event can be directly imaged by a plasmonic technique.

Light-Triggered Reversible Change in the Electronic Structure of MoO3 Nanosheets via an Excited-State Proton Transfer Mechanism.

Light is an attractive source of energy for regulating stimulus-responsive chemical systems. Here, we use light as a gating source to control the redox state, the localized surface plasmonic resonance (LSPR) peak, and the structure of molybdenum oxide (MoO3) nanosheets, which are important for various applications. However, the light excitation is not that of the MoO3 nanosheets but rather that of pyranine (HPTS) photoacids, which in turn undergo an excited-state proton transfer (ESPT) process. We show that the ESPT process from HPTS to the nanosheets and the intercalation of protons within the MoO3 nanosheets trigger the reduction of the nanosheets and the broadening of the LSPR peak, a process that is reversible, meaning that in the absence of light, the LSPR peak diminishes and the nanosheets return to their oxidized form. We further show that this reversible process is accompanied by a change in the nanosheet size and morphology.

Acousto-Drag Photovoltaic Effect by Piezoelectric Integration of Two-Dimensional Semiconductors.

Light-to-electricity conversion is crucial for energy harvesting and photodetection, requiring efficient electron-hole pair separation to prevent recombination. Traditional junction-based mechanisms using built-in electric fields fail in nonbarrier regions. Homogeneous material harvesting under a photovoltaic effect is appealing but is only realized in noncentrosymmetric systems via a bulk photovoltaic effect. Here we report the realization of a photovoltaic effect by employing surface acoustic waves (SAWs) to generate zero-bias photocurrent in the conventional layered semiconductor MoSe2. SAWs induce periodic modulation to electronic bands and drag the photoexcited pairs toward the traveling direction. The photocurrent is extracted from a local barrier. The separation of generation and extraction processes suppresses recombination and yields a large nonlocal photoresponse. We distinguish the acousto-electric drag and electron-hole pair separation effect by fabricating devices of different configurations. The acousto-drag photovoltaic effect, enabled by piezoelectric integration, offers an efficient light-to-electricity conversion method, independent of semiconductor crystal symmetry.

Crystalline Phase Engineering to Modulate the Interfacial Interaction of the Ruthenium/Molybdenum Carbide for Acidic Hydrogen Evolution.

Ruthenium (Ru) is an ideal substitute to commercial Pt/C for the acidic hydrogen evolution reaction (HER), but it still suffers from undesirable activity due to the strong adsorption free energy of H* (ΔGH*). Herein, we propose crystalline phase engineering by loading Ru clusters on precisely prepared cubic and hexagonal molybdenum carbide (α-MoC/ß-Mo2C) supports to modulate the interfacial interactions and achieve high HER activity. Advanced spectroscopies demonstrate that Ru on ß-Mo2C shows a lower valence state and withdraws more electrons from the support than that of Ru on α-MoC, indicative of a strong interfacial interaction. Density functional theory reveals that the ΔGH* of Ru/ß-Mo2C approaches 0 eV, illuminating an enhancement mechanism at the Ru/ß-Mo2C interface. The resultant Ru/ß-Mo2C exhibits an encouraging performance in a proton exchange membrane water electrolyzer with a low cell voltage (1.58 V@ 1.0 A cm-2) and long stability (500 h@ 1.0 A cm-2).

Tuning Exciton Emission via Ferroelectric Polarization at a Heterogeneous Interface between a Monolayer Transition Metal Dichalcogenide and a Perovskite Oxide Membrane.

We demonstrate the integration of a thin BaTiO3 (BTO) membrane with monolayer MoSe2 in a dual-gate device that enables in situ manipulation of the BTO ferroelectric polarization with a voltage pulse. While two-dimensional (2D) transition metal dichalcogenides (TMDs) offer remarkable adaptability, their hybrid integration with other families of functional materials beyond the realm of 2D materials has been challenging. Released functional oxide membranes offer a solution for 2D/3D integration via stacking. 2D TMD excitons can serve as a local probe of the ferroelectric polarization in BTO at a heterogeneous interface. Using photoluminescence (PL) of MoSe2 excitons to optically read out the doping level, we find that the relative population of charge carriers in MoSe2 depends sensitively on the ferroelectric polarization. This finding points to a promising avenue for future-generation versatile sensing devices with high sensitivity, fast readout, and diverse applicability for advanced signal processing.

The mitochondrial amidoxime reducing component-from prodrug-activation mechanism to drug-metabolizing enzyme and onward to drug target.

The mitochondrial amidoxime-reducing component (mARC) is one of five known molybdenum enzymes in eukaryotes. mARC belongs to the MOSC domain superfamily, a large group of so far poorly studied molybdoenzymes. mARC was initially discovered as the enzyme activating N-hydroxylated prodrugs of basic amidines but has since been shown to also reduce a variety of other N-oxygenated compounds, for example, toxic nucleobase analogs. Under certain circumstances, mARC might also be involved in reductive nitric oxide synthesis through reduction of nitrite. Recently, mARC enzymes have received a lot of attention due to their apparent involvement in lipid metabolism and, in particular, because many genome-wide association studies have shown a common variant of human mARC1 to have a protective effect against liver disease. The mechanism linking mARC enzymes with lipid metabolism remains unknown. Here, we give a comprehensive overview of what is currently known about mARC enzymes, their substrates, structure, and apparent involvement in human disease.

Obtaining the necessary molybdenum cofactor for sulfite oxidase activity in the nematode Caenorhabditis elegans surprisingly involves a dietary source.

Molybdenum cofactor (Moco) is a prosthetic group necessary for the activity of four unique enzymes, including the essential sulfite oxidase (SUOX-1). Moco is required for life; humans with inactivating mutations in the genes encoding Moco-biosynthetic enzymes display Moco deficiency, a rare and lethal inborn error of metabolism. Despite its importance to human health, little is known about how Moco moves among and between cells, tissues, and organisms. The prevailing view is that cells that require Moco must synthesize Moco de novo. Although, the nematode Caenorhabditis elegans appears to be an exception to this rule and has emerged as a valuable system for understanding fundamental Moco biology. C. elegans has the seemingly unique capacity to both synthesize its own Moco as well as acquire Moco from its microbial diet. However, the relative contribution of Moco from the diet or endogenous synthesis has not been rigorously evaluated or quantified biochemically. We genetically removed dietary or endogenous Moco sources in C. elegans and biochemically determined their impact on animal Moco content and SUOX-1 activity. We demonstrate that dietary Moco deficiency dramatically reduces both animal Moco content and SUOX-1 activity. Furthermore, these biochemical deficiencies have physiological consequences; we show that dietary Moco deficiency alone causes sensitivity to sulfite, the toxic substrate of SUOX-1. Altogether, this work establishes the biochemical consequences of depleting dietary Moco or endogenous Moco synthesis in C. elegans and quantifies the surprising contribution of the diet to maintaining Moco homeostasis in C. elegans.

Arsenite oxidase in complex with antimonite and arsenite oxyanions: Insights into the catalytic mechanism.

Arsenic contamination of groundwater is among one of the biggest health threats affecting millions of people in the world. There is an urgent need for efficient arsenic biosensors where the use of arsenic metabolizing enzymes can be explored. In this work, we have solved four crystal structures of arsenite oxidase (Aio) in complex with arsenic and antimony oxyanions and the structures determined correspond to intermediate states of the enzymatic mechanism. These structural data were complemented with density-functional theory calculations providing a unique view of the molybdenum active site at different time points that, together with mutagenesis data, enabled to clarify the enzymatic mechanism and the molecular determinants for the oxidation of As(III) to the less toxic As(V) species.

Prediagnostic whole blood cadmium and molybdenum associated with pancreatic cancer in an American cohort.

Environmental exposures such as cadmium might be contributing to the increasing incidence of pancreatic cancer. Few prospective studies have examined the association between trace elements and pancreatic ductal adenocarcinoma (PDAC). We conducted a nested case-control study in participants aged 55-74 years at baseline from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort to examine the association between 12 trace elements measured in predignostic whole blood and PDAC. From May 1998 through December 2014, 318 incident PDAC cases were identified during follow-up to 16.7 years. Two controls (n = 636) alive when each case was diagnosed were selected and matched by age (+ 5 years), sex, calendar date of blood draw (2-month blocks), and race and ethnic group. We used multivariable adjusted conditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI). Cadmium and molybdenum were associated with PDAC [highest compared to lowest quintile: cadmium OR=1.81; 95% CI: 01.12, 2.95; P-trend = 0.03; molybdenum OR=0.50; 95% CI: 0.32, 0.80; P-trend = 0.02]. The inverse molybdenum association was only observed among ever smokers (OR=0.31, 95% CI: 0.17, 0.58, P-trend= 0.003, P-interaction=0.03) with no association in never smokers. Lead, arsenic, and other trace elements were not associated with PDAC. Our results support that increasing prediagnostic whole blood cadmium increases while molybdenum reduces PDAC risk.

Pseudocapacitive Storage in Molybdenum Oxynitride Nanostructures Reactively Sputtered on Stainless-Steel Mesh Towards an All-Solid-State Flexible Supercapacitor.

Exploiting pseudocapacitance in rationally engineered nanomaterials offers greater energy storage capacities at faster rates. The present research reports a high-performance Molybdenum Oxynitride (MoON) nanostructured material deposited directly over stainless-steel mesh (SSM) via reactive magnetron sputtering technique for flexible symmetric supercapacitor (FSSC) application. The MoON/SSM flexible electrode manifests remarkable Na+-ion pseudocapacitive kinetics, delivering exceptional ≈881.83 F g-1 capacitance, thanks to the synergistically coupled interfaces and junctions between nanostructures of Mo2N, MoO2, and MoO3 co-existing phases, resulting in enhanced specific surface area, increased electroactive sites, improved ionic and electronic conductivity. Employing 3D Bode plots, b-value, and Dunn's analysis, a comprehensive insight into the charge-storage mechanism has been presented, revealing the superiority of surface-controlled capacitive and pseudocapacitive kinetics. Utilizing PVA-Na2SO4 gel electrolyte, the assembled all-solid-state FSSC (MoON/SSM||MoON/SSM) exhibits impressive cell capacitance of 30.7 mF cm-2 (438.59 F g-1) at 0.125 mA cm-2. Moreover, the FSSC device outputs a superior energy density of 4.26 µWh cm-2 (60.92 Wh kg-1) and high power density of 2.5 mW cm-2 (35.71 kW kg-1). The device manifests remarkable flexibility and excellent electrochemical cyclability of ≈91.94% over 10,000 continuous charge-discharge cycles. These intriguing pseudocapacitive performances combined with lightweight, cost-effective, industry-feasible, and environmentally sustainable attributes make the present MoON-based FSSC a potential candidate for energy-storage applications in flexible electronics.

Ultrafast Quasi-Solid-State Microwave Construction of Spongy Cobalt-Molybdenum Phosphide for Hydrogen Production Over Wide pH Range.

The developed strategies for synthesizing metal phosphides are usually cumbersome and pollute the environment. In this work, an ultrafast (30 s) quasi-solid-state microwave approach is developed to construct cobalt-molybdenum phosphide decorated with Ru (Ru/CoxP-MoP) featured porous morphology with interconnected channels. The specific nanostructure favors mass transport, such as electrolyte bubbles transfer and exposing rich active sites. Moreover, the coupling effects between metallic elements, especially the decorated Ru, also act as a pivotal role on enhancing the electrocatalytic performance. Benefiting from the effects of composition and specific nanostructure, the prepared Ru/CoxP-MoP exhibits efficient HER performance with a current density of 10 mA cm-2 achieved in 1 m KOH, 0.5 m H2SO4, seawater containing 1 m KOH and 1 m PBS, with overpotentials of 52, 59, 55, 90 mV, and coupling with good stability. This work opens a novel and fast avenue to design metal-phosphide-based nanomaterials in energy-conversion and storage fields.

3D Fast Sodium Transport Network of MoS2 Endowed by Coupling of Sulfur Vacancies and Sn Doping for Outstanding Sodium Storage.

A sulfur vacancy-rich, Sn-doped as well as carbon-coated MoS2 composite (Vs-SMS@C) is rationally synthesized via a simple hydrothermal method combined with ball-milling reduction, which enhances the sodium storage performance. Benefiting from the 3D fast Na+ transport network composed of the defective carbon coating, Mo─S─C bonds, enlarged interlayer spacing, S-vacancies, and lattice distortion in the composite, the Na+ storage kinetics is significantly accelerated. As expected, Vs-SMS@C releases an ultrahigh reversible capacity of 1089 mAh g-1 at 0.1 A g-1, higher than the theoretical capacity. It delivers a satisfactory capacity of 463 mAh g-1 at a high current density of 10 A g-1, which is the state-of-the-art rate capability compared to other MoS2 based sodium ion battery anodes to the knowledge. Moreover, a super long-term cycle stability is achieved by Vs-SMS@C, which keeps 91.6% of the initial capacity after 3000 cycles under the current density of 5 A g-1 in the voltage of 0.3-3.0 V. The sodium storage mechanism of Vs-SMS@C is investigated by employing electrochemical methods and ex situ techniques. The synergistic effect between S-vacancies and doped-Sn is evidenced by DFT calculations. This work opens new ideas for seeking excellent metal sulfide anodes.

High-Performance 2D Ambipolar MoTe2 Lateral Memristors by Mild Oxidation.

2D transition metal dichalcogenides (TMDCs) have been intensively explored in memristors for brain-inspired computing. Oxidation, which is usually unavoidable and harmful in 2D TMDCs, could also be used to enhance their memristive performances. However, it is still unclear how oxidation affects the resistive switching behaviors of 2D ambipolar TMDCs. In this work, a mild oxidation strategy is developed to greatly enhance the resistive switching ratio of ambipolar 2H-MoTe2 lateral memristors by more than 10 times. Such an enhancement results from the amplified doping due to O2 and H2O adsorption and the optimization of effective gate voltage distribution by mild oxidation. Moreover, the ambipolarity of 2H-MoTe2 also enables a change of resistive switching direction, which is uncommon in 2D memristors. Consequently, as an artificial synapse, the MoTe2 device exhibits a large dynamic range (≈200) and a good linearity (1.01) in long-term potentiation and depression, as well as a high-accuracy handwritten digit recognition (>96%). This work not only provides a feasible and effective way to enhance the memristive performance of 2D ambipolar materials, but also deepens the understanding of hidden mechanisms for RS behaviors in oxidized 2D materials.

Stabilizing and Activating Active Sites: 1T-MoS2 Supported Pd Single Atoms for Efficient Hydrogen Evolution Reaction.

Metallic 1T-MoS2 with high intrinsic electronic conductivity performs Pt-like catalytic activity for hydrogen evolution reaction (HER). However, obtaining pure 1T-MoS2 is challenging due to its high formation energy and metastable properties. Herein, an in situ SO4 2--anchoring strategy is reported to synthesize a thin layer of 1T-MoS2 loaded on commercial carbon. Single Pd atoms, constituting a substantial loading of 7.2 wt%, are then immobilized on the 1T-phase MoS2 via Pd─S bonds to modulate the electronic structure and ensure a stable active phase. The resulting Pd1/1T-MoS2/C catalyst exhibits superior HER performance, featuring a low overpotential of 53 mV at the current density of 10 mA cm-2, a small Tafel slope of 37 mV dec-1, and minimal charge transfer resistance in alkaline electrolyte. Moreover, the catalyst also demonstrates efficacy in acid and neutral electrolytes. Atomic structural characterization and theoretical calculations reveal that the high activity of Pd1/1T-MoS2/C is attributed to the near-zero hydrogen adsorption energy of the activated sulfur sites on the two adjacent shells of atomic Pd.