Influence of the community assemblage on sulfur distributions in the South China sea.

Marine distribution of dimethylsulfoniopropionate (DMSP) and its cleavage product dimethyl sulfide (DMS) is greatly affected by the community structures of bacteria, phytoplankton, and zooplankton. Spatial distributions of dissolved and particulate DMSP (DMSPd,p), and DMS were measured and their relationships with DMSP lyase activity (DLA), abundance of DMSP-consuming bacteria (DCB), and the community structures of phytoplankton, zooplankton, and bacteria were determined during summer in the South China Sea (SCS). The depth distributions of DMSPd,p exhibited a similar trend with Chl a, reaching their maxima in the mixing layer. The DMS concentration was positively correlated with DCB abundance and DLA, indicating that DCB and DMSP lyase had a significant effect on DMS production. High DMS concentrations in the horizontal distribution coincided with high DCB abundance and DLA and may be due to the rapid growth of phytoplankton resulting from the high dissolved inorganic nitrogen concentration brought by the cold vortices. Moreover, the highest copepod abundance at station G3 coincided with the highest DMS concentrations there among stations B4, F2, and G3. These results suggest that copepod may play an important role in DMS production. The bacterial SAR11 clade was positively correlated with DLA, indicating its significant contribution to DMSP degradation in the SCS. These findings contribute to the understanding of the effect of the community assemblage on DMSP/DMS distributions in the SCS dominated by mesoscale vortices.

ß-Carbonyl sulfonium enables cysteine-specific bioconjugation for activity-based protein profiling in live cells.

Chemical labeling methods for proteins are highly researched. Herein, we introduced ß-carbonyl sulfonium compounds for selective cysteine modification in proteins within biological systems. Structural tuning led to sulfonium-based probes with high reactivity and selectivity. These probes show excellent biocompatibility, cell uptake, and specificity towards cysteine profiling in live cells.

Deployment of Sulfinimines in Charge-Accelerated Sulfonium Rearrangement Enables a Surrogate Asymmetric Mannich Reaction.

ß-Amino acid derivatives are key structural elements in synthetic and biological chemistry. Despite being a hallmark method for their preparation, the direct Mannich reaction encounters significant challenges when carboxylic acid derivatives are employed. Indeed, not only is chemoselective enolate formation a pitfall (particularly with carboxamides), but most importantly the inability to reliably access α-tertiary amines through an enolate/ketimine coupling is an unsolved problem of this century-old reaction. Herein, we report a strategy enabling the first direct coupling of carboxamides with ketimines for the diastereo- and enantioselective synthesis of ß-amino amides. This conceptually novel approach hinges on the innovative deployment of enantiopure sulfinimines in sulfonium rearrangements, and at once solves the problems of chemoselectivity, reactivity, and (relative and absolute) stereoselectivity of the Mannich process. In-depth computational studies explain the observed, unexpected (dia)stereoselectivity and showcase the key role of intramolecular interactions, including London dispersion, for the accurate description of the reaction mechanism.

Comparative Analysis of Sulfonium-π, Ammonium-π, and Sulfur-π Interactions and Relevance to SAM-Dependent Methyltransferases.

We report the measurement and analysis of sulfonium-π, thioether-π, and ammonium-π interactions in a ß-hairpin peptide model system, coupled with computational investigation and PDB analysis. These studies indicated that the sulfonium-π interaction is the strongest and that polarizability contributes to the stronger interaction with sulfonium relative to ammonium. Computational studies demonstrate that differences in solvation of the trimethylsulfonium versus the trimethylammonium group also contribute to the stronger sulfonium-π interaction. In comparing sulfonium-π versus sulfur-π interactions in proteins, analysis of SAM- and SAH-bound enzymes in the PDB suggests that aromatic residues are enriched in close proximity to the sulfur of both SAM and SAH, but the populations of aromatic interactions of the two cofactors are not significantly different, with the exception of the Me-π interactions in SAM, which are the most prevalent interaction in SAM but are not possible for SAH. This suggests that the weaker interaction energies due to loss of the cation-π interaction in going from SAM to SAH may contribute to turnover of the cofactor.

Reaction of 3-Oxa-2-oxobicyclo[4.2.0]oct-4-ene-1-carboxylate with Dimethylsulfoxonium Methylide.

We have been interested in the reactivities of small-ring compounds and have reported reactions that proceed through cyclopropane intermediates starting from coumarin derivatives bearing an electron-withdrawing group at the 3-position or 2-oxo-2H-pyran-3-carboxylate derivatives and dimethylsulfoxonium methylide. This time, the reaction between 3-oxa-2-oxobicyclo[4.2.0]oct-4-ene-1-carboxylate and dimethylsulfoxonium methylide has been investigated. 3a,4,5,7a-Tetrahydro-7-hydroxybenzofuran-6-carboxylate and/or 2-hydroxybicyclo[4.1.0]hept-2-ene-3-carboxylate were obtained. The compounds were characterized using various spectral and X-ray crystallographic techniques. A plausible reaction mechanism has been discussed. This reaction was applied to some 3-oxa-2-oxobicyclo[4.2.0]oct-4-ene-1-carboxylate derivatives to clarify the generality.

A PI polyamide-TPP conjugate targeting a mtDNA mutation induces cell death of cancer cells with the mutation.

Mitochondrial DNA (mtDNA) mutations occur frequently in cancer cells, and some of them are often homoplasmic. Targeting such mtDNA mutations could be a new method for killing cancer cells with minimal impact on normal cells. Pyrrole-imidazole polyamides (PIPs) are cell-permeable minor groove binders that show sequence-specific binding to double-stranded DNA and inhibit the transcription of target genes. PIP conjugated with the lipophilic triphenylphosphonium (TPP) cation can be delivered to mitochondria without uptake into the nucleus. Here, we investigated the feasibility of the use of PIP-TPP to target a mtDNA mutation in order to kill cancer cells that harbor the mutation. We synthesized hairpin-type PIP-TPP targeting the A3243G mutation and examined its effects on the survival of HeLa cybrid cells with or without the mutation (HeLamtA3243G cells or HeLamtHeLa cells, respectively). A surface plasmon resonance assay demonstrated that PIP-TPP showed approximately 60-fold higher binding affinity for the mutant G-containing synthetic double-stranded DNA than for the wild-type A-containing DNA. When added to cells, it localized in mitochondria and induced mitochondrial reactive oxygen species production, extensive mitophagy, and apoptosis in HeLamtA3243G cells, while only slightly exerting these effects in HeLamtHeLa cells. These results suggest that PIP-TPPs targeting mtDNA mutations could be potential chemotherapeutic drugs to treat cancers without severe adverse effects.

Trivalent sulfonium compounds (TSCs): Tetrahydrothiophene-based amphiphiles exhibit similar antimicrobial activity to analogous ammonium-based amphiphiles.

Recent advances in the development of quaternary ammonium compounds (QACs) have focused on new structural motifs to increase bioactivity, but significantly less studied has been the change from ammonium- to sulfonium-based disinfectants. Herein, we report the synthesis of structurally analogous series of quaternary ammonium and trivalent sulfonium compounds (TSCs). The bioactivity profiles of these compounds generally mirror each other, and the antibacterial activity of sulfonium-based THT-18 was found to be comparable to the commercial disinfectant, BAC. The development of these compounds presents a new avenue for further study of disinfectants to combat the growing threat of bacterial resistance.

Application of Ionic Liquids in Electrochemistry-Recent Advances.

In this review, the roles of room temperature ionic liquids (RTILs) and RTIL based solvent systems as proposed alternatives for conventional organic electrolyte solutions are described. Ionic liquids are introduced as well as the relevant properties for their use in electrochemistry (reduction of ohmic losses), such as diffusive molecular motion and ionic conductivity. We have restricted ourselves to provide a survey on the latest, most representative developments and progress made in the use of ionic liquids as electrolytes, in particular achieved by the cyclic voltammetry technique. Thus, the present review comprises literature from 2015 onward covering the different aspects of RTILs, from the knowledge of these media to the use of their properties for electrochemical processes. Out of the scope of this review are heat transfer applications, medical or biological applications, and multiphasic reactions.

Electrophilic Chlorine from Chlorosulfonium Salts: A Highly Chemoselective Reduction of Sulfoxides.

Herein, we describe a selective late-stage deoxygenation of sulfoxides based on a novel application of chlorosulfonium salts and demonstrate a new process using these species generated in situ from sulfoxides as the source of electrophilic chlorine. The use of highly nucleophilic 1,3,5-trimethoxybenzene (TMB) as the reducing agent is described for the first time and applied in the deoxygenation of simple and functionalized sulfoxides. The method is easy to handle, economic, suitable for gram-scale operations, and readily applied for poly-functionalized molecules, as demonstrated with more than 45 examples, including commercial medicines and analogues. We also report the results of competition experiments that define the more reactive sulfoxide and we present a mechanistic proposal based on substrate and product observations.

Ring-Opening Cyclization of Spirocyclopropanes Using Sulfoxonium Ylides.

Ring-opening cyclization of cyclohexane-1,3-dione-2-spirocyclopropanes using dimethylsulfoxonium methylide proceeded regioselectively to produce 2,3,4,6,7,8-hexahydro-5H-1-benzopyran-5-ones in good to high yields. The reactions of cycloheptane- and cyclopentane-1,3-dione-2-spirocyclopropanes could construct [7.6]- and [5.6]-fused ring systems. This reaction was also carried out using sulfoxonium ethylide, butylide, and benzylide, resulting in the formation of the corresponding 2,3-trans-disubstituted products in good to high yields, and it was shown that the dimethyl group can act as a dummy substituent. It was found that the 2- and 3-phenyhexahydrobenzopyran-5-ones can be readily converted into 5-hydroxyflavan and 5-hydroxyisoflavan, respectively.

Intramolecular methionine alkylation constructs sulfonium tethered peptides for protein conjugation.

Continuous efforts have been invested in the selective modification of proteins. Herein, we first report the construction of sulfonium tethered cyclic peptides via an intramolecular cyclization by an aliphatic halide. This cyclization could enhance the stability and cellular uptake of peptides. Furthermore, the sulfonium center could be recognized by cysteine in the vicinity of the protein-peptide interacting interface and form a peptide-protein conjugate.

Sulfonium-Based Homolytic Substitution Observed for the Radical SAM Enzyme HemN.

Sulfur-based homolytic substitution (SH reaction) plays an important role in synthetic chemistry, yet whether such a reaction could occur on the positively charged sulfonium compounds remains unknown. In the study of the anaerobic coproporphyrinogen III oxidase HemN, a radical S-adenosyl-l-methionine (SAM) enzyme involved in heme biosynthesis, we observed the production of di-(5'-deoxyadenosyl)methylsulfonium, which supports a deoxyadenosyl (dAdo) radical-mediated SH reaction on the sulfonium center of SAM. The sulfonium-based SH reactions were then investigated in detail by density functional theory calculations and model reactions, which showed that this type of reactions is thermodynamically favorable and kinetically competent. These findings represent the first report of sulfonium-based SH reactions, which could be useful in synthetic chemistry. Our study also demonstrates the remarkable catalytic promiscuity of the radical SAM superfamily enzymes.

Synthesis, characterization, and the antioxidant activity of the acetylated chitosan derivatives containing sulfonium salts.

In this study, a new class of chitosan derivatives possessing sulfonium salts was synthesized, and characterized by FT-IR, 1H NMR, 13C NMR, and elemental analyses. IR spectra, 1H NMR and 13C NMR of the structural units of these polymers validated the designed chitosan derivatives were successfully synthesized. In addition, the antioxidant potential of chitosan and chitosan derivatives was assessed in vitro, screened by 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging, hydroxyl radical scavenging, and superoxide radical scavenging, respectively. Results revealed that designed chitosan derivatives could effectively scavenge DPPH radical, hydroxyl radical, and superoxide radical with inhibition rate of more than 90% at 1.6 mg/mL, higher than chitosan. Moreover, in the cytotoxicity assay, no cytotoxicity was observed for the L929 cells with chitosan and its derivatives at all the testing concentrations. These results indicated that the acetylated chitosan derivatives containing sulfonium salts may be a promising natural antioxidant for the pharmaceutics, food, cosmetics and agriculture management.

Recent Progress in the Construction of Natural De-O-Sulfonated Sulfonium Sugars with Antidiabetic Activities.

A group of sulfonium salts equipped with a polyhydroxylated side-chain structure have been isolated and identified as potent α-glycosidase inhibitors. Consequently, they have become an attractive target in diverse research disciplines, including organic synthesis, drug discovery, and chemical biology. To this end, the development of practical and effective synthetic strategies, especially for more bioactive de-O-sulfonated sulfonium salts, is a significant research area in organic synthesis. An ideal synthetic methodology should provide easily accessible intermediates with high chemical stability for the key coupling reaction to diastereoselectively construct the sulfonium cation center. This minireview summarizes recently developed strategies applied in the construction of natural de-O-sulfonated sulfonium sugars: 1) acid-catalyzed de-O-sulfonation of sulfonium sulfate inner salts, 2) a coupling reaction between side-chain fragments containing leaving groups and a thiosugar, 3) a coupling reaction between side-chain fragments containing epoxide structures and a thiosugar, and 4) a two-step sequential SN 2 nucleophilic substitution between side-chain fragments containing thiol groups and a diiodide derivative.

Biogenic production of DMSP and its degradation to DMS-their roles in the global sulfur cycle.

Dimethyl sulfide (DMS) is the most abundant form of volatile sulfur in Earth's oceans, and is mainly produced by the enzymatic clevage of dimethylsulfoniopropionate (DMSP). DMS and DMSP play important roles in driving the global sulfur cycle and may affect climate. DMSP is proposed to serve as an osmolyte, a grazing deterrent, a signaling molecule, an antioxidant, a cryoprotectant and/or as a sink for excess sulfur. It was long believed that only marine eukaryotes such as phytoplankton produce DMSP. However, we recently discovered that marine heterotrophic bacteria can also produce DMSP, making them a potentially important source of DMSP. At present, one prokaryotic and two eukaryotic DMSP synthesis enzymes have been identified. Marine heterotrophic bacteria are likely the major degraders of DMSP, using two known pathways: demethylation and cleavage. Many phytoplankton and some fungi can also cleave DMSP. So far seven different prokaryotic and one eukaryotic DMSP lyases have been identified. This review describes the global distribution pattern of DMSP and DMS, the known genes for biosynthesis and cleavage of DMSP, and the physiological and ecological functions of these important organosulfur molecules, which will improve understanding of the mechanisms of DMSP and DMS production and their roles in the environment.

Structure-Function Analysis Indicates that an Active-Site Water Molecule Participates in Dimethylsulfoniopropionate Cleavage by DddK.

The osmolyte dimethylsulfoniopropionate (DMSP) is produced in petagram quantities in marine environments and has important roles in global sulfur and carbon cycling. Many marine microorganisms catabolize DMSP via DMSP lyases, generating the climate-active gas dimethyl sulfide (DMS). DMS oxidation products participate in forming cloud condensation nuclei and, thus, may influence weather and climate. SAR11 bacteria are the most abundant marine heterotrophic bacteria; many of them contain the DMSP lyase DddK, and their dddK transcripts are relatively abundant in seawater. In a recently described catalytic mechanism for DddK, Tyr64 is predicted to act as the catalytic base initiating the ß-elimination reaction of DMSP. Tyr64 was proposed to be deprotonated by coordination to the metal cofactor or its neighboring His96. To further probe this mechanism, we purified and characterized the DddK protein from Pelagibacter ubique strain HTCC1062 and determined the crystal structures of wild-type DddK and its Y64A and Y122A mutants (bearing a change of Y to A at position 64 or 122, respectively), where the Y122A mutant is complexed with DMSP. The structural and mutational analyses largely support the catalytic role of Tyr64, but not the method of its deprotonation. Our data indicate that an active water molecule in the active site of DddK plays an important role in the deprotonation of Tyr64 and that this is far more likely than coordination to the metal or His96. Sequence alignment and phylogenetic analysis suggest that the proposed catalytic mechanism of DddK has universal significance. Our results provide new mechanistic insights into DddK and enrich our understanding of DMS generation by SAR11 bacteria.IMPORTANCE The climate-active gas dimethyl sulfide (DMS) plays an important role in global sulfur cycling and atmospheric chemistry. DMS is mainly produced through the bacterial cleavage of marine dimethylsulfoniopropionate (DMSP). When released into the atmosphere from the oceans, DMS can be photochemically oxidized into DMSO or sulfate aerosols, which form cloud condensation nuclei that influence the reflectivity of clouds and, thereby, global temperature. SAR11 bacteria are the most abundant marine heterotrophic bacteria, and many of them contain DMSP lyase DddK to cleave DMSP, generating DMS. In this study, based on structural analyses and mutational assays, we revealed the catalytic mechanism of DddK, which has universal significance in SAR11 bacteria. This study provides new insights into the catalytic mechanism of DddK, leading to a better understanding of how SAR11 bacteria generate DMS.

Structural and Functional Characterization of Sulfonium Carbon-Oxygen Hydrogen Bonding in the Deoxyamino Sugar Methyltransferase TylM1.

The N-methyltransferase TylM1 from Streptomyces fradiae catalyzes the final step in the biosynthesis of the deoxyamino sugar mycaminose, a substituent of the antibiotic tylosin. The high-resolution crystal structure of TylM1 bound to the methyl donor S-adenosylmethionine (AdoMet) illustrates a network of carbon-oxygen (CH···O) hydrogen bonds between the substrate's sulfonium cation and residues within the active site. These interactions include hydrogen bonds between the methyl and methylene groups of the AdoMet sulfonium cation and the hydroxyl groups of Tyr14 and Ser120 in the enzyme. To examine the functions of these interactions, we generated Tyr14 to phenylalanine (Y14F) and Ser120 to alanine (S120A) mutations to selectively ablate the CH···O hydrogen bonding to AdoMet. The TylM1 S120A mutant exhibited a modest decrease in its catalytic efficiency relative to that of the wild type (WT) enzyme, whereas the Y14F mutation resulted in an approximately 30-fold decrease in catalytic efficiency. In contrast, site-specific substitution of Tyr14 by the noncanonical amino acid p-aminophenylalanine partially restored activity comparable to that of the WT enzyme. Correlatively, quantum mechanical calculations of the activation barrier energies of WT TylM1 and the Tyr14 mutants suggest that substitutions that abrogate hydrogen bonding with the AdoMet methyl group impair methyl transfer. Together, these results offer insights into roles of CH···O hydrogen bonding in modulating the catalytic efficiency of TylM1.

In Vitro Reconstitution of Bacterial DMSP Biosynthesis.

Dimethylsulfoniopropionate (DMSP) is one of the most abundant sulfur metabolites in marine environments. The biosynthesis of DMSP and its degradation to dimethylsulfide are important links in the planetary sulfur cycle. Herein, the first complete description of a DMSP biosynthetic pathway is provided by the in vitro reconstitution of four enzymes from Streptomyces mobaraensis. The isolation of DMSP from S. mobaraensis cells grown at high salinity confirmed that this actinobacterium is indeed is a DMSP-producing organism. The described DMSP biosynthesis follows the same route as that previously described for angiosperm plants. Despite this chemical congruence, limited sequence similarity between plant and bacterial enzymes suggests that the two biosynthetic activities emerged by convergent evolution.

An efficient method for synthesizing dimethylsulfonio-34 S-propionate hydrochloride from 34 S8.

Dimethylsulfoniopropionate (DMSP, (2-carboxyethyl)dimethylsulfonium) is a highly abundant compound in marine environments. As a precursor to the climatically active gas, dimethylsulfide (DMS), DMSP connects the marine and terrestrial sulfur cycles. However, the fate of DMSP in microbial biomass is not well understood as only a few studies have performed isotopic labeling experiments. A previously published method synthesized 34 S-labeled DMSP from 34 S8 , but the efficiency was only 26% and required five separate reactions, expensive reagents, and purification of the products of each reaction. In this study, a method of synthesizing 34 S-labeled DMSP from 34 S8 is described. Improvements include elemental steps, inexpensive reagents, purification of only one intermediate, and less time to complete. The efficiency of this method is 65% and results in pure DMSP with more than 98% isotope enrichment as determined by 1 H-nuclear magnetic resonance (NMR) and gas chromatography-mass spectrometry (GC-MS).

Synthesis of Zwitterionic Polymers Containing a Tertiary Sulfonium Group for Protein Stabilization.

The present study demonstrates the controlled synthesis and biological potential of poly( N-acryloyl-l-methionine methyl sulfonium salt)s (poly(A-Met(S+)-OH)s), which mimic dimethylsulfoniopropionate (DMSP), a compound produced by marine algae to protect their proteins. The novel sulfonium-containing zwitterionic polymers were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization of the amino acid-based monomer N-acryloyl-l-methionine (A-Met-OH) followed by a postmodification process in which the sulfide groups were reacted with iodomethane. The DMSP-mimic zwitterionic macromolecules were shown for the first time to exhibit low cytotoxicity and the ability to stabilize proteins. By adding the resulting poly(A-Met(S+)-OH)s to horse radish peroxidase (HRP) solution, the activity of HRP was maintained even after storage at 4 °C for several days. In addition, the protein activities were tested using peroxidase-labeled antibody to mouse immunoglobulin G (IgG-HRP) and alkaline phosphatase (ALP) after storage and for HRP after freeze-thaw cycles. Amphiphilic random copolymers, poly(A-Met(S+)-OH- co-BA)s, also exhibited excellent properties for protein stabilization.