Diversity and distribution of sulfur metabolism in the human gut microbiome and its association with colorectal cancer

ABSTRACTMicrobial sulfidogenesis produces genotoxic hydrogen sulfide (H2S) in the human gut using inorganic (sulfate) and organic (taurine/cysteine/methionine) substrates, however the majority of studies have focused on sulfate reduction using dissimilatory sulfite reductases (Dsr). Recent evidence implicates microbial sulfidogenesis as a potential trigger of colorectal cancer (CRC), highlighting the need for comprehensive knowledge of sulfur metabolism within the human gut. Here we show that microbial sulfur metabolism is more abundant and diverse than previously studied and is statistically associated with CRC. Using ~17,000 bacterial genomes from publicly available stool metagenomes, we studied the diversity of sulfur metabolic genes in 667 participants across different health statuses: healthy, adenoma, and carcinoma. Sulfidogenic genes were harbored by 142 bacterial genera and both organic and inorganic sulfidogenic genes were associated with carcinoma. Significantly, anaerobic sulfite reductases were twice as abundant as dsr. We identified twelve potential pathways for reductive taurine metabolism including novel pathways, and prevalence of organic sulfur metabolic genes indicate these substrates may be the most abundant source of microbially derived H2S. Our findings significantly expand knowledge of microbial sulfur metabolism in the human gut, and highlight key gaps that limit understanding of its potential contributions to the pathogenesis of CRC.

Modulation of the complex regulatory network for methionine biosynthesis in fungi

The assimilation of inorganic sulfate and the synthesis of the sulfur-containing amino acids methionine and cysteine is mediated by a multibranched biosynthetic pathway. We have investigated this circuitry in the fungal pathogen Candida albicans, which is phylogenetically intermediate between the filamentous fungi and Saccharomyces cerevisiae. In S. cerevisiae, this pathway is regulated by a collection of five transcription factors (Met4, Cbf1, Met28, and Met31/Met32), while in the filamentous fungi the pathway is controlled by a single Met4-like factor. We found that in C. albicans, the Met4 ortholog is also a core regulator of methionine biosynthesis, where it functions together with Cbf1. While C. albicans encodes this Met4 protein, a Met4 paralog designated Met28 (Orf19.7046), and a Met31 protein, deletion, and activation constructs suggest that of these proteins only Met4 is actually involved in the regulation of methionine biosynthesis. Both Met28 and Met31 are linked to other functions; Met28 appears essential, and Met32 appears implicated in the regulation of genes of central metabolism. Therefore, while S. cerevisiae and C. albicans share Cbf1 and Met4 as central elements of the methionine biosynthesis control, the other proteins that make up the circuit in S. cerevisiae are not members of the C. albicans control network, and so the S. cerevisiae circuit likely represents a recently evolved arrangement.

An Activity-Based Fluorescent Sensor for the Detection of the Phenol Sulfotransferase SULT1A1 in Living Cells

<p>The biological activation and incorporation of inorganic sulfate proceeds via a process known as sulfurylation. Transfer of a sulfuryl moiety from the activated sulfate donor, 3’-phosphoadenosine-5’-phosphosulfate (PAPS), to hydroxy-containing substrates by human phenol sulfotransferases (SULT1 family) alters substrate solubility and charge to affect the metabolism of endogenous metabolites, xenobiotics, and drugs. Current methods to monitor SULT1 activity in living cells primarily rely on radiolabeling and/or cell extractions, but these methods do not provide a direct readout of enzyme activity with a dynamic, temporally resolved spatial map in live, intact cells. To fill this gap, here, we present the development, computational modeling, <i>in vitro</i> enzymology, and biological application of Sulfotransferase Sensor-3, STS-3, an activity-based fluorescent sensor for SULT1A1, the most widely expressed and promiscuous SULT1 isoform. </p>

An Activity-Based Fluorescent Sensor for the Detection of the Phenol Sulfotransferase SULT1A1 in Living Cells

<p>The biological activation and incorporation of inorganic sulfate proceeds via a process known as sulfurylation. Transfer of a sulfuryl moiety from the activated sulfate donor, 3’-phosphoadenosine-5’-phosphosulfate (PAPS), to hydroxy-containing substrates by human phenol sulfotransferases (SULT1 family) alters substrate solubility and charge to affect the metabolism of endogenous metabolites, xenobiotics, and drugs. Current methods to monitor SULT1 activity in living cells primarily rely on radiolabeling and/or cell extractions, but these methods do not provide a direct readout of enzyme activity with a dynamic, temporally resolved spatial map in live, intact cells. To fill this gap, here, we present the development, computational modeling, <i>in vitro</i> enzymology, and biological application of Sulfotransferase Sensor-3, STS-3, an activity-based fluorescent sensor for SULT1A1, the most widely expressed and promiscuous SULT1 isoform. </p>

Modular Chitosan-Based Adsorbents for Tunable Uptake of Sulfate from Water

The context of this study responds to the need for sorbent technology development to address the controlled removal of inorganic sulfate (SO42−) from saline water and the promising potential of chitosan as a carrier system for organosulfates in pharmaceutical and nutraceutical applications. This study aims to address the controlled removal of sulfate using chitosan as a sustainable biopolymer platform, where a modular synthetic approach was used for chitosan bead preparation that displays tunable sulfate uptake. The beads were prepared via phase-inversion synthesis, followed by cross-linking with glutaraldehyde, and impregnation of Ca2+ ions. The sulfate adsorption properties of the beads were studied at pH 5 and variable sulfate levels (50–1000 ppm), where beads with low cross-linking showed moderate sulfate uptake (35 mg/g), while cross-linked beads imbibed with Ca2+ had greater sulfate adsorption (140 mg/g). Bead stability, adsorption properties, and the point-of-zero charge (PZC) from 6.5 to 6.8 were found to depend on the cross-linking ratio and the presence of Ca2+. The beads were regenerated over multiple adsorption-desorption cycles to demonstrate the favorable uptake properties and bead stability. This study contributes to the development of chitosan-based adsorbent technology via a modular materials design strategy for the controlled removal of sulfate. The results of this study are relevant to diverse pharmaceutical and nutraceutical applications that range from the controlled removal of dextran sulfate from water to the controlled release of chondroitin sulfate.

Insights into the morphology of multicomponent organic and inorganic aerosols from molecular dynamics simulations

We explore the morphologies of multicomponent nanoparticles through atomistic molecular dynamics simulations under atmospherically relevant conditions. The particles investigated consist of both organic (cis-pinonic acid – CPA, 3-methyl-1,2,3-butanetricarboxylic acid – MBTCA, n-C20H42, n-C24H50, n-C30H62 or mixtures thereof) and inorganic (sulfate, ammonium and water) compounds. The effects of relative humidity, organic mass content and type of organic compound present in the nanoparticle are investigated. Phase separation is predicted for almost all simulated nanoparticles either between organics and inorganics or between hydrophobic and hydrophilic constituents. For oxygenated organics, our simulations predict an enrichment of the nanoparticle surface in organics, often in the form of islands depending on the level of humidity and organic mass fraction, giving rise to core–shell structures. In several cases the organics separate from the inorganics, especially from the ions. For particles containing water-insoluble linear alkanes, separate hydrophobic and hydrophilic domains are predicted to develop. The surface partitioning of organics is enhanced as the humidity increases. The presence of organics in the interior of the nanoparticle increases as their overall mass fraction in the nanoparticle increases, but this also depends on the humidity conditions. Apart from the organics–inorganics and hydrophobics–hydrophilics separation, our simulations predict a third type of separation (layering) between CPA and MBTCA molecules under certain conditions.

Alum (KAl(SO4)2.12H2O) - An Eco-friendly and Versatile Acid-catalyst in Organic Transformations: A Recent Update

Potassium alum (KAl(SO4)2.12H2O), commonly known as ‘alum’, has recently drawn the attention of synthetic chemists as an efficient, safe and eco-friendly acid catalyst in implementing a large number of organic transformations, thereby generating interesting molecular frameworks. The present review article offers an overview of the potent catalytic applications of this commercially available and low-cost inorganic sulfate salt in organic reactions reported during the period of 2014 to 2018.