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Sulfite oxidase (SOX) deficiency is a rare inborn error of cysteine metabolism resulting in severe neurological damage. In patients, sulfite accumulates to toxic levels, causing a rise in the downstream products S -sulfocysteine, which mediates excitotoxicity, and thiosulfate, a catabolic intermediate/product of hydrogen sulfide (H 2 S) metabolism. Here, we report a full-body knockout mouse model for SOX deficiency (SOXD) with a severely impaired phenotype. Among the urinary biomarkers, thiosulfate showed a 45-fold accumulation in SOXD mice, representing the major excreted S-metabolite. Consistently, we found increased plasma H 2 S, which was derived from sulfite-induced release from persulfides, as demonstrated in vitro and in vivo. Mass spectrometry analysis of total protein persulfidome identified a major loss of S-persulfidation in 20% of the proteome, affecting enzymes in amino acids, fatty acid metabolism, and cytosolic iron-sulfur cluster biogenesis. Urinary amino acid profiles indicated metabolic rewiring and mitochondrial dysfunction, thus identifying an altered H 2 S metabolism and persulfidation in SOXD. Finally, oxidized glutathione and glutathione trisulfide were able to scavenge sulfite in vitro and in vivo, extending the lifespan of SOXD mice and providing a mechanistic concept of sulfite scavenging for the treatment of this severe metabolic disorder of cysteine catabolism.

Abstract Sulfate/sulfite-reducing microorganisms (SRM) are ubiquitous in nature, driving the global sulfur cycle. A hallmark of SRM is the dissimilatory sulfite reductase encoded by the genes dsrAB. Based on analysis of 950 mainly metagenome-derived dsrAB-carrying genomes, we redefine the global diversity of microorganisms with the potential for dissimilatory sulfate/sulfite reduction and uncover genetic repertoires that challenge earlier generalizations regarding their mode of energy metabolism. We show: (i) 19 out of 23 bacterial and 2 out of 4 archaeal phyla harbor uncharacterized SRM, (ii) four phyla including the Desulfobacterota harbor microorganisms with the genetic potential to switch between sulfate/sulfite reduction and sulfur oxidation, and (iii) the combination as well as presence/absence of different dsrAB-types, dsrL-types and dsrD provides guidance on the inferred direction of dissimilatory sulfur metabolism. We further provide an updated dsrAB database including > 60% taxonomically resolved, uncultured family-level lineages and recommendations on existing dsrAB-targeted primers for environmental surveys. Our work summarizes insights into the inferred ecophysiology of newly discovered SRM, puts SRM diversity into context of the major recent changes in bacterial and archaeal taxonomy, and provides an up-to-date framework to study SRM in a global context. Sulfate/sulfite reducing microorganisms are shaping Earth's interconnected sulfur and carbon cycles since the Archaean: this legacy unfolds in 27 archaeal and bacterial phyla encountered in diverse marine, terrestrial, and deep-subsurface environments.

Escherichia coli NADPH-dependent assimilatory sulfite reductase (SiR) reduces sulfite by six electrons to make sulfide for incorporation into sulfur-containing biomolecules. SiR has two subunits: an NADPH, FMN, and FAD-binding diflavin flavoprotein and a siroheme/Fe 4 S 4 cluster-containing hemoprotein. The molecular interactions that govern subunit binding have been unknown since the discovery of SiR over 50 years ago because SiR is flexible, thus has been intransigent for traditional high-resolution structural analysis. We use a combination of the chameleon® plunging system with a fluorinated lipid to overcome the challenges of preserving a flexible molecule to determine a 2.78 Å-resolution cryo-EM structure of a minimal heterodimer complex. Chameleon®, combined with the fluorinated lipid, overcomes persistent denaturation at the air-water interface. Using a previously characterized minimal heterodimer reduces the heterogeneity of a structurally heterogeneous complex to a level that we analyze using multi-conformer cryo-EM image analysis algorithms. Here, we report the near-atomic resolution structure of the flavoprotein/hemoprotein complex, revealing how they interact in a minimal interface. Further, we determine the structural elements that discriminate between pairing a hemoprotein with a diflavin reductase, as in the E. coli homolog, or a ferredoxin partner, as in maize ( Zea mays ). Here, the authors probe E. coli NADPH-dependent assimilatory sulfite reductase (SiR) by determining the cryo-EM structure of the SiRFP/SiRHP dimer, revealing the minimal binding interface for diflavin reductase and electron transfer partner binding.

Main conclusion This review highlights the sulfur transporters, key enzymes and their encoding genes involved in plant sulfur anabolism, focusing on their occurrence, chemistry, location, function, and regulation within sulfur assimilation pathways. Sulfur, a vital element for plant life, plays diverse roles in metabolism and stress response. This review provides a comprehensive overview of the sulfur assimilation pathway in plants, highlighting the intricate network of enzymes and their regulatory mechanisms. The primary focus is on the key enzymes involved: ATP sulfurylase (ATPS), APS reductase (APR), sulfite reductase (SiR), serine acetyltransferase (SAT), and O-acetylserine(thiol)lyase (OAS-TL). ATPS initiates the process by activating sulfate to form APS, which is then reduced to sulfite by APR. SiR further reduces sulfite to sulfide, a crucial step that requires significant energy. The cysteine synthase complex (CSC), formed by SAT and OAS-TL, facilitates the synthesis of cysteine, thereby integrating serine metabolism with sulfur assimilation. The alternative sulfation pathway, catalyzed by APS kinase and sulfotransferases, is explored for its role in synthesizing essential secondary metabolites. This review also delves into the regulatory mechanism of these enzymes such as environmental stresses, sulfate availability, phytohormones, as well as translational and post-translational regulations. Understanding the key transporters and enzymes in sulfur assimilation pathways and their corresponding regulation mechanisms can help researchers grasp the importance of sulfur anabolism for the life cycle of plants, clarify how these enzymes and their regulatory processes are integrated to balance plant life systems in response to changes in both external conditions and intrinsic signals.

Isolated sulfite oxidase deficiency (ISOD; OMIM #272300) is a devastating rare neurometabolic disorder due to biallelic pathogenic variants in the SUOX gene, that typically results in neonatal refractory epilepsy and progressive severe encephalopathy. Knowledge on the quantitative natural history of ISOD is limited and clinical outcome parameters for future clinical trials remain to be defined. We performed a comprehensive analysis of published cases (N=74) with ISOD applying quantitative retrospective natural history modeling (QUARNAM). Main outcome parameters were age of disease onset, diagnostic delay and survival. Clinical characteristics and potential associations between biochemical parameters and clinical outcome (i.e. age of disease onset, survival) were explored. The median survival period of the study cohort was 60 months. ISOD typically presented shortly after birth with a median age of onset of 3 days. Median age at diagnosis was 10 months, leading to a substantial median diagnostic delay of 5.7 months. Homocysteine concentrations in plasma correlated with age of disease onset. An association of biochemical parameters of cysteine metabolism and survival could not be identified. The present analysis describes long-term outcome measures adding to the quantitative understanding of the natural history of ISOD, which might be helpful in the planning of prospective clinical trials and potentially stimulate development of targeted therapies in the future.

Specialized glial subtypes provide support to developing and functioning neural networks. Astrocytes modulate information processing by neurotransmitter recycling and release of neuromodulatory substances, whereas ensheathing glial cells have not been associated with neuromodulatory functions yet. To decipher a possible role of ensheathing glia in neuronal information processing, we screened for glial genes required in the Drosophila central nervous system for normal locomotor behavior. Shopper encodes a mitochondrial sulfite oxidase that is specifically required in ensheathing glia to regulate head bending and peristalsis. shopper mutants show elevated sulfite levels affecting the glutamate homeostasis which then act on neuronal network function. Interestingly, human patients lacking the Shopper homolog SUOX develop neurological symptoms, including seizures. Given an enhanced expression of SUOX by oligodendrocytes, our findings might indicate that in both invertebrates and vertebrates more than one glial cell type may be involved in modulating neuronal activity. In Drosophila , ensheathing glia encase the neuropil but their function is not well understood. Here the authors show a surprising role of ensheathing glia in regulating glutamate homeostasis and locomotion which is controlled by the sulfite oxidase Shopper.

Isolated sulfite oxidase (ISOD) and molybdenum cofactor (MoCD) deficiencies are genetic diseases biochemically characterized by the toxic accumulation of sulfite in the tissues of patients, including the brain. Neurological dysfunction and brain abnormalities are commonly observed soon after birth, and some patients also have neuropathological alterations in the prenatal period (in utero). Thus, we investigated the effects of sulfite on redox and mitochondrial homeostasis, as well as signaling proteins in the cerebral cortex of rat pups. One-day-old Wistar rats received an intracerebroventricular administration of sulfite (0.5 µmol/g) or vehicle and were euthanized 30 min after injection. Sulfite administration decreased glutathione levels and glutathione S-transferase activity, and increased heme oxygenase-1 content in vivo in the cerebral cortex. Sulfite also reduced the activities of succinate dehydrogenase, creatine kinase, and respiratory chain complexes II and II–III. Furthermore, sulfite increased the cortical content of ERK1/2 and p38. These findings suggest that redox imbalance and bioenergetic impairment induced by sulfite in the brain are pathomechanisms that may contribute to the neuropathology of newborns with ISOD and MoCD. Graphical Abstract Sulfite disturbs antioxidant defenses, bioenergetics, and signaling pathways in the cerebral cortex of neonatal rats. CII: complex II; CII-III: complex II-III; CK: creatine kinase; GST: glutathione S-transferase; HO-1: heme oxygenase-1; SDH: succinate dehydrogenase; SO 3 2− : sulfite.

Sulfite oxidase is one of five molybdenum-containing enzymes known in eukaryotes where it catalyzes the oxidation of sulfite to sulfate. This review covers the history of sulfite oxidase research starting out with the early years of its discovery as a hepatic mitochondrial enzyme in vertebrates, leading to basic biochemical and structural properties that have inspired research for decades. A personal view on sulfite oxidase in plants, that sulfates are assimilated for their de novo synthesis of cysteine, is presented by Ralf Mendel with numerous unexpected findings and unique properties of this single-cofactor sulfite oxidase localized to peroxisomes. Guenter Schwarz connects his research to sulfite oxidase via its deficiency in humans, demonstrating its unique role amongst all molybdenum enzymes in humans. In essence, in both the plant and animal kingdoms, sulfite oxidase represents an important player in redox regulation, signaling and metabolism, thereby connecting sulfur and nitrogen metabolism in multiple ways.

Background/Objectives Sulfites are additives commonly used in food and wine industries that are associated to adverse clinical effects such as headaches. The objective of this study is to investigate the possible association between sulfite concentration in wine and the occurrence of headaches in young adults. Subjects/Methods Eighty volunteers, aged between 18 and 25 years, were evaluated. Sub-groups (with or without previous headaches related with wine) were created and volunteers were submitted to two wine tests (minimum and maximum sulfite concentration accordingly to weight). A questionnaire was handed out after the test regarding the presence or not of headaches, their main characteristics, as well as other symptoms associated. Results Subjects that refer a previous headache history upon wine ingestion presented a risk 2266 greater of developing headaches after wine ingestion with a greater sulfite concentration. Those that refer constant headaches related to wine ingestion previous to the test present a risk of 6232 times more of developing headaches compared to those who refer sporadic headaches related to wine consumption. Conclusions In our group of subjects, sulfite concentration in wine is related to the risk of developing headaches in individuals who are susceptible to wine induced headaches.

The energy metabolism of essential microbial guilds in the biogeochemical sulfur cycle is based on a DsrAB-type dissimilatory (bi)sulfite reductase that either catalyzes the reduction of sulfite to sulfide during anaerobic respiration of sulfate, sulfite and organosulfonates, or acts in reverse during sulfur oxidation. Common use of dsrAB as a functional marker showed that dsrAB richness in many environments is dominated by novel sequence variants and collectively represents an extensive, largely uncharted sequence assemblage. Here, we established a comprehensive, manually curated dsrAB /DsrAB database and used it to categorize the known dsrAB diversity, reanalyze the evolutionary history of dsrAB and evaluate the coverage of published dsrAB -targeted primers. Based on a DsrAB consensus phylogeny, we introduce an operational classification system for environmental dsrAB sequences that integrates established taxonomic groups with operational taxonomic units (OTUs) at multiple phylogenetic levels, ranging from DsrAB enzyme families that reflect reductive or oxidative DsrAB types of bacterial or archaeal origin, superclusters, uncultured family-level lineages to species-level OTUs. Environmental dsrAB sequences constituted at least 13 stable family-level lineages without any cultivated representatives, suggesting that major taxa of sulfite/sulfate-reducing microorganisms have not yet been identified. Three of these uncultured lineages occur mainly in marine environments, while specific habitat preferences are not evident for members of the other 10 uncultured lineages. In summary, our publically available dsrAB /DsrAB database, the phylogenetic framework, the multilevel classification system and a set of recommended primers provide a necessary foundation for large-scale dsrAB ecology studies with next-generation sequencing methods.