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Many prokaryotic species generate hydrogen sulfide (H₂S) in their natural environments. However, the biochemistry and physiological role of this gas in nonsulfur bacteria remain largely unknown. Here we demonstrate that inactivation of putative cystathionine β-synthase, cystathionine γ-lyase, or 3-mercaptopyruvate sulfurtransferase in Bacillus anthracis, Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli suppresses H₂S production, rendering these pathogens highly sensitive to a multitude of antibiotics. Exogenous H₂S suppresses this effect. Moreover, in bacteria that normally produce H₂S and nitric oxide, these two gases act synergistically to sustain growth. The mechanism of gas-mediated antibiotic resistance relies on mitigation of oxidative stress imposed by antibiotics.

Cystathionine-β-synthase (CBS), the first (and rate-limiting) enzyme in the transsulfuration pathway, is an important mammalian enzyme in health and disease. Its biochemical functions under physiological conditions include the metabolism of homocysteine (a cytotoxic molecule and cardiovascular risk factor) and the generation of hydrogen sulfide (H2S), a gaseous biological mediator with multiple regulatory roles in the vascular, nervous, and immune system. CBS is up-regulated in several diseases, including Down syndrome and many forms of cancer; in these conditions, the preclinical data indicate that inhibition or inactivation of CBS exerts beneficial effects. This article overviews the current information on the expression, tissue distribution, physiological roles, and biochemistry of CBS, followed by a comprehensive overview of direct and indirect approaches to inhibit the enzyme. Among the small-molecule CBS inhibitors, the review highlights the specificity and selectivity problems related to many of the commonly used “CBS inhibitors” (e.g., aminooxyacetic acid) and provides a comprehensive review of their pharmacological actions under physiological conditions and in various disease models.

Cystathionine beta-synthase deficiency (CBSD) is the most prevalent inherited disorder of homocysteine metabolism in the transsulphuration pathway. Research have suggested oxidative stress and inflammation as candidate pathogenic mechanisms in CBSD. This study aims to evaluate mitochondrial dysfunction and oxidative stress biomarkers in cystathionine beta-synthase deficiency (CBSD) patients, which may aid in understanding the pathogenesis of CBSD and improving treatment. The study group comprised 23 patients with a diagnosis of CBSD and healthy controls. We analysed serum levels of NAD + and NADH by fluorometric assay, FGF-21 and GDF-15 by ELISA, mitochondrial DAMPs by real time qRT-PCR, total homocysteine levels in plasma by enzymatic test and compared the results in CBSD group with healthy controls. In patient group, a positive correlation was found between the total homocysteine level and both GDF-15 and NAD + /NADH levels. Furthermore, there was a negative correlation between total homocysteine levels and both total NAD + +NADH and NADH levels. The alterations in NAD + , FGF-21, GDF-15 levels, and NAD + /NADH ratio in patients suggest that oxidative damage coexists with mitochondrial dysfunction in CBSD. Assessment of oxidative damage and addition of anti-oxidant therapy together with mitochondrial support may have additional benefits in reducing long-term morbidity in CBSD patients.

Plant thioredoxins (Trxs) participate in two redox systems found in different cellular compartments: the NADP-Trx system (NTS) in the cytosol and mitochondria and the ferredoxin-Trx system (FTS) in the chloroplast, where they function as redox regulators by regulating the activity of various target enzymes. The identities of the master regulators that maintain cellular homeostasis and modulate timed development through redox regulating systems have remained completely unknown. Here, we show that proteins consisting of a single cystathionine β-synthase (CBS) domain pair stabilize cellular redox homeostasis and modulate plant development via regulation of Trx systems by sensing changes in adenosine-containing ligands. We identified two CBS domain–containing proteins in Arabidopsis thaliana, CBSX1 and CBSX2, which are localized to the chloroplast, where they activate all four Trxs in the FTS. CBSX3 was found to regulate mitochondrial Trx members in the NTS. CBSX1 directly regulates Trxs and thereby controls H2O2 levels and regulates lignin polymerization in the anther endothecium. It also affects plant growth by regulating Calvin cycle enzymes, such as malate dehydrogenase, via homeostatic regulation of Trxs. Based on our findings, we suggest that the CBSX proteins (or a CBS pair) are ubiquitous redox regulators that regulate Trxs in the FTS and NTS to modulate development and maintain homeostasis under conditions that are threatening to the cell.

Significance Cystathionine β-synthase (CBS), the pivotal enzyme of the transsulfuration pathway, regulates flux through the pathway to yield compounds, such as cysteine, glutathione, taurine, and H ₂S, that control cellular redox status and signaling. Our crystal structure of an engineered human CBS construct bound to S -adenosylmethionine (AdoMet) reveals the unique binding site of the allosteric activator and the architecture of the human CBS enzyme in its activated conformation. Together with the basal conformation that we reported earlier, these structures unravel the molecular mechanism of human CBS activation by AdoMet. Current knowledge will allow for modeling of numerous pathogenic mutations causing inherited homocystinuria and for design of compounds modulating CBS activity.

Enhancement of cerebral blood flow by hypoxia is critical for brain function, but signaling systems underlying its regulation have been unclear. We report a pathway mediating hypoxia-induced cerebral vasodilation in studies monitoring vascular disposition in cerebellar slices and in intact mouse brains using two-photon intravital laser scanning microscopy. In this cascade, hypoxia elicits cerebral vasodilation via the coordinate actions of H2S formed by cystathionine β-synthase (CBS) and CO generated by heme oxygenase (HO)-2. Hypoxia diminishes CO generation by HO-2, an oxygen sensor. The constitutive CO physiologically inhibits CBS, and hypoxia leads to increased levels of H2S that mediate the vasodilation of precapillary arterioles. Mice with targeted deletion of HO-2 or CBS display impaired vascular responses to hypoxia. Thus, in intact adult brain cerebral cortex of HO-2–null mice, imaging mass spectrometry reveals an impaired ability to maintain ATP levels on hypoxia.

Background Classical homocystinuria (HCU), caused by cystathionine beta‐synthase (CBS) deficiency, exhibits significant geographic variability in its mutational spectrum. Although over 191 CBS mutations have been reported worldwide, Chinese cases remain rare and lack common hotspot mutations. This study aimed to characterize novel CBS variants in a Chinese family to expand the known mutational spectrum and inform genetic counseling practices. Materials and Methods A Chinese Yi family affected by HCU was analyzed. Clinical features, whole‐exome sequencing (WES), and metabolic data were collected. Ancestry composition was evaluated using principal component analysis (PCA) and ADMIXTURE analysis. The pathogenicity of CBS variants was assessed through three‐dimensional protein modeling, Western blotting, and enzyme activity assays. Results The proband, a 9‐year‐old girl with lens dislocation and seizures, carried compound heterozygous CBS mutations: c.1006C>T (p.Arg336Cys) and c.1061_1069del (p.Val354_Val356del), both located within the catalytic domain of the CBS protein. Structural and functional analyses demonstrated that the latter variant disrupts CBS expression and enzymatic activity. Her asymptomatic brother also carried the same compound heterozygous variants and exhibited mild hyperhomocysteinemia. Ancestry analysis revealed predominant East Asian ancestry with 5.2% Central African Pygmy admixture. Conclusion This study identifies the first CBS c.1061_1069del variant and confirms c.1006C>T pathogenicity in China. The findings expand the CBS mutation spectrum, underscore the importance of ethnicity‐specific variants, and provide valuable insights for prenatal diagnosis and genetic counseling in Chinese populations. Schematic representation of the study design and findings. Whole‐exome sequencing identified compound heterozygous CBS variants (c.1006C>T and c.1061_1069del) in a Chinese family with classical homocystinuria. Structural modeling, Western blotting, and enzyme activity assays revealed that the novel deletion variant impaired CBS folding and abolished enzymatic activity. These findings expand the CBS mutational spectrum in the Chinese population and provide important implications for genetic counseling and prenatal diagnosis.

The sulfur-containing amino acids (SAAs) play a key role in the occurrence and development of tumors. However, the clinical prognostic value of SAAs metabolism (SAAM) regulators in stomach adenocarcinoma (STAD) remains unclear. We systematically evaluated the clinical and immune characteristics of SAAM-related genes in STAD. Furthermore, a SAAM score model was constructed, and patients in the low-SAAM score group had a better prognosis. As the core gene in the model, the low expression of cystathionine beta-synthase (CBS) indicated a better prognosis for patients. Interfering with CBS expression in MKN-45 cells inhibited cell proliferation, reduced the production of glutathione (GSH), and promoted cellular oxidative stress. Importantly, the downregulation of CBS heightened sensitivity to ferroptosis inducers in STAD cells, highlighting the involvement of CBS in ferroptosis. In conclusion, the utilization of SAAM for the identification and personalized scoring of patients might potentially play a significant role in evaluating prognosis, immune infiltrates, and guiding treatment for STAD.

The symbiosis between leguminous plants and soil rhizobia culminates in the formation of nitrogen-fixing organs called nodules that support plant growth. Two Medicago truncatula Tnt1-insertion mutants were identified that produced small nodules, which were unable to fix nitrogen effectively due to ineffective rhizobial colonization. The gene underlying this phenotype was found to encode a protein containing a putative membrane-localized domain of unknown function (DUF21) and a cystathionine-β-synthase domain. The cbs1 mutants had defective infection threads that were sometimes devoid of rhizobia and formed small nodules with greatly reduced numbers of symbiosomes. We studied the expression of the gene, designated M. truncatula Cystathionine-β-Synthase-like1 (MtCBS1), using a promoter-β-glucuronidase gene fusion, which revealed expression in infected root hair cells, developing nodules, and in the invasion zone of mature nodules. An MtCBS1-GFP fusion protein localized itself to the infection thread and symbiosomes. Nodulation factor-induced Ca²⁺ responses were observed in the cbs1 mutant, indicating that MtCBS1 acts downstream of nodulation factor signaling. MtCBS1 expression occurred exclusively during Medicago-rhizobium symbiosis. Induction of MtCBS1 expression during symbiosis was found to be dependent on Nodule Inception (NIN), a key transcription factor that controls both rhizobial infection and nodule organogenesis. Interestingly, the closest homolog of MtCBS1, MtCBS2, was specifically induced in mycorrhizal roots, suggesting common infection mechanisms in nodulation and mycorrhization. Related proteins in Arabidopsis have been implicated in cell wall maturation, suggesting a potential role for CBS1 in the formation of the infection thread wall.

Regulatory cystathionine β-synthase (CBS) domains are widespread in proteins; however, difficulty in structure determination prevents a comprehensive understanding of the underlying regulation mechanism. Tetrameric microbial inorganic pyrophosphatase containing such domains (CBS-PPase) is allosterically inhibited by AMP and ADP and activated by ATP and cell alarmones diadenosine polyphosphates. Each CBS-PPase subunit contains a pair of CBS domains but binds cooperatively to only one molecule of the mono-adenosine derivatives. We used site-directed mutagenesis of Desulfitobacterium hafniense CBS-PPase to identify the key elements determining the direction of the effect (activation or inhibition) and the “half-of-the-sites” ligand binding stoichiometry. Seven amino acid residues were selected in the CBS1 domain, based on the available X-ray structure of the regulatory domains, and substituted by alanine and other residues. The interaction of 11 CBS-PPase variants with the regulating ligands was characterized by activity measurements and isothermal titration calorimetry. Lys100 replacement reversed the effect of ADP from inhibition to activation, whereas Lys95 and Gly118 replacements made ADP an activator at low concentrations but an inhibitor at high concentrations. Replacement of these residues for alanine increased the stoichiometry of mono-adenosine phosphate binding by twofold. These findings identified several key protein residues and suggested a “two non-interacting pairs of interacting regulatory sites” concept in CBS-PPase regulation.