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Biochimica Et Biophysica Acta Nov 2011The role of endogenously produced H(2)S in mediating varied physiological effects in mammals has spurred enormous recent interest in understanding its biology and in... (Review)
Review
The role of endogenously produced H(2)S in mediating varied physiological effects in mammals has spurred enormous recent interest in understanding its biology and in exploiting its pharmacological potential. In these early days in the field of H(2)S signaling, large gaps exist in our understanding of its biological targets, its mechanisms of action and the regulation of its biogenesis and its clearance. Two branches within the sulfur metabolic pathway contribute to H(2)S production: (i) the reverse transsulfuration pathway in which two pyridoxal 5'-phosphate-dependent (PLP) enzymes, cystathionine β-synthase and cystathionine γ-lyase convert homocysteine successively to cystathionine and cysteine and (ii) a branch of the cysteine catabolic pathway which converts cysteine to mercaptopyruvate via a PLP-dependent cysteine aminotransferase and subsequently, to mercaptopyruvate sulfur transferase-bound persulfide from which H(2)S can be liberated. In this review, we present an overview of the kinetics of the H(2)S-generating reactions, compare the structures of the PLP-enzymes involved in its biogenesis and discuss strategies for their regulation. This article is part of a Special Issue entitled: Pyridoxal Phospate Enzymology.
Topics: Animals; Catalytic Domain; Cystathionine beta-Synthase; Cystathionine gamma-Lyase; Hydrogen Sulfide; Kinetics; Models, Molecular; Pyridoxal Phosphate
PubMed: 21315854
DOI: 10.1016/j.bbapap.2011.02.004 -
Biomolecules Apr 2020Cystathionine-β-synthase (CBS), the first (and rate-limiting) enzyme in the transsulfuration pathway, is an important mammalian enzyme in health and disease. Its... (Review)
Review
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 (HS), 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.
Topics: Animals; Cystathionine beta-Synthase; Down Syndrome; Enzyme Inhibitors; Humans; Hydrogen Sulfide; Neoplasms; Tacrolimus
PubMed: 32365821
DOI: 10.3390/biom10050697 -
Biomolecules Jan 2022The studies concerned the expression of sulfurtransferases and cystathionine beta-synthase in six human leukemia cell lines: B cell acute lymphoblastic leukemia-B-ALL...
The studies concerned the expression of sulfurtransferases and cystathionine beta-synthase in six human leukemia cell lines: B cell acute lymphoblastic leukemia-B-ALL (REH cells), T cell acute lymphoblastic leukemia-T-ALL (DND-41 and MOLT-4 cells), acute myeloid leukemia-AML (MV4-11 and MOLM-14 cells), and chronic myeloid leukemia-CML (K562 cells). Reverse transcription-polymerase chain reaction (RT-PCR) and Western blot analysis were performed to determine the expression of thiosulfate sulfurtransferase, 3-mercaptopyruvate sulfurtransferase, gamma-cystathionase, and cystathionine beta-synthase on the mRNA and protein level. Interestingly, we found significant differences in the mRNA and protein levels of sulfurtransferases and cystathionine beta-synthase in the studied leukemia cells. The obtained results may contribute to elucidating the significance of the differences between the studied cells in the field of sulfur compound metabolism and finding new promising ways to inhibit the proliferation of various types of leukemic cells by modulating the activity of sulfurtransferases, cystathionine beta-synthase, and, consequently, the change of intracellular level of sulfane sulfur as well as HS and reactive oxygen species production.
Topics: Cell Line; Cystathionine beta-Synthase; Humans; Leukemia; Sulfur; Sulfurtransferases
PubMed: 35204649
DOI: 10.3390/biom12020148 -
Cancer Biology & Medicine Jun 2023Lung oncogenesis relies on intracellular cysteine to overcome oxidative stress. Several tumor types, including non-small cell lung cancer (NSCLC), upregulate the system... (Review)
Review
Lung oncogenesis relies on intracellular cysteine to overcome oxidative stress. Several tumor types, including non-small cell lung cancer (NSCLC), upregulate the system x cystine/glutamate antiporter (xCT) through overexpression of the cystine transporter SLC7A11, thus sustaining intracellular cysteine levels to support glutathione synthesis. Nuclear factor erythroid 2-related factor 2 (NRF2) serves as a master regulator of oxidative stress resistance by regulating SLC7A11, whereas Kelch-like ECH-associated protein (KEAP1) acts as a cytoplasmic repressor of the oxidative responsive transcription factor NRF2. Mutations in KEAP1/NRF2 and p53 induce SLC7A11 activation in NSCLC. Extracellular cystine is crucial in supplying the intracellular cysteine levels necessary to combat oxidative stress. Disruptions in cystine availability lead to iron-dependent lipid peroxidation, thus resulting in a type of cell death called ferroptosis. Pharmacologic inhibitors of xCT (either SLC7A11 or GPX4) induce ferroptosis of NSCLC cells and other tumor types. When cystine uptake is impaired, the intracellular cysteine pool can be sustained by the transsulfuration pathway, which is catalyzed by cystathionine-B-synthase (CBS) and cystathionine g-lyase (CSE). The involvement of exogenous cysteine/cystine and the transsulfuration pathway in the cysteine pool and downstream metabolites results in compromised CD8 T cell function and evasion of immunotherapy, diminishing immune response and potentially reducing the effectiveness of immunotherapeutic interventions. Pyroptosis is a previously unrecognized form of regulated cell death. In NSCLCs driven by EGFR, ALK, or KRAS, selective inhibitors induce pyroptotic cell death as well as apoptosis. After targeted therapy, the mitochondrial intrinsic apoptotic pathway is activated, thus leading to the cleavage and activation of caspase-3. Consequently, gasdermin E is activated, thus leading to permeabilization of the cytoplasmic membrane and cell-lytic pyroptosis (indicated by characteristic cell membrane ballooning). Breakthroughs in KRAS G12C allele-specific inhibitors and potential mechanisms of resistance are also discussed herein.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Cystine; Cysteine; Reactive Oxygen Species; Kelch-Like ECH-Associated Protein 1; Cystathionine; NF-E2-Related Factor 2; Proto-Oncogene Proteins p21(ras); Lung Neoplasms
PubMed: 37381723
DOI: 10.20892/j.issn.2095-3941.2023.0108 -
International Immunopharmacology Jul 2023The chronic articular disease osteoarthritis (OA) is characterized by osteophyte generation, subchondral bone remodeling, and cartilage deterioration. Low levels of H2S...
The chronic articular disease osteoarthritis (OA) is characterized by osteophyte generation, subchondral bone remodeling, and cartilage deterioration. Low levels of H2S catalyzed by cystathionine-γ-lyase (CSE) encoded by Cthhas neuroprotective, cardioprotective, anti-apoptotic, and anti-inflammatory effects thus, Cth is being developed as a potential therapy for the management of the pathogenesis and symptoms of osteoarthritis. Single-cell RNA sequencing (scRNA-seq) and immunohistochemistry of human cartilage revealed that the expression of CTH was decreased in OA patients. We found that Cthoverexpression decrease IL-1β-induced overactivation of the NF-κB signaling pathway. In vivo, Cthoverexpression relieved pain response and cartilage damage in the anterior cruciate ligament transection (ACLT) rat model. In vitro, CSE alleviated chondrocytes catabolism, inflammation, apoptosis, and senescence, and suppressed the NF-κB pathway. We postulate that CSE has therapeutic effects in suppressing inflammation and degeneration in OA and should be further investigated clinically.
Topics: Humans; Rats; Animals; NF-kappa B; Cystathionine; Cystathionine gamma-Lyase; Osteoarthritis; Inflammation; Pain; Chondrocytes; Cartilage, Articular; Disease Models, Animal
PubMed: 37182456
DOI: 10.1016/j.intimp.2023.110289 -
Postepy Higieny I Medycyny... Jan 2014γ-Cystathionase (CTH, EC: 4.4.1.1), an enzyme widely distributed in the world of prokaryotic and eukaryotic organisms, catalyzes the formation and transformations of... (Review)
Review
γ-Cystathionase (CTH, EC: 4.4.1.1), an enzyme widely distributed in the world of prokaryotic and eukaryotic organisms, catalyzes the formation and transformations of sulfane sulfur-containing compounds and plays a pivotal role in the L-cysteine desulfuration pathway. Human, tetrameric CTH is composed of two dimers and each monomer binds pyridoxal phosphate (PLP). The gene, located on the short arm of chromosome 1, consists of 13 exons and 12 introns. As a result of alternative splicing, three isoforms of human CTH arise. Analysis of genetic variations of the CTH encoding gene showed a large number of polymorphisms. A decrease of the expression of CTH entails a drop in the level of cysteine , glutathione (GSH), taurine and hydrogen sulfide (H2S) in the cells and, more importantly, leads to cystathioninuria. H2S, endogenously formed by CTH, affects the vasodilation and regulation of blood pressure. CTH knockout mice have decreased levels of H2S, hypertension, and reduced capacity for vascular endothelium relaxation. Overexpression of the gene encoding CTH in the cells leads to increased production of H2S. H2S plays a role in protection of neurons against oxidative stress, and stimulates an increase in γ-glutamylcysteine synthetase and thereby an increase in the level of GSH. Sulfurtransferases, including CTH, can locally prevent oxidative stress due to reversible oxidation of - SH groups in the presence of increased levels of reactive oxygen species, and reduction in the presence of GSH and/or reduced thioredoxin.
Topics: Animals; Cystathionine gamma-Lyase; Cysteine; Gene Expression; Glutathione; Humans; Hydrogen Sulfide; Hyperhomocysteinemia; Hypertension; Mice; Mice, Knockout; Oxidation-Reduction; Oxidative Stress; Polymorphism, Genetic; Reactive Oxygen Species
PubMed: 24491890
DOI: 10.5604/17322693.1085372 -
Indian Journal of Ophthalmology Jul 2022Homocystinuria is a rare metabolic inborn disorder caused due to dysfunctional cystathionine β-synthase (CBS) enzyme activity, thus resulting in elevated levels of... (Review)
Review
Homocystinuria is a rare metabolic inborn disorder caused due to dysfunctional cystathionine β-synthase (CBS) enzyme activity, thus resulting in elevated levels of methionine and homocysteine in the blood and urine. The timely recognition of this rare metabolic disorder and prompt methionine-restricted diet are crucial in lessening the systemic consequences. The recalcitrant cases have a higher risk for cardiovascular diseases, neurodegenerative diseases, neural tube defects, and other severe clinical complications. This review aims to present the ophthalmic spectrum of homocystinuria and its molecular basis, the disease management, as well as the current and potential treatment approaches with a greater emphasis on preventive strategies.
Topics: Cystathionine beta-Synthase; Homocystinuria; Humans; Methionine
PubMed: 35791106
DOI: 10.4103/ijo.IJO_309_22 -
Redox Biology Jul 2022The expression of the reverse transsulfuration enzyme cystathionine-β-synthase (CBS) is markedly increased in many forms of cancer, including colorectal, ovarian, lung,... (Review)
Review
The expression of the reverse transsulfuration enzyme cystathionine-β-synthase (CBS) is markedly increased in many forms of cancer, including colorectal, ovarian, lung, breast and kidney, while in other cancers (liver cancer and glioma) it becomes downregulated. According to the clinical database data in high-CBS-expressor cancers (e.g. colon or ovarian cancer), high CBS expression typically predicts lower survival, while in the low-CBS-expressor cancers (e.g. liver cancer), low CBS expression is associated with lower survival. In the high-CBS expressing tumor cells, CBS, and its product hydrogen sulfide (HS) serves as a bioenergetic, proliferative, cytoprotective and stemness factor; it also supports angiogenesis and epithelial-to-mesenchymal transition in the cancer microenvironment. The current article reviews the various tumor-cell-supporting roles of the CBS/HS axis in high-CBS expressor cancers and overviews the anticancer effects of CBS silencing and pharmacological CBS inhibition in various cancer models in vitro and in vivo; it also outlines potential approaches for biomarker identification, to support future targeted cancer therapies based on pharmacological CBS inhibition.
Topics: Cell Proliferation; Cystathionine beta-Synthase; Energy Metabolism; Humans; Hydrogen Sulfide; Liver Neoplasms; Tumor Microenvironment
PubMed: 35618601
DOI: 10.1016/j.redox.2022.102331 -
Journal of Neurochemistry Apr 2010Nitric oxide (NO) and carbon monoxide (CO) are well established as messenger molecules throughout the body, gasotransmitters, based on striking alterations in mice... (Review)
Review
Nitric oxide (NO) and carbon monoxide (CO) are well established as messenger molecules throughout the body, gasotransmitters, based on striking alterations in mice lacking the appropriate biosynthetic enzymes. Hydrogen sulfide (H(2)S) is even more chemically reactive, but until recently there was little definitive evidence for its physiologic formation. Cystathionine beta-synthase (EC 4.2.1.22), and cystathionine gamma-lyase (CSE; EC 4.4.1.1), also known as cystathionine, can generate H(2)S from cyst(e)ine. Very recent studies with mice lacking these enzymes have established that CSE is responsible for H(2)S formation in the periphery, while in the brain cystathionine beta-synthase is the biosynthetic enzyme. Endothelial-derived relaxing factor activity is reduced 80% in the mesenteric artery of mice with deletion of CSE, establishing H(2)S as a major physiologic endothelial-derived relaxing factor. H(2)S appears to signal predominantly by S-sulfhydrating cysteines in its target proteins, analogous to S-nitrosylation by NO. Whereas S-nitrosylation typically inhibits enzymes, S-sulfhydration activates them. S-nitrosylation basally affects 1-2% of its target proteins, while 10-25% of H(2)S target proteins are S-sulfhydrated. In summary, H(2)S appears to be a physiologic gasotransmitter of comparable importance to NO and carbon monoxide.
Topics: Animals; Blood Pressure; Carbon Monoxide; Cystathionine beta-Synthase; Cystathionine gamma-Lyase; Endothelium, Vascular; Endothelium-Dependent Relaxing Factors; Humans; Hydrogen Sulfide; Hypertension; Mice; Mice, Knockout; Models, Molecular; Nitric Oxide; Signal Transduction
PubMed: 20067586
DOI: 10.1111/j.1471-4159.2010.06580.x -
Antioxidants & Redox Signaling Feb 2022Hydrogen sulfide (HS) plays critical roles in redox biology, and its regulatory effects are tightly controlled by its cellular location and concentration. The imbalance... (Review)
Review
Hydrogen sulfide (HS) plays critical roles in redox biology, and its regulatory effects are tightly controlled by its cellular location and concentration. The imbalance of HS is believed to contribute to some pathological processes. Downregulation of HS requires chemical tools such as inhibitors of HS-producing enzymes and HS scavengers. Recent efforts have discovered some promising inhibitors and scavengers. These advances pave the road toward better understanding of the functions of HS. Precise HS downregulation is challenging. The potency and specificity of current inhibitors are still far from ideal. HS-producing enzymes are involved in complex sulfur metabolic pathways and ubiquitously present in biological matrices. The inhibition of these enzymes can cause unwanted side effects. HS scavengers allow targeted HS clearance, but their options are still limited. In addition, the scavenging process often results in biologically active by-products. Further development of potent and specific inhibitors for HS-producing enzymes is needed. Scavengers that can rapidly and selectively remove HS while generating biocompatible by-products are needed. Potential therapeutic applications of scavengers and inhibitors are worth exploring. . 36, 294-308.
Topics: Cystathionine beta-Synthase; Cystathionine gamma-Lyase; Hydrogen Sulfide; Oxidation-Reduction
PubMed: 34162216
DOI: 10.1089/ars.2021.0088