GO:0070813 hydrogen sulfide metabolic process: Signaling Pathway, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0070813 hydrogen sulfide metabolic process describes the chemical reactions and pathways involving hydrogen sulfide (H2S), a gasotransmitter with roles in redox metabolism and signaling [1,2].
• H2S is produced mainly by CBS, CSE, and 3-MST, and its levels are controlled by oxidation via SQR and other enzymes [4,7].
• H2S signals through persulfidation of cysteine residues and interacts with polysulfide signaling.
• Dysregulated H2S metabolism contributes to diabetic cardiomyopathy, colon cancer metabolic reprogramming, and oxidative stress-related aging [3,6,8].
• H2S can perturb mitochondrial bioenergetics and trigger metabolic reprogramming in colon cells.
• CRISPR-based models (KO, point mutation, knock-in, overexpression) enable causal dissection of H2S metabolic genes in disease contexts.
Description
Hydrogen sulfide (H2S) is a gaseous signaling molecule that participates in diverse physiological and pathological processes. The Gene Ontology term GO:0070813, hydrogen sulfide metabolic process, is defined as the chemical reactions and pathways involving hydrogen sulfide, H2S. This term encompasses both the biosynthesis and the catabolism of H2S, as well as its downstream signaling effects [1,2]. Research over the past two decades has established H2S as a key regulator of redox metabolism, vascular tone, neurotransmission, and cellular bioenergetics [4,5]. The importance of H2S metabolism is underscored by its involvement in human diseases ranging from diabetic cardiomyopathy to cancer [3,6]. Understanding the enzymes, regulatory mechanisms, and signaling pathways that constitute GO:0070813 is therefore critical for both basic biology and therapeutic development.
hydrogen sulfide metabolic process At A Glance
| GO ID | GO:0070813 |
|---|---|
| GO term | hydrogen sulfide metabolic process |
| Ontology | biological_process |
| Synonym | hydrogen sulfide metabolism; hydrogen sulphide metabolic process; hydrogen sulphide metabolism |
| Major function | Production, transformation, and degradation of hydrogen sulfide (H2S), including its role in redox metabolism and signaling |
| Key enzymes | CBS, CSE, 3-MST, SQR, TST, ETHE1 |
| Signaling mechanism | Persulfidation of cysteine residues; interaction with polysulfide signaling |
| Associated diseases | Diabetic cardiomyopathy, colon cancer, oxidative stress-related aging |
What Is GO:0070813?
GO:0070813 hydrogen sulfide metabolic process refers to the set of biochemical reactions and pathways that produce, transform, and degrade hydrogen sulfide (H2S). This includes enzymatic synthesis from cysteine and other sulfur-containing substrates, oxidation to sulfate or thiosulfate, and the modification of protein cysteine residues (persulfidation) that mediates H2S signaling [1,2,4].
Why Is hydrogen sulfide metabolic process Important in Cell Biology?
GO:0070813 is important because H2S is a pleiotropic gasotransmitter that regulates fundamental cellular processes such as mitochondrial bioenergetics, glucose metabolism, and oxidative stress responses [1,2,5]. Dysregulation of H2S metabolism is linked to metabolic disorders, cancer, and aging, making it a target for therapeutic intervention [3,6,8].
• H2S is a signaling molecule that modulates redox balance and cellular stress responses [1,2].
• H2S metabolism influences glucose metabolism and mitochondrial function [6,8].
• Altered H2S levels are observed in diabetic cardiomyopathy and metabolic disorders.
• H2S perturbs mitochondrial bioenergetics and triggers metabolic reprogramming in colon cancer cells.
• H2S signaling declines with age and contributes to age-related pathologies.
• Enzymes of H2S metabolism are potential drug targets for cancer and cardiovascular diseases [4,7].
• H2S interacts with polysulfide signaling, expanding its regulatory scope.
• Genetic models (KO, knock-in) are essential to establish causal roles of H2S enzymes in disease.
What Happens During hydrogen sulfide metabolic process?
Biosynthesis of H2S
In simple terms: Cells make H2S from amino acids like cysteine using specific enzymes.
H2S is primarily synthesized by three enzymes: cystathionine beta-synthase (CBS), cystathionine gamma-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3-MST) in conjunction with cysteine aminotransferase (CAT). CBS and CSE are pyridoxal 5'-phosphate-dependent enzymes that convert cysteine and homocysteine to H2S. 3-MST produces H2S from 3-mercaptopyruvate, often in mitochondria. The relative contribution of each enzyme varies by tissue and physiological context.
Oxidation and clearance of H2S
In simple terms: H2S is broken down in mitochondria to prevent toxic accumulation.
The primary route of H2S catabolism is mitochondrial oxidation. Sulfide quinone oxidoreductase (SQR) catalyzes the oxidation of H2S to thiosulfate, which is further converted to sulfite by thiosulfate sulfurtransferase (TST) and then to sulfate by sulfite oxidase (SUOX). This pathway is critical for maintaining low intracellular H2S concentrations and for energy production. Dysregulation of SQR leads to H2S accumulation and mitochondrial dysfunction.
Persulfidation and signaling
In simple terms: H2S modifies proteins by adding sulfur to cysteine residues, changing their activity.
H2S exerts many of its biological effects through persulfidation, a post-translational modification that converts cysteine -SH groups to -SSH. This modification can alter protein function, localization, and activity. H2S also interacts with polysulfide signaling, where polysulfides serve as more potent persulfidating agents. Key targets of persulfidation include kinases, ion channels, and metabolic enzymes [1,6].
Regulation of glucose metabolism by H2S
In simple terms: H2S can change how cells use sugar, affecting energy production.
H2S coordinates a glucose metabolism switch by destabilizing tetrameric pyruvate kinase M2 (PKM2), shifting metabolism toward oxidative phosphorylation. This regulation links H2S to the Warburg effect and cancer cell metabolism. In colon cells, H2S perturbs mitochondrial bioenergetics and triggers metabolic reprogramming, including changes in glycolysis and glutaminolysis.
H2S in oxidative stress and aging
In simple terms: H2S helps cells cope with oxidative stress, but its levels decline with age.
H2S signaling is intertwined with oxidative stress responses. H2S can scavenge reactive oxygen species and upregulate antioxidant defenses, but excessive H2S can also inhibit cytochrome c oxidase and impair mitochondrial function. Aging is associated with reduced H2S production and increased oxidative damage, suggesting a role for H2S in longevity.
Key Genes Involved in GO:0070813 hydrogen sulfide metabolic process
The following genes encode enzymes and regulators directly involved in hydrogen sulfide metabolic process (GO:0070813).
| Gene | Major Role | Research Relevance |
|---|---|---|
| CBS | Primary H2S-producing enzyme; condenses homocysteine and cysteine | Mutations cause homocystinuria; target in cancer and cardiovascular disease |
| CSE | Produces H2S from cysteine; major in vascular and hepatic tissues | Knockout models show hypertension and metabolic defects |
| 3-MST | Mitochondrial H2S production from 3-mercaptopyruvate | Linked to neuroprotection and energy metabolism |
| CAT | Provides 3-mercaptopyruvate for 3-MST | Regulates mitochondrial H2S synthesis |
| SQR | Oxidizes H2S to thiosulfate; key for clearance | Deficiency causes H2S accumulation and mitochondrial toxicity |
| TST | Converts thiosulfate to sulfite | Deficiency leads to ethylmalonic encephalopathy |
| ETHE1 | Sulfur dioxygenase in H2S oxidation pathway | Mutations cause ethylmalonic encephalopathy |
| SUOX | Oxidizes sulfite to sulfate | Deficiency causes sulfite oxidase deficiency |
| PKM2 | Target of H2S-mediated destabilization; regulates glucose metabolism | H2S-PKM2 axis in cancer metabolism |
| MPST | Another name for 3-MST | Redundant with 3-MST |
| GOT1 | Aspartate aminotransferase; contributes to cysteine metabolism | Indirect role in H2S production |
| GOT2 | Mitochondrial aspartate aminotransferase | Supports 3-MST pathway |
| NFS1 | Cysteine desulfurase; provides sulfur for H2S synthesis | Essential for iron-sulfur cluster and H2S metabolism |
| SLC7A11 | Cystine/glutamate antiporter; affects cysteine availability | Modulates H2S production in cancer |
| GCLM | Glutamate-cysteine ligase modifier subunit; glutathione synthesis | Cross-talk with H2S in redox regulation |
| GCLC | Glutamate-cysteine ligase catalytic subunit | Glutathione and H2S interplay |
| TRX | Thioredoxin; reduces oxidized proteins | Interacts with H2S signaling |
| NFE2L2 | Nrf2; transcription factor regulating antioxidant genes | H2S induces Nrf2 and vice versa |
How Is hydrogen sulfide metabolic process Regulated?
H2S metabolism is regulated at multiple levels. Enzyme expression of CBS, CSE, and 3-MST is controlled by transcription factors such as Nrf2 and HIF-1α [4,5]. Post-translational modifications, including phosphorylation and persulfidation, modulate enzyme activity. Substrate availability (cysteine, homocysteine) and cofactors (PLP, iron-sulfur clusters) also influence H2S production. Mitochondrial oxidation capacity, particularly SQR levels, determines H2S clearance rates. Additionally, H2S can feedback-regulate its own synthesis by modifying enzyme cysteine residues.
hydrogen sulfide metabolic process and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| CBS | Homocystinuria, cardiovascular disease | CBS knockout mice; point mutation knock-in |
| CSE | Hypertension, diabetic cardiomyopathy | CSE knockout rats; overexpression in cardiomyocytes |
| SQR | H2S accumulation, mitochondrial toxicity | SQR knockout cell lines; rescue with SQR overexpression |
| PKM2 | Cancer metabolism (Warburg effect) | PKM2 point mutants (tetramerization-deficient) knock-in |
| ETHE1 | Ethylmalonic encephalopathy | ETHE1 knockout zebrafish; patient-derived iPSCs |
Diabetic cardiomyopathy
H2S plays a protective role in diabetic cardiomyopathy by reducing oxidative stress and improving mitochondrial function. Reduced H2S levels are observed in diabetic hearts, and H2S donors improve cardiac function in animal models. Targeting H2S metabolism may offer a therapeutic strategy for diabetic cardiomyopathy.
Colon cancer
H2S perturbs mitochondrial bioenergetics and triggers metabolic reprogramming in colon cancer cells, supporting their proliferation and survival. Colon cancer cells often upregulate H2S-producing enzymes, and inhibition of H2S synthesis reduces tumor growth. The H2S-PKM2 axis links H2S to the Warburg effect.
Oxidative stress and aging
Aging is associated with decreased H2S production and increased oxidative damage. H2S supplementation extends lifespan in animal models, partly through activation of antioxidant defenses and inhibition of mitochondrial reactive oxygen species. H2S also regulates senescence and inflammation.
From hydrogen sulfide metabolic process-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of CSE affect H2S levels and blood pressure? | CSE knockout mouse |
| Does a specific point mutation in CBS alter H2S production? | CBS point-mutation knock-in cell line |
| Can overexpression of SQR rescue H2S-induced mitochondrial dysfunction? | SQR overexpression in colon cancer cells |
| Does persulfidation of PKM2 regulate its tetramerization? | PKM2 cysteine-to-serine knock-in |
| What is the role of 3-MST in neuroprotection? | 3-MST knockout neurons |
| Can CRISPR activation of CBS increase H2S and protect against ischemia? | CRISPRa overexpression model |
How to Study the hydrogen sulfide metabolic process Process
| Method | What It Measures | Typical Application |
|---|---|---|
| Methylene blue assay | Free H2S and acid-labile sulfide | Tissue homogenates, cell lysates |
| Fluorescent probes (WSP-1, SF7) | Intracellular H2S levels | Live-cell imaging |
| Biotin switch assay | Protein persulfidation | Identification of H2S targets |
| Seahorse XF | Mitochondrial respiration and glycolysis | Metabolic reprogramming studies |
| LC-MS metabolomics | Sulfur and glucose metabolites | Pathway flux analysis |
| Western blot | Enzyme expression (CBS, CSE, 3-MST) | Knockout validation |
| CRISPR screening | Genes affecting H2S sensitivity | Functional genomics |
Measuring H2S levels
H2S can be quantified using colorimetric assays (methylene blue method), fluorescent probes (e.g., WSP-1, SF7), or electrochemical sensors. These methods measure free H2S or acid-labile sulfide in biological samples [1,4].
Persulfidation detection
Persulfidation is detected by the modified biotin switch assay, maleimide-based fluorescent labeling, or mass spectrometry. These techniques identify specific cysteine residues modified by H2S.
Enzyme activity assays
CBS, CSE, and 3-MST activities are measured using substrate-specific assays that detect H2S production via lead acetate or fluorescent probes. SQR activity is measured by monitoring quinone reduction.
Metabolic profiling
Seahorse extracellular flux analysis measures mitochondrial respiration and glycolysis in response to H2S donors or enzyme knockout. Metabolomics (LC-MS) quantifies intermediates of sulfur and glucose metabolism [6,8].
How CRISPR Can Be Used to Study GO:0070813 hydrogen sulfide metabolic process
Knockout
CRISPR knockout of CBS, CSE, or 3-MST eliminates H2S production, enabling studies of its physiological roles. Knockout cell lines and mice are used to assess effects on metabolism, oxidative stress, and disease progression [4,6].
Point Mutation
Point mutations in H2S enzymes (e.g., CBS catalytic residues, PKM2 cysteine residues) can be introduced to dissect specific functions such as persulfidation or substrate binding. These models help distinguish enzymatic activity from non-enzymatic roles [1,6].
Knock-in
Knock-in of tagged versions (e.g., HA-tagged CBS) allows tracking of enzyme localization and interactions. Knock-in of disease-associated mutations (e.g., CBS mutations in homocystinuria) models human pathology.
Overexpression
Overexpression of H2S-producing enzymes or SQR can elevate or reduce H2S levels, respectively. This approach is used to test therapeutic potential of modulating H2S metabolism in cancer and cardiovascular disease [3,7].
How EDITGENE Supports hydrogen sulfide metabolic process Research
Researchers studying hydrogen sulfide metabolic process-related genes often need to determine whether a candidate gene is causally involved in H2S production, signaling, or disease. EDITGENE provides CRISPR-based services to generate precisely engineered cell models for such investigations.
Contact EDITGENE today to design your custom CRISPR model for hydrogen sulfide metabolic process research.
Frequently Asked Questions About hydrogen sulfide metabolic process
What is hydrogen sulfide metabolic process?
It is the set of biochemical reactions involving hydrogen sulfide (H2S), including its synthesis, oxidation, and signaling functions, as defined by GO:0070813 [1,2].
What genes are involved in hydrogen sulfide metabolic process?
Key genes include CBS, CSE, 3-MST, SQR, TST, ETHE1, and SUOX, which produce or degrade H2S [4,7].
How is H2S produced in cells?
H2S is mainly produced by CBS, CSE, and 3-MST from cysteine or homocysteine.
What is the role of H2S in disease?
H2S is implicated in diabetic cardiomyopathy, colon cancer, and aging-related oxidative stress [3,5,8].
How does H2S signal?
H2S signals primarily through persulfidation of cysteine residues on target proteins.
What is the function of SQR in H2S metabolism?
SQR oxidizes H2S to thiosulfate, initiating its clearance and contributing to mitochondrial energy production.
Can CRISPR be used to study H2S metabolism?
Yes, CRISPR knockout, point mutation, knock-in, and overexpression models are widely used to dissect H2S gene functions [4,6].
What diseases are linked to H2S metabolic genes?
Mutations in CBS cause homocystinuria, ETHE1 mutations cause ethylmalonic encephalopathy, and dysregulated H2S is linked to cancer and diabetes [3,4,8].
How is H2S measured in the lab?
Common methods include the methylene blue assay, fluorescent probes, and electrochemical sensors [1,4].
What is persulfidation?
Persulfidation is a post-translational modification where H2S adds a sulfur atom to cysteine residues, altering protein function.
Conclusion
GO:0070813 hydrogen sulfide metabolic process encompasses a complex network of enzymes and signaling pathways that regulate redox balance, metabolism, and disease. Understanding this process is essential for developing therapies targeting H2S-related pathologies. CRISPR-based models provide powerful tools to dissect the causal roles of H2S metabolic genes.
References
- 1. Kimura H. 2017. Hydrogen Sulfide and Polysulfide Signaling.. Antioxid Redox Signal 27(10):619-621 PMID: 28558483
- 2. Banerjee R. 2011. Hydrogen sulfide: redox metabolism and signaling.. Antioxid Redox Signal 15(2):339-41 PMID: 21275829
- 3. Deng NH et al.. 2022. Hydrogen sulfide plays a potential alternative for the treatment of metabolic disorders of diabetic cardiomyopathy.. Mol Cell Biochem 477(1):255-265 PMID: 34687394
- 4. Bian JS et al.. 2016. Hydrogen Sulfide: Biogenesis, Physiology, and Pathology.. Oxid Med Cell Longev 2016:6549625 PMID: 27148431
- 5. Yang G et al.. 2015. Hydrogen Sulfide Signaling in Oxidative Stress and Aging Development.. Oxid Med Cell Longev 2015:357824 PMID: 26075033
- 6. Wang RH et al.. 2024. Hydrogen sulfide coordinates glucose metabolism switch through destabilizing tetrameric pyruvate kinase M2.. Nat Commun 15(1):7463 PMID: 39198443
- 7. Roman JV et al.. 2025. Hydrogen sulfide-dependent activation of human sulfide quinone oxidoreductase.. J Biol Chem 301(10):110681 PMID: 40912653
- 8. Libiad M et al.. 2019. Hydrogen sulfide perturbs mitochondrial bioenergetics and triggers metabolic reprogramming in colon cells.. J Biol Chem 294(32):12077-12090 PMID: 31213529
