Cystathionine gamma-lyase (CTH; also CSE/CGL; EC 4.4.1.1) is a cytosolic, pyridoxal-5'-phosphate (PLP)-dependent enzyme that catalyses the second and final step of the transsulfuration pathway, converting the homocysteine-derived intermediate L,L-cystathionine into L-cysteine, 2-oxobutanoate and ammonia. It thereby channels methionine/homocysteine-derived sulfur into de novo L-cysteine biosynthesis, supplying cysteine for downstream metabolism including glutathione synthesis. The enzyme is a homotetramer with PLP bound covalently to Lys212 and is most highly expressed in liver. Beyond its canonical transsulfuration role, CTH is a major enzymatic source of the gaseous signaling molecule hydrogen sulfide (H2S): using L-cysteine and, at lower rates, L-homocysteine as substrates it produces H2S (together with pyruvate/2-oxobutanoate and ammonia), and in vitro also generates lanthionine and homolanthionine. Through H2S generation and by acting as a cysteine-protein sulfhydrase (persulfidating target cysteines on proteins such as GAPDH, PTP1B/PTPN1 and NF-kB RELA), CTH participates in vascular tone, smooth-muscle biology, inflammation and the ER stress response. Loss-of-function variants cause cystathioninuria, an autosomal recessive condition marked by elevated plasma/urinary cystathionine that is largely clinically benign.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation placing CTH activity in the cytoplasm. CTH is a soluble cytosolic enzyme, consistent with UniProt's subcellular location and the Reactome cytosol annotations. Reason: CTH is a well-characterized cytosolic transsulfuration enzyme; the cytoplasmic localization is correct and consistent across sources. Supporting Evidence: file:human/CTH/CTH-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0019344 L-cysteine biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic annotation for L-cysteine biosynthesis. CTH catalyses the final step of the transsulfuration route that produces L-cysteine, so this is a core process. Reason: CTH generates L-cysteine from L,L-cystathionine; this is one of its two canonical catalytic outputs and a core biological role. Supporting Evidence: PMID:19428278 the enzyme that catalyzes the conversion of cystathionine to cysteine, ammonia, and 2-oxobutyrate |
| GO:0019346 transsulfuration | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic annotation to transsulfuration, the pathway by which methionine/ homocysteine sulfur is transferred to cysteine. CTH catalyses the second step. Reason: CTH is a defining enzyme of the transsulfuration pathway; the term is correct and core. Supporting Evidence: file:human/CTH/CTH-uniprot.txt Catalyzes the last step in the trans-sulfuration pathway from |
| GO:0030170 pyridoxal phosphate binding | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic annotation for PLP binding. CTH is a PLP-dependent lyase, with PLP bound covalently at Lys212; this cofactor binding is essential for catalysis. Reason: PLP binding is directly demonstrated for human CTH and is required for its activity. Supporting Evidence: PMID:19428278 Pyridoxal 5β²-phosphate (PLP) is a cofactor for CTH |
| GO:0004123 cystathionine gamma-lyase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic annotation for the defining molecular function. Directly supported by biochemical characterization of recombinant human CTH. Reason: This is the core molecular function of CTH, corroborated by IDA annotations (PMID:10212249, PMID:19019829, PMID:19428278). Supporting Evidence: PMID:10212249 While the enzyme showed high gamma-lyase activity toward |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic annotation of cytoplasmic localization from UniProt subcellular-location mapping. Consistent with the IBA cytoplasm and Reactome cytosol annotations. Reason: Correct localization; a duplicate of the IBA cytoplasm annotation but from an independent (SubCell) source. Supporting Evidence: file:human/CTH/CTH-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0019346 transsulfuration | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO electronic annotation to transsulfuration based on the Cys/Met metabolism PLP-dependent enzyme domain (IPR000277). Consistent with the core role. Reason: Correct process; duplicate of the IBA/IDA transsulfuration annotations via a domain-based electronic method. Supporting Evidence: file:human/CTH/CTH-uniprot.txt Belongs to the trans-sulfuration enzymes family |
| GO:0030170 pyridoxal phosphate binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO electronic annotation for PLP binding from the PLP-dependent enzyme domain. Consistent with experimentally demonstrated PLP dependence. Reason: Correct cofactor binding; duplicate of the IDA/IBA PLP-binding annotations. Supporting Evidence: PMID:19428278 Pyridoxal 5β²-phosphate (PLP) is a cofactor for CTH |
| GO:0047982 homocysteine desulfhydrase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic (Rhea/EC) annotation for homocysteine desulfhydrase activity (EC 4.4.1.2), reflecting CTH's ability to convert L-homocysteine to 2-oxobutanoate, H2S and ammonia. This is a genuine, experimentally documented alternative activity. Reason: UniProt records EC 4.4.1.2 and the L-homocysteine to H2S reaction (RHEA:14501) with experimental evidence (PubMed:18476726, 19261609). This is a real but secondary (H2S-generating) activity, not the primary transsulfuration function. Supporting Evidence: file:human/CTH/CTH-uniprot.txt Reaction=L-homocysteine + H2O = 2-oxobutanoate + hydrogen sulfide + |
| GO:0080146 L-cysteine desulfhydrase activity | IEA GO_REF:0000116 | KEEP AS NON CORE | Summary: Electronic (Rhea) annotation for L-cysteine desulfhydrase activity (RHEA:24931), i.e. L-cysteine to H2S + pyruvate + ammonia. This underlies CTH-mediated H2S production from cysteine and is experimentally documented. Reason: A real alternative activity of CTH (the cysteine to H2S/pyruvate reaction is in UniProt with experimental evidence), central to its gasotransmitter role but secondary to the canonical cystathionine gamma-lyase function. Supporting Evidence: file:human/CTH/CTH-uniprot.txt Reaction=L-cysteine + H2O = hydrogen sulfide + pyruvate + NH4(+) + |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Bare protein-binding IPI from a proteome-scale binary interactome (Y2H) screen, with IntAct-listed partners (e.g. RECK/Q6P9E2, NTAQ1/Q96HA8, GUCD1/Q96NT3). The term is uninformative about molecular function. Reason: High-throughput 'protein binding' conveys no specific function and per curation guidelines is not a useful functional annotation. Not removed (experimental IPI), but flagged as over-annotated. UniProt does list these as corroborated interactions in its INTERACTION block. Supporting Evidence: file:human/CTH/CTH-uniprot.txt P32929; Q6P9E2: RECK; NbExp=6; IntAct=EBI-749763, EBI-10253121; |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Bare protein-binding IPI from the HuRI reference binary interactome (Y2H). Partners listed by IntAct include RECK and a GUCD1 isoform. Uninformative molecular-function term. Reason: Same rationale as the other HT 'protein binding' IPI: not informative about function; retained (experimental) but marked over-annotated. Supporting Evidence: file:human/CTH/CTH-uniprot.txt P32929; Q96NT3-2: GUCD1; NbExp=3; IntAct=EBI-749763, EBI-11978177; |
| GO:0042802 identical protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | KEEP AS NON CORE | Summary: Self-interaction (CTH:CTH) detected by binary interactome mapping. This is consistent with the biologically documented homotetrameric quaternary structure of the enzyme. Reason: Identical-protein binding reflects CTH self-association into its functional homotetramer; a real structural property but not the enzyme's core catalytic function. Corroborated by the crystallographic homotetramer (PMID:19019829). Supporting Evidence: file:human/CTH/CTH-uniprot.txt Homotetramer (PubMed:19019829) |
| GO:0042802 identical protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | KEEP AS NON CORE | Summary: Self-interaction (CTH:CTH) from a proteome-scale interactome study, consistent with homotetramer formation. Reason: Duplicate evidence for CTH self-association (homotetramer). Structural property, non-core. Supporting Evidence: file:human/CTH/CTH-uniprot.txt Homotetramer (PubMed:19019829) |
| GO:0042802 identical protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: Self-interaction (CTH:CTH) from the HuRI binary interactome, again consistent with the homotetramer. Reason: Duplicate evidence for CTH homo-oligomerization; structural, non-core. Supporting Evidence: file:human/CTH/CTH-uniprot.txt Homotetramer (PubMed:19019829) |
| GO:0001887 selenium compound metabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic annotation transferred from the mouse ortholog for selenium-compound metabolism, reflecting CTH's ability to cleave selenocystathionine (a dietary selenium compound) to selenocysteine, and participation in selenoamino-acid metabolism (Reactome R-HSA-2408508). Reason: A plausible, by-similarity secondary activity on selenium analogs of the normal substrate; not a core physiological function in humans. Supporting Evidence: file:human/CTH/CTH-uniprot.txt Catalyzes the elimination of selenocystathionine (which can be derived |
| GO:0004123 cystathionine gamma-lyase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (Rhea/ortholog) annotation for the defining cystathionine gamma-lyase activity, duplicating the IDA/IBA annotations. Reason: Correct core molecular function; electronic corroboration of the experimentally established activity. Supporting Evidence: file:human/CTH/CTH-uniprot.txt Reaction=L,L-cystathionine + H2O = 2-oxobutanoate + L-cysteine + |
| GO:0005829 cytosol | IEA GO_REF:0000107 | ACCEPT | Summary: Electronic annotation (from mouse ortholog) placing CTH activity in the cytosol. Consistent with the enzyme's soluble cytosolic nature. Reason: Correct subcellular location; consistent with UniProt Cytoplasm and Reactome cytosol. Supporting Evidence: file:human/CTH/CTH-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0043066 negative regulation of apoptotic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic annotation transferred from the mouse ortholog. Reflects reported cytoprotective/anti-apoptotic effects of CTH-derived H2S signaling in various tissues. Reason: A downstream physiological consequence of CTH-mediated H2S production rather than a direct molecular activity; keep as non-core pending human experimental support. Supporting Evidence: PMID:22169477 H2S has been implicated in the control of cell proliferation and survival in cardiomyocytes |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic annotation transferred from the mouse ortholog. CTH-derived H2S sulfhydrates the NF-kB subunit RELA (p65), modulating NF-kB signaling. Reason: A downstream H2S/sulfhydration-mediated signaling effect (UniProt notes RELA among sulfhydration targets), not a core catalytic function; keep as non-core. Supporting Evidence: file:human/CTH/CTH-uniprot.txt specific cysteine residues of target proteins such as GAPDH, PTPN1 and |
| GO:0044540 L-cystine L-cysteine-lyase (deaminating) activity | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic annotation (from mouse ortholog) for a cystine/cysteine-lyase activity. Related to CTH's promiscuous H2S-generating reactions on cysteine substrates. Reason: Reflects a real but secondary/promiscuous H2S-generating lyase activity on cysteine substrates; not the core transsulfuration function. Also supported experimentally (IMP, PMID:22169477). Supporting Evidence: file:human/CTH/CTH-uniprot.txt In vitro, it converts two L-cysteine molecules into |
| GO:0098606 selenocystathionine gamma-lyase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic (Rhea/ortholog) annotation for selenocystathionine gamma-lyase activity (RHEA:31151), the selenium analog of the canonical reaction. Reason: By-similarity activity on the selenium analog of cystathionine; a plausible promiscuous activity, not a core human function. Supporting Evidence: file:human/CTH/CTH-uniprot.txt Reaction=L-selenocystathionine + H2O = L-selenocysteine + 2- |
| GO:0019344 L-cysteine biosynthetic process | IEA GO_REF:0000041 | ACCEPT | Summary: UniPathway-based electronic annotation for L-cysteine biosynthesis (UPA00136), duplicating the IDA/IBA L-cysteine biosynthesis annotations. Reason: Correct core process; CTH performs step 2/2 of L-cysteine biosynthesis from L-homocysteine and L-serine (UniProt PATHWAY). Supporting Evidence: file:human/CTH/CTH-uniprot.txt L-cysteine from L-homocysteine and L-serine: step 2/2 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1614567 | ACCEPT | Summary: Reactome traceable-author-statement localizing CTH to the cytosol in the reaction 'Excess homocysteine yields homolanthionine and H2S'. Reason: Correct cytosolic localization from a curated pathway source; consistent with all other localization evidence. Supporting Evidence: file:human/CTH/CTH-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1614583 | ACCEPT | Summary: Reactome TAS localizing CTH to the cytosol for the reaction 'PXLP-K212-CTH cleaves L-Cystathionine' (the canonical cystathionine gamma-lyase step, showing PLP at Lys212). Reason: Correct cytosolic localization from Reactome; duplicate of other cytosol annotations. Supporting Evidence: file:human/CTH/CTH-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1614591 | ACCEPT | Summary: Reactome TAS localizing CTH to the cytosol for the reaction 'Excess cysteine yields lanthionine and H2S'. Reason: Correct cytosolic localization from Reactome; duplicate of other cytosol annotations. Supporting Evidence: file:human/CTH/CTH-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1614614 | ACCEPT | Summary: Reactome TAS localizing CTH to the cytosol for the reaction 'Cysteine is degraded to pyruvate and H2S'. Reason: Correct cytosolic localization from Reactome; duplicate of other cytosol annotations. Supporting Evidence: file:human/CTH/CTH-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005829 cytosol | TAS Reactome:R-HSA-1614631 | ACCEPT | Summary: Reactome TAS localizing CTH to the cytosol for the reaction 'Homocysteine is degraded to oxobutanoate and H2S'. Reason: Correct cytosolic localization from Reactome; duplicate of other cytosol annotations. Supporting Evidence: file:human/CTH/CTH-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:1904831 positive regulation of aortic smooth muscle cell differentiation | IMP PMID:21659522 Specificity protein-1 as a critical regulator of human cysta... | KEEP AS NON CORE | Summary: Experimental (IMP) annotation: in human aortic smooth muscle cells, CSE/CTH expression and CSE-derived H2S promote SMC differentiation; carotid ligation reduced CSE and increased neointima, and exogenous H2S stimulated differentiation. Reason: A genuine, experimentally supported physiological role of CTH-derived H2S in the vasculature, but a downstream/tissue-specific effect rather than the enzyme's core molecular/metabolic function. Supporting Evidence: PMID:21659522 suggesting an important role of CSE in SMC PMID:21659522 Exogenously applied H(2)S at 100 ΞΌM stimulated SMC differentiation, |
| GO:0004123 cystathionine gamma-lyase activity | IDA PMID:19428278 Cystathionine gamma-lyase: Clinical, metabolic, genetic, and... | ACCEPT | Summary: Direct experimental annotation of cystathionine gamma-lyase activity; the paper expressed CTH and mutant proteins and assayed CTH (cysteine-forming) activity. Reason: Core molecular function, directly demonstrated on the human enzyme. Supporting Evidence: PMID:19428278 the enzyme that catalyzes the conversion of cystathionine to cysteine, ammonia, and 2-oxobutyrate |
| GO:0019344 L-cysteine biosynthetic process | IDA PMID:19428278 Cystathionine gamma-lyase: Clinical, metabolic, genetic, and... | ACCEPT | Summary: Direct experimental annotation for L-cysteine biosynthesis, based on assay of the cysteine-forming CTH reaction. Reason: Core process; the assay directly measures cysteine formation by CTH. Supporting Evidence: PMID:19428278 an acid ninhydrin reagent reacts specifically with cysteine, which is a product of the CTH reaction |
| GO:0019346 transsulfuration | IDA PMID:19428278 Cystathionine gamma-lyase: Clinical, metabolic, genetic, and... | ACCEPT | Summary: Direct experimental annotation to transsulfuration; the study characterizes CTH, the enzyme catalysing the transsulfuration step converting cystathionine to cysteine. Reason: Core process, directly supported. Supporting Evidence: PMID:19428278 is caused by mutations that decrease the activity of cystathionine Ξ³-lyase |
| GO:0070814 hydrogen sulfide biosynthetic process | TAS PMID:19428278 Cystathionine gamma-lyase: Clinical, metabolic, genetic, and... | ACCEPT | Summary: Traceable-author-statement that CTH participates in H2S biosynthesis, the second major physiological function of the enzyme. Reason: H2S generation from cysteine/homocysteine is a genuine, well-established core function of CTH (a major mammalian H2S source); supported here and by IDA (PMID:19019829). Supporting Evidence: PMID:22169477 constitute a transulfuration pathway that provides a route for converting dietary methionine to cysteine |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | MARK AS OVER ANNOTATED | Summary: High-throughput mass-spectrometry detection of CTH among ~1132 proteins profiled in human urinary exosomes. This is a proteomic co-detection, not evidence of a functional extracellular/exosomal role. Reason: CTH is a cytosolic enzyme; detection in urinary-exosome proteomics likely reflects general cytosolic protein packaging into exosomes rather than a bona fide functional localization. Flagged as over-annotated rather than removed (experimental HDA). Supporting Evidence: PMID:19056867 the analysis identified 1132 proteins unambiguously |
| GO:0044524 protein sulfhydration | IMP PMID:22169477 H2S-Induced sulfhydration of the phosphatase PTP1B and its r... | ACCEPT | Summary: Experimental (IMP) annotation: CTH-derived H2S is required for sulfhydration (persulfidation) of target-protein cysteines; suppression of CSE/CTH abolished PTP1B sulfhydration in cells. Reason: CTH functions as a cysteine-protein sulfhydrase (via H2S), a genuine second/ moonlighting function directly demonstrated by CSE knockdown. Core to CTH's signaling role. Supporting Evidence: PMID:22169477 The effects of H2S are mediated through its sulfhydration of specific Cys residues in target proteins |
| GO:0044540 L-cystine L-cysteine-lyase (deaminating) activity | IMP PMID:22169477 H2S-Induced sulfhydration of the phosphatase PTP1B and its r... | KEEP AS NON CORE | Summary: Experimental (IMP) annotation of a cysteine-directed lyase (H2S-generating) activity of CTH, underlying its H2S production required for protein sulfhydration in cells. Reason: Reflects CTH's H2S-generating lyase activity on cysteine substrates (secondary to the canonical cystathionine gamma-lyase reaction); experimentally supported, kept as non-core. Supporting Evidence: PMID:22169477 cystathionine-Ξ³-lyase (CSE), which together constitute a transulfuration pathway |
| GO:0005515 protein binding | IPI PMID:22169477 H2S-Induced sulfhydration of the phosphatase PTP1B and its r... | MARK AS OVER ANNOTATED | Summary: Protein-binding IPI recording the CTHβPTP1B(PTPN1)/interactor relationship (WITH/FROM UniProtKB:P18031) in the context of H2S-mediated PTP1B regulation. Reason: The bare 'protein binding' term is uninformative. The functionally meaningful relationship (CTH-derived H2S sulfhydrating/regulating PTP1B) is better captured by the protein-sulfhydration annotation; retained (experimental) but marked over-annotated as a molecular-function term. Supporting Evidence: PMID:22169477 Sulfhydration of PTP1B in cells required the |
| GO:0030968 endoplasmic reticulum unfolded protein response | TAS PMID:22169477 H2S-Induced sulfhydration of the phosphatase PTP1B and its r... | KEEP AS NON CORE | Summary: Traceable-author-statement linking CTH/CSE-derived H2S to the ER stress-induced unfolded protein response: CSE-dependent H2S sulfhydrates PTP1B, modulating PERK activation during ER stress. Reason: A genuine downstream signaling role of CTH-derived H2S, but a physiological consequence rather than the enzyme's core metabolic function; keep as non-core. Supporting Evidence: PMID:22169477 H2S production, mediated by cystathionine-Ξ³-lyase (CSE), has been linked to the ER stress-induced Unfolded Protein Response (UPR) |
| GO:0004123 cystathionine gamma-lyase activity | IDA PMID:10212249 Kinetics and inhibition of recombinant human cystathionine g... | ACCEPT | Summary: Direct biochemical demonstration of cystathionine gamma-lyase activity on recombinant human CTH (Km = 0.5 mM, Vmax = 2.5 units/mg for L,L-cystathionine, optimum pH 8.2), with only marginal activity toward L-cystine/L-cysteine. Reason: Definitive experimental evidence for the core molecular function. Supporting Evidence: PMID:10212249 While the enzyme showed high gamma-lyase activity toward PMID:10212249 only marginal reactivity toward |
| GO:0004123 cystathionine gamma-lyase activity | IDA PMID:19019829 Structural basis for the inhibition mechanism of human cysta... | ACCEPT | Summary: Direct experimental/structural characterization of human CSE/CTH cystathionine gamma-lyase activity, with crystal structures in apo, PLP, and PLP-PAG (inhibitor) forms. Reason: Core molecular function, directly demonstrated and structurally characterized. Supporting Evidence: PMID:19019829 an enzyme responsible for the production of H(2)S |
| GO:0018272 protein-pyridoxal-5-phosphate linkage via peptidyl-N6-pyridoxal phosphate-L-lysine | IDA PMID:19019829 Structural basis for the inhibition mechanism of human cysta... | ACCEPT | Summary: Direct (structural) evidence for covalent PLP attachment via a Schiff base to an active-site lysine (Lys212), as seen in the PLP-bound crystal structures. Reason: The covalent PLP-Lys212 linkage is directly observed and annotated by UniProt (MOD_RES 212, N6-(pyridoxal phosphate)lysine, ECO:0000269|PubMed:19019829). Supporting Evidence: file:human/CTH/CTH-uniprot.txt N6-(pyridoxal phosphate)lysine |
| GO:0019344 L-cysteine biosynthetic process | IDA PMID:10212249 Kinetics and inhibition of recombinant human cystathionine g... | ACCEPT | Summary: Direct experimental annotation for L-cysteine biosynthesis, based on the characterized cysteine-forming gamma-lyase reaction of recombinant human CTH. Reason: Core process; the enzyme's high gamma-lyase activity on L-cystathionine yields L-cysteine. Supporting Evidence: PMID:10212249 While the enzyme showed high gamma-lyase activity toward |
| GO:0030170 pyridoxal phosphate binding | IDA PMID:10212249 Kinetics and inhibition of recombinant human cystathionine g... | ACCEPT | Summary: Direct experimental annotation for PLP binding; the enzyme is characterized as PLP-dependent, and inhibition by mechanism-based PLP-directed inactivators (propargylglycine etc.) confirms cofactor engagement. Reason: PLP is the essential cofactor of CTH, directly supported. Supporting Evidence: PMID:10212249 the mechanism-based inactivators propargylglycine, trifluoroalanine, and |
| GO:0030170 pyridoxal phosphate binding | IDA PMID:19019829 Structural basis for the inhibition mechanism of human cysta... | ACCEPT | Summary: Direct structural evidence for PLP binding, from crystal structures of hCSE in complex with PLP. Reason: PLP binding directly observed in the structures; core cofactor function. Supporting Evidence: PMID:19019829 in complex with PLP and PLP.PAG |
| GO:0051289 protein homotetramerization | IPI PMID:19019829 Structural basis for the inhibition mechanism of human cysta... | ACCEPT | Summary: Evidence that CTH assembles into a homotetramer, based on the crystal structure and biophysical characterization of the human enzyme (self-interaction, WITH/FROM UniProtKB:P32929). Reason: The homotetramer is the functional quaternary structure of CTH, directly supported by structural work and recorded in UniProt SUBUNIT. Supporting Evidence: file:human/CTH/CTH-uniprot.txt Homotetramer (PubMed:19019829) |
| GO:0070814 hydrogen sulfide biosynthetic process | IDA PMID:19019829 Structural basis for the inhibition mechanism of human cysta... | ACCEPT | Summary: Direct experimental annotation for H2S biosynthesis; the paper explicitly characterizes hCSE/CTH as the enzyme responsible for H2S production and studies its inhibition. Reason: H2S production is a genuine core function of CTH; directly supported and structurally contextualized (PAG inhibition of H2S production). Supporting Evidence: PMID:19019829 an enzyme responsible for the production of H(2)S |
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Download this section (compressed HTML)Q: To what extent does CTH-derived H2S versus its canonical cysteine-biosynthetic output account for its physiological roles in different human tissues (e.g. liver vs vasculature)?
Q: Is the reported anti-apoptotic / NF-kB-activating role (currently IEA from the mouse ortholog) directly demonstrable for human CTH, and via which sulfhydration targets?
Experiment: Tissue-specific conditional Cth knockout combined with H2S measurement and persulfidation (sulfhydration) proteomics to dissect the metabolic (cysteine biosynthesis) versus gasotransmitter (H2S/protein-sulfhydration) contributions.
Experiment: Quantitative substrate-preference and kinetic comparison of human CTH on L,L-cystathionine, L-cysteine and L-homocysteine at physiological substrate concentrations to establish in vivo flux toward cysteine versus H2S.
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