id: P32929
gene_symbol: CTH
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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.
alternative_products:
- name: '1'
  id: P32929-1
- name: '2'
  id: P32929-2
  sequence_note: VSP_006306
- name: '3'
  id: P32929-3
  sequence_note: VSP_047274
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    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.
    action: ACCEPT
    reason: >-
      CTH is a well-characterized cytosolic transsulfuration enzyme; the cytoplasmic
      localization is correct and consistent across sources.
    supported_by:
    - reference_id: file:human/CTH/CTH-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Cytoplasm"
- term:
    id: GO:0019344
    label: L-cysteine biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: >-
      CTH generates L-cysteine from L,L-cystathionine; this is one of its two canonical
      catalytic outputs and a core biological role.
    supported_by:
    - reference_id: PMID:19428278
      supporting_text: "the enzyme that catalyzes the conversion of cystathionine to cysteine, ammonia, and 2-oxobutyrate"
- term:
    id: GO:0019346
    label: transsulfuration
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Phylogenetic annotation to transsulfuration, the pathway by which methionine/
      homocysteine sulfur is transferred to cysteine. CTH catalyses the second step.
    action: ACCEPT
    reason: >-
      CTH is a defining enzyme of the transsulfuration pathway; the term is correct and core.
    supported_by:
    - reference_id: file:human/CTH/CTH-uniprot.txt
      supporting_text: "Catalyzes the last step in the trans-sulfuration pathway from"
- term:
    id: GO:0030170
    label: pyridoxal phosphate binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      PLP binding is directly demonstrated for human CTH and is required for its activity.
    supported_by:
    - reference_id: PMID:19428278
      supporting_text: "Pyridoxal 5′-phosphate (PLP) is a cofactor for CTH"
- term:
    id: GO:0004123
    label: cystathionine gamma-lyase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Phylogenetic annotation for the defining molecular function. Directly supported by
      biochemical characterization of recombinant human CTH.
    action: ACCEPT
    reason: >-
      This is the core molecular function of CTH, corroborated by IDA annotations
      (PMID:10212249, PMID:19019829, PMID:19428278).
    supported_by:
    - reference_id: PMID:10212249
      supporting_text: "While the enzyme showed high gamma-lyase activity toward"
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation of cytoplasmic localization from UniProt subcellular-location
      mapping. Consistent with the IBA cytoplasm and Reactome cytosol annotations.
    action: ACCEPT
    reason: >-
      Correct localization; a duplicate of the IBA cytoplasm annotation but from an
      independent (SubCell) source.
    supported_by:
    - reference_id: file:human/CTH/CTH-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Cytoplasm"
- term:
    id: GO:0019346
    label: transsulfuration
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO electronic annotation to transsulfuration based on the Cys/Met
      metabolism PLP-dependent enzyme domain (IPR000277). Consistent with the core role.
    action: ACCEPT
    reason: >-
      Correct process; duplicate of the IBA/IDA transsulfuration annotations via a
      domain-based electronic method.
    supported_by:
    - reference_id: file:human/CTH/CTH-uniprot.txt
      supporting_text: "Belongs to the trans-sulfuration enzymes family"
- term:
    id: GO:0030170
    label: pyridoxal phosphate binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      InterPro2GO electronic annotation for PLP binding from the PLP-dependent enzyme
      domain. Consistent with experimentally demonstrated PLP dependence.
    action: ACCEPT
    reason: >-
      Correct cofactor binding; duplicate of the IDA/IBA PLP-binding annotations.
    supported_by:
    - reference_id: PMID:19428278
      supporting_text: "Pyridoxal 5′-phosphate (PLP) is a cofactor for CTH"
- term:
    id: GO:0047982
    label: homocysteine desulfhydrase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/CTH/CTH-uniprot.txt
      supporting_text: "Reaction=L-homocysteine + H2O = 2-oxobutanoate + hydrogen sulfide +"
- term:
    id: GO:0080146
    label: L-cysteine desulfhydrase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/CTH/CTH-uniprot.txt
      supporting_text: "Reaction=L-cysteine + H2O = hydrogen sulfide + pyruvate + NH4(+) +"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: file:human/CTH/CTH-uniprot.txt
      supporting_text: "P32929; Q6P9E2: RECK; NbExp=6; IntAct=EBI-749763, EBI-10253121;"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Same rationale as the other HT 'protein binding' IPI: not informative about
      function; retained (experimental) but marked over-annotated.
    supported_by:
    - reference_id: file:human/CTH/CTH-uniprot.txt
      supporting_text: "P32929; Q96NT3-2: GUCD1; NbExp=3; IntAct=EBI-749763, EBI-11978177;"
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: >-
      Self-interaction (CTH:CTH) detected by binary interactome mapping. This is
      consistent with the biologically documented homotetrameric quaternary structure
      of the enzyme.
    action: KEEP_AS_NON_CORE
    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).
    supported_by:
    - reference_id: file:human/CTH/CTH-uniprot.txt
      supporting_text: "Homotetramer (PubMed:19019829)"
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    summary: >-
      Self-interaction (CTH:CTH) from a proteome-scale interactome study, consistent with
      homotetramer formation.
    action: KEEP_AS_NON_CORE
    reason: >-
      Duplicate evidence for CTH self-association (homotetramer). Structural property,
      non-core.
    supported_by:
    - reference_id: file:human/CTH/CTH-uniprot.txt
      supporting_text: "Homotetramer (PubMed:19019829)"
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Self-interaction (CTH:CTH) from the HuRI binary interactome, again consistent with
      the homotetramer.
    action: KEEP_AS_NON_CORE
    reason: >-
      Duplicate evidence for CTH homo-oligomerization; structural, non-core.
    supported_by:
    - reference_id: file:human/CTH/CTH-uniprot.txt
      supporting_text: "Homotetramer (PubMed:19019829)"
- term:
    id: GO:0001887
    label: selenium compound metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    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).
    action: KEEP_AS_NON_CORE
    reason: >-
      A plausible, by-similarity secondary activity on selenium analogs of the normal
      substrate; not a core physiological function in humans.
    supported_by:
    - reference_id: file:human/CTH/CTH-uniprot.txt
      supporting_text: "Catalyzes the elimination of selenocystathionine (which can be derived"
- term:
    id: GO:0004123
    label: cystathionine gamma-lyase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic (Rhea/ortholog) annotation for the defining cystathionine gamma-lyase
      activity, duplicating the IDA/IBA annotations.
    action: ACCEPT
    reason: >-
      Correct core molecular function; electronic corroboration of the experimentally
      established activity.
    supported_by:
    - reference_id: file:human/CTH/CTH-uniprot.txt
      supporting_text: "Reaction=L,L-cystathionine + H2O = 2-oxobutanoate + L-cysteine +"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: is_active_in
  review:
    summary: >-
      Electronic annotation (from mouse ortholog) placing CTH activity in the cytosol.
      Consistent with the enzyme's soluble cytosolic nature.
    action: ACCEPT
    reason: >-
      Correct subcellular location; consistent with UniProt Cytoplasm and Reactome cytosol.
    supported_by:
    - reference_id: file:human/CTH/CTH-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Cytoplasm"
- term:
    id: GO:0043066
    label: negative regulation of apoptotic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation transferred from the mouse ortholog. Reflects reported
      cytoprotective/anti-apoptotic effects of CTH-derived H2S signaling in various tissues.
    action: KEEP_AS_NON_CORE
    reason: >-
      A downstream physiological consequence of CTH-mediated H2S production rather than a
      direct molecular activity; keep as non-core pending human experimental support.
    supported_by:
    - reference_id: PMID:22169477
      supporting_text: "H2S has been implicated in the control of cell proliferation and survival in cardiomyocytes"
- term:
    id: GO:0043123
    label: positive regulation of canonical NF-kappaB signal transduction
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Electronic annotation transferred from the mouse ortholog. CTH-derived H2S
      sulfhydrates the NF-kB subunit RELA (p65), modulating NF-kB signaling.
    action: KEEP_AS_NON_CORE
    reason: >-
      A downstream H2S/sulfhydration-mediated signaling effect (UniProt notes RELA among
      sulfhydration targets), not a core catalytic function; keep as non-core.
    supported_by:
    - reference_id: file:human/CTH/CTH-uniprot.txt
      supporting_text: "specific cysteine residues of target proteins such as GAPDH, PTPN1 and"
- term:
    id: GO:0044540
    label: L-cystine L-cysteine-lyase (deaminating) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: >-
      Electronic annotation (from mouse ortholog) for a cystine/cysteine-lyase activity.
      Related to CTH's promiscuous H2S-generating reactions on cysteine substrates.
    action: KEEP_AS_NON_CORE
    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).
    supported_by:
    - reference_id: file:human/CTH/CTH-uniprot.txt
      supporting_text: "In vitro, it converts two L-cysteine molecules into"
- term:
    id: GO:0098606
    label: selenocystathionine gamma-lyase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic (Rhea/ortholog) annotation for selenocystathionine gamma-lyase activity
      (RHEA:31151), the selenium analog of the canonical reaction.
    action: KEEP_AS_NON_CORE
    reason: >-
      By-similarity activity on the selenium analog of cystathionine; a plausible
      promiscuous activity, not a core human function.
    supported_by:
    - reference_id: file:human/CTH/CTH-uniprot.txt
      supporting_text: "Reaction=L-selenocystathionine + H2O = L-selenocysteine + 2-"
- term:
    id: GO:0019344
    label: L-cysteine biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: >-
      UniPathway-based electronic annotation for L-cysteine biosynthesis (UPA00136),
      duplicating the IDA/IBA L-cysteine biosynthesis annotations.
    action: ACCEPT
    reason: >-
      Correct core process; CTH performs step 2/2 of L-cysteine biosynthesis from
      L-homocysteine and L-serine (UniProt PATHWAY).
    supported_by:
    - reference_id: file:human/CTH/CTH-uniprot.txt
      supporting_text: "L-cysteine from L-homocysteine and L-serine: step 2/2"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1614567
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author-statement localizing CTH to the cytosol in the reaction
      'Excess homocysteine yields homolanthionine and H2S'.
    action: ACCEPT
    reason: >-
      Correct cytosolic localization from a curated pathway source; consistent with all
      other localization evidence.
    supported_by:
    - reference_id: file:human/CTH/CTH-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Cytoplasm"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1614583
  qualifier: located_in
  review:
    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).
    action: ACCEPT
    reason: >-
      Correct cytosolic localization from Reactome; duplicate of other cytosol annotations.
    supported_by:
    - reference_id: file:human/CTH/CTH-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Cytoplasm"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1614591
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localizing CTH to the cytosol for the reaction 'Excess cysteine yields
      lanthionine and H2S'.
    action: ACCEPT
    reason: >-
      Correct cytosolic localization from Reactome; duplicate of other cytosol annotations.
    supported_by:
    - reference_id: file:human/CTH/CTH-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Cytoplasm"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1614614
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localizing CTH to the cytosol for the reaction 'Cysteine is degraded to
      pyruvate and H2S'.
    action: ACCEPT
    reason: >-
      Correct cytosolic localization from Reactome; duplicate of other cytosol annotations.
    supported_by:
    - reference_id: file:human/CTH/CTH-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Cytoplasm"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1614631
  qualifier: located_in
  review:
    summary: >-
      Reactome TAS localizing CTH to the cytosol for the reaction 'Homocysteine is
      degraded to oxobutanoate and H2S'.
    action: ACCEPT
    reason: >-
      Correct cytosolic localization from Reactome; duplicate of other cytosol annotations.
    supported_by:
    - reference_id: file:human/CTH/CTH-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Cytoplasm"
- term:
    id: GO:1904831
    label: positive regulation of aortic smooth muscle cell differentiation
  evidence_type: IMP
  original_reference_id: PMID:21659522
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:21659522
      supporting_text: "suggesting an important role of CSE in SMC"
    - reference_id: PMID:21659522
      supporting_text: "Exogenously applied H(2)S at 100 μM stimulated SMC differentiation,"
- term:
    id: GO:0004123
    label: cystathionine gamma-lyase activity
  evidence_type: IDA
  original_reference_id: PMID:19428278
  qualifier: enables
  review:
    summary: >-
      Direct experimental annotation of cystathionine gamma-lyase activity; the paper
      expressed CTH and mutant proteins and assayed CTH (cysteine-forming) activity.
    action: ACCEPT
    reason: >-
      Core molecular function, directly demonstrated on the human enzyme.
    supported_by:
    - reference_id: PMID:19428278
      supporting_text: "the enzyme that catalyzes the conversion of cystathionine to cysteine, ammonia, and 2-oxobutyrate"
- term:
    id: GO:0019344
    label: L-cysteine biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:19428278
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental annotation for L-cysteine biosynthesis, based on assay of the
      cysteine-forming CTH reaction.
    action: ACCEPT
    reason: >-
      Core process; the assay directly measures cysteine formation by CTH.
    supported_by:
    - reference_id: PMID:19428278
      supporting_text: "an acid ninhydrin reagent reacts specifically with cysteine, which is a product of the CTH reaction"
- term:
    id: GO:0019346
    label: transsulfuration
  evidence_type: IDA
  original_reference_id: PMID:19428278
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental annotation to transsulfuration; the study characterizes CTH,
      the enzyme catalysing the transsulfuration step converting cystathionine to cysteine.
    action: ACCEPT
    reason: >-
      Core process, directly supported.
    supported_by:
    - reference_id: PMID:19428278
      supporting_text: "is caused by mutations that decrease the activity of cystathionine γ-lyase"
- term:
    id: GO:0070814
    label: hydrogen sulfide biosynthetic process
  evidence_type: TAS
  original_reference_id: PMID:19428278
  qualifier: involved_in
  review:
    summary: >-
      Traceable-author-statement that CTH participates in H2S biosynthesis, the second
      major physiological function of the enzyme.
    action: ACCEPT
    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).
    supported_by:
    - reference_id: PMID:22169477
      supporting_text: "constitute a transulfuration pathway that provides a route for converting dietary methionine to cysteine"
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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).
    supported_by:
    - reference_id: PMID:19056867
      supporting_text: "the analysis identified 1132 proteins unambiguously"
- term:
    id: GO:0044524
    label: protein sulfhydration
  evidence_type: IMP
  original_reference_id: PMID:22169477
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:22169477
      supporting_text: "The effects of H2S are mediated through its sulfhydration of specific Cys residues in target proteins"
- term:
    id: GO:0044540
    label: L-cystine L-cysteine-lyase (deaminating) activity
  evidence_type: IMP
  original_reference_id: PMID:22169477
  qualifier: enables
  review:
    summary: >-
      Experimental (IMP) annotation of a cysteine-directed lyase (H2S-generating) activity
      of CTH, underlying its H2S production required for protein sulfhydration in cells.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:22169477
      supporting_text: "cystathionine-γ-lyase (CSE), which together constitute a transulfuration pathway"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22169477
  qualifier: enables
  review:
    summary: >-
      Protein-binding IPI recording the CTH–PTP1B(PTPN1)/interactor relationship
      (WITH/FROM UniProtKB:P18031) in the context of H2S-mediated PTP1B regulation.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:22169477
      supporting_text: "Sulfhydration of PTP1B in cells required the"
- term:
    id: GO:0030968
    label: endoplasmic reticulum unfolded protein response
  evidence_type: TAS
  original_reference_id: PMID:22169477
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:22169477
      supporting_text: "H2S production, mediated by cystathionine-γ-lyase (CSE), has been linked to the ER stress-induced Unfolded Protein Response (UPR)"
- term:
    id: GO:0004123
    label: cystathionine gamma-lyase activity
  evidence_type: IDA
  original_reference_id: PMID:10212249
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      Definitive experimental evidence for the core molecular function.
    supported_by:
    - reference_id: PMID:10212249
      supporting_text: "While the enzyme showed high gamma-lyase activity toward"
    - reference_id: PMID:10212249
      supporting_text: "only marginal reactivity toward"
- term:
    id: GO:0004123
    label: cystathionine gamma-lyase activity
  evidence_type: IDA
  original_reference_id: PMID:19019829
  qualifier: enables
  review:
    summary: >-
      Direct experimental/structural characterization of human CSE/CTH cystathionine
      gamma-lyase activity, with crystal structures in apo, PLP, and PLP-PAG (inhibitor)
      forms.
    action: ACCEPT
    reason: >-
      Core molecular function, directly demonstrated and structurally characterized.
    supported_by:
    - reference_id: PMID:19019829
      supporting_text: "an enzyme responsible for the production of H(2)S"
- term:
    id: GO:0018272
    label: protein-pyridoxal-5-phosphate linkage via peptidyl-N6-pyridoxal phosphate-L-lysine
  evidence_type: IDA
  original_reference_id: PMID:19019829
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: >-
      The covalent PLP-Lys212 linkage is directly observed and annotated by UniProt
      (MOD_RES 212, N6-(pyridoxal phosphate)lysine, ECO:0000269|PubMed:19019829).
    supported_by:
    - reference_id: file:human/CTH/CTH-uniprot.txt
      supporting_text: "N6-(pyridoxal phosphate)lysine"
- term:
    id: GO:0019344
    label: L-cysteine biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:10212249
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental annotation for L-cysteine biosynthesis, based on the
      characterized cysteine-forming gamma-lyase reaction of recombinant human CTH.
    action: ACCEPT
    reason: >-
      Core process; the enzyme's high gamma-lyase activity on L-cystathionine yields
      L-cysteine.
    supported_by:
    - reference_id: PMID:10212249
      supporting_text: "While the enzyme showed high gamma-lyase activity toward"
- term:
    id: GO:0030170
    label: pyridoxal phosphate binding
  evidence_type: IDA
  original_reference_id: PMID:10212249
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      PLP is the essential cofactor of CTH, directly supported.
    supported_by:
    - reference_id: PMID:10212249
      supporting_text: "the mechanism-based inactivators propargylglycine, trifluoroalanine, and"
- term:
    id: GO:0030170
    label: pyridoxal phosphate binding
  evidence_type: IDA
  original_reference_id: PMID:19019829
  qualifier: enables
  review:
    summary: >-
      Direct structural evidence for PLP binding, from crystal structures of hCSE in
      complex with PLP.
    action: ACCEPT
    reason: >-
      PLP binding directly observed in the structures; core cofactor function.
    supported_by:
    - reference_id: PMID:19019829
      supporting_text: "in complex with PLP and PLP.PAG"
- term:
    id: GO:0051289
    label: protein homotetramerization
  evidence_type: IPI
  original_reference_id: PMID:19019829
  qualifier: involved_in
  review:
    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).
    action: ACCEPT
    reason: >-
      The homotetramer is the functional quaternary structure of CTH, directly supported
      by structural work and recorded in UniProt SUBUNIT.
    supported_by:
    - reference_id: file:human/CTH/CTH-uniprot.txt
      supporting_text: "Homotetramer (PubMed:19019829)"
- term:
    id: GO:0070814
    label: hydrogen sulfide biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:19019829
  qualifier: involved_in
  review:
    summary: >-
      Direct experimental annotation for H2S biosynthesis; the paper explicitly
      characterizes hCSE/CTH as the enzyme responsible for H2S production and studies its
      inhibition.
    action: ACCEPT
    reason: >-
      H2S production is a genuine core function of CTH; directly supported and structurally
      contextualized (PAG inhibition of H2S production).
    supported_by:
    - reference_id: PMID:19019829
      supporting_text: "an enzyme responsible for the production of H(2)S"
core_functions:
- description: >-
    Cystathionine gamma-lyase catalysing the final step of the transsulfuration pathway:
    PLP-dependent cleavage of L,L-cystathionine to L-cysteine, 2-oxobutanoate and ammonia,
    supplying de novo L-cysteine (cysteine biosynthesis from homocysteine/methionine sulfur).
  molecular_function:
    id: GO:0004123
    label: cystathionine gamma-lyase activity
  directly_involved_in:
  - id: GO:0019344
    label: L-cysteine biosynthetic process
  - id: GO:0019346
    label: transsulfuration
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:10212249
    supporting_text: "While the enzyme showed high gamma-lyase activity toward"
  - reference_id: PMID:19428278
    supporting_text: "the enzyme that catalyzes the conversion of cystathionine to cysteine, ammonia, and 2-oxobutyrate"
  - reference_id: file:human/CTH/CTH-uniprot.txt
    supporting_text: "Catalyzes the last step in the trans-sulfuration pathway from"
- description: >-
    Hydrogen sulfide (H2S) biosynthesis: using L-cysteine and (at lower rates)
    L-homocysteine as substrates, CTH is a major enzymatic source of the gasotransmitter
    H2S, generating H2S together with pyruvate/2-oxobutanoate and ammonia. This is a
    genuine second physiological function.
  molecular_function:
    id: GO:0080146
    label: L-cysteine desulfhydrase activity
  directly_involved_in:
  - id: GO:0070814
    label: hydrogen sulfide biosynthetic process
  supported_by:
  - reference_id: PMID:19019829
    supporting_text: "an enzyme responsible for the production of H(2)S"
  - reference_id: file:human/CTH/CTH-uniprot.txt
    supporting_text: "Reaction=L-cysteine + H2O = hydrogen sulfide + pyruvate + NH4(+) +"
- description: >-
    Cysteine-protein sulfhydrase / persulfidation activity: via generated H2S, CTH
    persulfidates target-protein cysteine residues (converting -SH to -SSH) on proteins
    such as GAPDH, PTP1B/PTPN1 and NF-kB RELA, contributing to redox signaling.
  molecular_function:
    id: GO:0004123
    label: cystathionine gamma-lyase activity
  directly_involved_in:
  - id: GO:0044524
    label: protein sulfhydration
  supported_by:
  - reference_id: PMID:22169477
    supporting_text: "The effects of H2S are mediated through its sulfhydration of specific Cys residues in target proteins"
  - reference_id: file:human/CTH/CTH-uniprot.txt
    supporting_text: "cysteine-protein sulfhydrase by mediating sulfhydration of target"
- description: >-
    PLP cofactor binding: CTH is a pyridoxal-5'-phosphate-dependent enzyme, binding PLP
    covalently via a Schiff base to Lys212, which is essential for all of its catalytic
    activities.
  molecular_function:
    id: GO:0030170
    label: pyridoxal phosphate binding
  supported_by:
  - reference_id: PMID:19428278
    supporting_text: "Pyridoxal 5′-phosphate (PLP) is a cofactor for CTH"
  - reference_id: file:human/CTH/CTH-uniprot.txt
    supporting_text: "N6-(pyridoxal phosphate)lysine"
proposed_new_terms: []
suggested_questions:
- question: >-
    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)?
- question: >-
    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?
suggested_experiments:
- description: >-
    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.
- description: >-
    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.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000116
  title: Automatic Gene Ontology annotation based on Rhea mapping
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10212249
  title: Kinetics and inhibition of recombinant human cystathionine gamma-lyase. Toward
    the rational control of transsulfuration.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Abstract-only in cache but directly establishes the core cystathionine gamma-lyase
      activity of recombinant human CTH (Km/Vmax, pH optimum) and its PLP-directed
      inhibition; supports the core catalytic function and PLP-binding annotations.
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      High-throughput Y2H interactome map (CCSB-HI1); source of an identical-protein
      binding (CTH self) IPI consistent with the homotetramer, but conveys no specific
      function for CTH.
- id: PMID:19019829
  title: Structural basis for the inhibition mechanism of human cystathionine gamma-lyase,
    an enzyme responsible for the production of H(2)S.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Crystal structures (apo/PLP/PLP-PAG) of human CSE/CTH; supports the core catalytic
      function, PLP binding (covalent, Lys212), homotetramer, and the H2S-production role.
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Large-scale MS profiling of urinary exosomes; CTH is one of ~1132 co-detected
      proteins. Supports the HDA extracellular-exosome localization only as a proteomic
      co-detection, not a functional site.
- id: PMID:19428278
  title: 'Cystathionine gamma-lyase: Clinical, metabolic, genetic, and structural
    studies.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full-text; clinical/metabolic/genetic/structural review of human CTH. Establishes
      the cystathionine-to-cysteine reaction, PLP cofactor, disease (cystathioninuria)
      variants, and the largely benign nature of CTH deficiency.
- id: PMID:21659522
  title: Specificity protein-1 as a critical regulator of human cystathionine gamma-lyase
    in smooth muscle cells.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Shows CSE/CTH and its H2S product promote smooth-muscle-cell differentiation and
      that Sp1 regulates the hCSE promoter; supports the (non-core) positive-regulation-of-
      aortic-SMC-differentiation IMP.
- id: PMID:22169477
  title: H2S-Induced sulfhydration of the phosphatase PTP1B and its role in the endoplasmic
    reticulum stress response.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full-text; demonstrates that CSE/CTH-derived H2S is required for sulfhydration of
      PTP1B and modulates the ER-stress (PERK) response. Supports the protein-sulfhydration
      and (non-core) ER-UPR annotations.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Proteome-scale binary interactome; source of bare protein-binding and identical-
      protein-binding IPIs for CTH (partners RECK, NTAQ1, GUCD1, CTH self). Uninformative
      for CTH molecular function.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      HuRI reference binary interactome; source of bare protein-binding and identical-
      protein-binding IPIs for CTH. Uninformative for molecular function.
- id: Reactome:R-HSA-1614567
  title: Excess homocysteine yields homolanthionine and H2S
  findings: []
- id: Reactome:R-HSA-1614583
  title: PXLP-K212-CTH cleaves L-Cystathionine
  findings: []
- id: Reactome:R-HSA-1614591
  title: Excess cysteine yields lanthionine and H2S
  findings: []
- id: Reactome:R-HSA-1614614
  title: Cysteine is degraded to pyruvate and H2S
  findings: []
- id: Reactome:R-HSA-1614631
  title: Homocysteine is degraded to oxobutanoate and H2S
  findings: []