id: P23434
gene_symbol: GCSH
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  GCSH is the H-protein of the mitochondrial glycine cleavage system (GCS). It is a small,
  non-catalytic lipoyl-carrier protein: a lipoyl group is covalently attached to a specific
  lysine (N6-lipoyllysine, Lys107) and acts as a swinging arm that shuttles the reaction
  intermediate between the other GCS components. During glycine cleavage the H-protein accepts
  the aminomethyl moiety produced by the P-protein (glycine dehydrogenase/decarboxylating, GLDC),
  presents the aminomethyl-dihydrolipoyl intermediate to the T-protein (aminomethyltransferase,
  AMT) which releases ammonia and transfers the methylene group to tetrahydrofolate, and its
  resulting dihydrolipoyl form is reoxidised by the L-protein (dihydrolipoyl dehydrogenase, DLD).
  Because it is a substrate-carrier rather than an enzyme, its most informative functional
  attributes are its covalently bound lipoyl cofactor, its participation in glycine
  catabolism/decarboxylation, and its membership in the glycine cleavage complex. GCSH is
  localised to the mitochondrion/mitochondrial matrix and its lipoyl cofactor is generated in
  place by octanoyl transfer (LIPT2) and sulfur insertion (LIAS); it additionally serves as a
  lipoyl donor for other mitochondrial 2-oxo-acid dehydrogenase E2 subunits (DLAT, DLST) via
  LIPT1, a moonlighting role in cellular bioenergetics. Biallelic loss-of-function variants in
  GCSH are a rare cause of nonketotic hyperglycinemia (glycine encephalopathy), presenting as a
  combined disorder of glycine metabolism and protein lipoylation (multiple mitochondrial
  dysfunctions syndrome 7).
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      InterPro2GO pipeline mapping the GCV_H family (IPR002930/IPR017453) to the glycine
      cleavage complex and glycine decarboxylation. Consistent with the well-established
      identity of GCSH; broad but appropriate.
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PAN-GO/GO_Central phylogenetic (IBA) annotations for the GcvH family. Captures the
      three core, well-supported facets of GCSH biology (glycine cleavage complex,
      glycine decarboxylation, mitochondrion).
- 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: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      UniProt SubCell mapping (SL-0173 Mitochondrion) to GO:0005739. Consistent with the
      experimentally verified mitochondrial localization.
- id: PMID:16189514
  title: Towards a proteome-scale map of the human protein-protein interaction network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: LOW_QUALITY
    review_notes: >-
      Large-scale yeast two-hybrid interactome (CCSB-HI1). Source of a bare protein binding
      IPI; the interactor is not a GCS/lipoylation partner and does not inform GCSH function.
- id: PMID:1671321
  title: 'The glycine cleavage system: structure of a cDNA encoding human H-protein,
    and partial characterization of its gene in patients with hyperglycinemias.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Original human H-protein cDNA paper; establishes GCSH identity, lipoylation at Lys107
      and the (R)-lipoate cofactor, and links defects to nonketotic hyperglycinemia.
      Abstract-only in cache but the underlying assignments are corroborated by UniProt.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: LOW_QUALITY
    review_notes: >-
      HuRI binary interactome map. Source of multiple bare protein binding IPIs
      (NMI, MAGEA6/11, MED11, MIS18A, RHBDD2); none are GCS or lipoylation-pathway
      partners, so they do not inform GCSH molecular function.
- id: PMID:3348809
  title: Cloning of cDNA encoding human H-protein, a constituent of the glycine cleavage
    system.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Cloning of the human H-protein cDNA; confirms GCSH is a constituent of the glycine
      cleavage system. Abstract-only in cache; supports the complex-membership annotation.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      MitoCoP high-confidence mitochondrial proteome; provides orthogonal high-throughput
      support for mitochondrial localization of GCSH.
- id: PMID:36190515
  title: Pathogenic variants in GCSH encoding the moonlighting H-protein cause combined
    nonketotic hyperglycinemia and lipoate deficiency.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Key functional paper. Establishes the H-protein cycle (lipoate carrier in the GCS
      and lipoyl donor for DLAT/DLST), the swinging lipoyl-arm, experimental mitochondrial
      localization, and disease mechanism. Full text available.
- id: Reactome:R-HSA-5693967
  title: PXLP-K754-GLDC dimer decarboxylates Gly
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Reactome glycine-cleavage reaction (P-protein step producing aminomethyl-lipoyl-GCSH);
      places GCSH in the mitochondrial matrix.
- id: Reactome:R-HSA-5693977
  title: AMT transfers NH2CH2 from GCSH:SAMDLL to THF
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Reactome T-protein step; GCSH-bound aminomethyl intermediate donated to
      tetrahydrofolate. Matrix localization.
- id: Reactome:R-HSA-5694018
  title: DLD dimer:2xFAD oxidises GCSH:DHLL to GCSH:lipoate
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Reactome L-protein step reoxidising the dihydrolipoyl-GCSH; matrix localization.
- id: Reactome:R-HSA-6792572
  title: LIPT1 transfers lipoyl group from lipoyl-GCSH to DBT/DLST
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Reactome lipoyl-transfer reaction (GCSH as lipoyl donor to DBT/DLST); supports the
      moonlighting lipoylation role and matrix localization.
- id: Reactome:R-HSA-6793590
  title: LIPT2 transfers octanoyl group to GCSH
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Reactome octanoyl-transfer reaction generating octanoyl-GCSH; matrix localization.
- id: Reactome:R-HSA-6793591
  title: LIAS synthesizes lipoyl-GCSH
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Reactome lipoyl-synthesis reaction on GCSH; matrix localization.
- id: Reactome:R-HSA-9858752
  title: LIPT1 transfers lipoyl group from lipoyl-GCSH to DLAT
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Reactome lipoyl-transfer reaction (GCSH as lipoyl donor to DLAT/PDH E2); supports the
      moonlighting lipoylation role and matrix localization.
- id: file:human/GCSH/GCSH-uniprot.txt
  title: UniProtKB P23434 (GCSH_HUMAN) entry
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Curated UniProt record: FUNCTION (H-protein shuttles the methylamine group between P
      and T proteins; lipoylation role), COFACTOR (covalent (R)-lipoate), lipoyl-binding
      domain and N6-lipoyllysine at position 107, and mitochondrial localization.
existing_annotations:
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic (IBA) annotation placing GCSH in the mitochondrion. GCSH carries an
      N-terminal mitochondrial transit peptide and the entire glycine cleavage system operates
      in the mitochondrial matrix; localization is experimentally confirmed for the human
      protein.
    action: ACCEPT
    reason: >-
      Correct compartment, well supported across the GcvH family and by experimental evidence
      for the human protein. The more precise mitochondrial matrix location is captured by
      other annotations.
    supported_by:
    - reference_id: PMID:36190515
      supporting_text: >-
        Representative merged images (40X objective lens) showing colocalization of
        mitochondrial marker cytochrome C (red) and GCS H-protein (green) in knockdown COS7
        cells co-transfected with pCMV-GCSH WT or variants.
- term:
    id: GO:0005960
    label: glycine cleavage complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: >-
      GCSH is the H-protein subunit of the glycine cleavage complex. This is the defining,
      core cellular-component annotation for the gene and is strongly supported phylogenetically
      and experimentally.
    action: ACCEPT
    reason: >-
      Core annotation. GCSH is one of the four canonical GCS proteins (P/H/T/L) and functions as
      the lipoyl-carrier subunit of the complex.
    supported_by:
    - reference_id: file:human/GCSH/GCSH-uniprot.txt
      supporting_text: >-
        SUBUNIT: Interacts with GLDC (By similarity). The glycine cleavage
    - reference_id: PMID:36190515
      supporting_text: >-
        Lipoate is also a critical cofactor of the glycine cleavage enzyme system (GCS), where
        the H-protein itself is the lipoate carrier of this enzyme complex.
- term:
    id: GO:0019464
    label: glycine decarboxylation via glycine cleavage system
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      GCSH participates in glycine decarboxylation via the glycine cleavage system. Its lipoyl
      arm accepts the aminomethyl group from the P-protein and presents it to the T-protein,
      making it essential to the cleavage reaction. Core biological-process annotation.
    action: ACCEPT
    reason: >-
      Core function, precisely describing the GCS pathway in which GCSH acts. Strongly supported
      phylogenetically and by the functional literature.
    supported_by:
    - reference_id: PMID:36190515
      supporting_text: >-
        Glycine is decarboxylated to carbon dioxide and the resulting aminomethyl-group
        transferred to lipoyl-H-protein as aminomethyl-lipoate. The T-protein releases ammonia
        while transferring the methyl-group to tetrahydrofolate. The L-protein reoxidizes the
        reduced lipoyl-group.
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Electronic annotation from the UniProt subcellular-location mapping (SL-0173 Mitochondrion).
      Correct but less specific than the mitochondrial matrix annotations.
    action: ACCEPT
    reason: >-
      Consistent with experimental localization; a broadly correct IEA. Retained as a
      supporting, non-core localization annotation.
    supported_by:
    - reference_id: file:human/GCSH/GCSH-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion'
- term:
    id: GO:0005960
    label: glycine cleavage complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: part_of
  review:
    summary: >-
      InterPro2GO electronic annotation (GCV_H family IPR002930/IPR017453) placing GCSH in the
      glycine cleavage complex. Duplicates the well-supported IBA/TAS complex-membership
      annotation.
    action: ACCEPT
    reason: >-
      Correct family-to-complex mapping, consistent with the experimentally established role of
      GCSH as the H-protein subunit.
    supported_by:
    - reference_id: PMID:36190515
      supporting_text: >-
        Lipoate is also a critical cofactor of the glycine cleavage enzyme system (GCS), where
        the H-protein itself is the lipoate carrier of this enzyme complex.
- term:
    id: GO:0019464
    label: glycine decarboxylation via glycine cleavage system
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO electronic annotation to the GCS decarboxylation process. Duplicates the
      core IBA/TAS process annotation.
    action: ACCEPT
    reason: >-
      Correct family-based mapping to the pathway in which GCSH acts.
    supported_by:
    - reference_id: PMID:36190515
      supporting_text: >-
        Glycine is decarboxylated to carbon dioxide and the resulting aminomethyl-group
        transferred to lipoyl-H-protein as aminomethyl-lipoate. The T-protein releases ammonia
        while transferring the methyl-group to tetrahydrofolate. The L-protein reoxidizes the
        reduced lipoyl-group.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16189514
  qualifier: enables
  review:
    summary: >-
      Bare protein binding IPI from a large-scale yeast two-hybrid interactome screen. The
      interactor is not a glycine-cleavage-system or lipoylation-pathway partner and this term
      conveys no specific molecular function for GCSH.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      protein binding (GO:0005515) is uninformative; the supporting high-throughput interaction
      does not correspond to GCSH's known biology (a substrate-carrier acting via its covalent
      lipoyl arm). Per curation policy this experimental IPI is not removed but flagged as an
      over-annotation. The informative molecular function for GCSH is its lipoyl-carrier role,
      captured by the proposed lipoic acid binding term.
    supported_by:
    - reference_id: PMID:16189514
      supporting_text: >-
        Here we describe an initial version of a proteome-scale map of
- 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 binary interactome map. The recorded interactors
      (e.g. NMI, MAGEA6/11, MED11, MIS18A, RHBDD2) are not GCS or lipoylation-pathway partners
      and the term is uninformative for GCSH function.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      protein binding (GO:0005515) tells us nothing about GCSH's actual function. The
      high-throughput binary hits do not reflect its role as the lipoyl-carrier H-protein of
      the GCS. Retained (experimental IPI) but flagged as over-annotation; the informative MF
      is the proposed lipoic acid binding term.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: reference map of the human binary protein interactome
- term:
    id: GO:0006091
    label: generation of precursor metabolites and energy
  evidence_type: TAS
  original_reference_id: PMID:36190515
  qualifier: involved_in
  review:
    summary: >-
      Reflects GCSH's moonlighting role in lipoate biosynthesis and transfer to bioenergetic
      2-oxo-acid dehydrogenases (PDH via DLAT, 2-KGDH via DLST), which is upstream of energy
      metabolism. Correct but a broad, non-core process for this gene.
    action: KEEP_AS_NON_CORE
    reason: >-
      GCSH indirectly supports energy metabolism by providing the lipoyl cofactor required for
      PDH and 2-KGDH activity, but the term is very general and describes a downstream
      consequence rather than GCSH's direct molecular role. Kept as a non-core annotation.
    supported_by:
    - reference_id: PMID:36190515
      supporting_text: >-
        The H-protein is pivotal in the biosynthesis and transfer of the cofactor lipoate to
        several critical cellular energetics enzymes
- term:
    id: GO:0019464
    label: glycine decarboxylation via glycine cleavage system
  evidence_type: TAS
  original_reference_id: PMID:1671321
  qualifier: involved_in
  review:
    summary: >-
      Author-traceable annotation (original human H-protein cDNA paper) to the glycine
      cleavage decarboxylation process. Duplicates and corroborates the core IBA annotation.
    action: ACCEPT
    reason: >-
      Core process, supported by the foundational literature establishing GCSH as the H-protein
      of the glycine cleavage system.
    supported_by:
    - reference_id: PMID:1671321
      supporting_text: >-
        which encodes the entire structure of a
    - reference_id: file:human/GCSH/GCSH-uniprot.txt
      supporting_text: 'FUNCTION: The glycine cleavage system catalyzes the degradation of'
- term:
    id: GO:0051604
    label: protein maturation
  evidence_type: TAS
  original_reference_id: PMID:36190515
  qualifier: involved_in
  review:
    summary: >-
      Captures GCSH's moonlighting role as a lipoyl donor for maturation (lipoylation) of the E2
      subunits DLAT and DLST. Legitimate but a secondary, non-core process relative to glycine
      cleavage.
    action: KEEP_AS_NON_CORE
    reason: >-
      GCSH provides the lipoyl group transferred by LIPT1 to mature bioenergetic E2 enzymes, so
      the annotation is accurate; however this moonlighting maturation role is distinct from
      GCSH's core carrier function in the GCS. Kept as non-core. A more specific term such as
      protein lipoylation (GO:0009249) would better describe this role.
    supported_by:
    - reference_id: PMID:36190515
      supporting_text: >-
        The H-protein is pivotal in the biosynthesis and transfer of the cofactor lipoate to
        several critical cellular energetics enzymes
    - reference_id: file:human/GCSH/GCSH-uniprot.txt
      supporting_text: in the lipoylation of enzymes involved in cellular energetics such as
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5693967
  qualifier: located_in
  review:
    summary: >-
      Reactome-traceable localization to the mitochondrial matrix, where the P-protein step of
      glycine cleavage produces the aminomethyl-lipoyl-GCSH intermediate. Precise, core
      localization.
    action: ACCEPT
    reason: >-
      The glycine cleavage system and GCSH act in the mitochondrial matrix; this is the most
      specific and correct localization annotation.
    supported_by:
    - reference_id: PMID:36190515
      supporting_text: >-
        Representative merged images (40X objective lens) showing colocalization of
        mitochondrial marker cytochrome C (red) and GCS H-protein (green) in knockdown COS7
        cells co-transfected with pCMV-GCSH WT or variants.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5693977
  qualifier: located_in
  review:
    summary: >-
      Reactome-traceable matrix localization (T-protein step transferring the GCSH-bound
      aminomethyl group to tetrahydrofolate). Precise, core localization.
    action: ACCEPT
    reason: >-
      Correct and specific localization for GCSH within the GCS reaction cycle in the matrix.
    supported_by:
    - reference_id: file:human/GCSH/GCSH-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion'
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput proteomics annotation placing GCSH in the high-confidence human
      mitochondrial proteome (MitoCoP). Correct compartment; less specific than the matrix
      annotations.
    action: ACCEPT
    reason: >-
      Orthogonal high-throughput support for mitochondrial localization.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: >-
        defined a human mitochondrial high-confidence proteome (MitoCoP) of 1,134 protein-coding
        genes
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: EXP
  original_reference_id: PMID:36190515
  qualifier: located_in
  review:
    summary: >-
      Direct experimental evidence: GCS H-protein colocalizes with the mitochondrial marker
      cytochrome C by immunofluorescence in COS7 cells. Confirms mitochondrial localization.
    action: ACCEPT
    reason: >-
      Experimental localization for the human protein; strongly supports the mitochondrion
      annotation. The matrix sub-compartment is captured by other annotations.
    supported_by:
    - reference_id: PMID:36190515
      supporting_text: >-
        Representative merged images (40X objective lens) showing colocalization of
        mitochondrial marker cytochrome C (red) and GCS H-protein (green) in knockdown COS7
        cells co-transfected with pCMV-GCSH WT or variants.
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5694018
  qualifier: located_in
  review:
    summary: >-
      Reactome-traceable matrix localization (L-protein reoxidation of dihydrolipoyl-GCSH).
      Precise, core localization.
    action: ACCEPT
    reason: >-
      Correct and specific localization for GCSH within the matrix GCS reaction cycle.
    supported_by:
    - reference_id: file:human/GCSH/GCSH-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion'
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6792572
  qualifier: located_in
  review:
    summary: >-
      Reactome-traceable matrix localization associated with the lipoyl-transfer reaction from
      lipoyl-GCSH to DBT/DLST (moonlighting lipoylation role). Correct compartment.
    action: ACCEPT
    reason: >-
      GCSH and the lipoyl-transfer machinery act in the mitochondrial matrix; correct and
      specific localization.
    supported_by:
    - reference_id: file:human/GCSH/GCSH-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion'
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6793591
  qualifier: located_in
  review:
    summary: >-
      Reactome-traceable matrix localization associated with LIAS synthesis of lipoyl-GCSH.
      Correct compartment.
    action: ACCEPT
    reason: >-
      Lipoyl cofactor synthesis on GCSH occurs in the mitochondrial matrix; correct and
      specific localization.
    supported_by:
    - reference_id: file:human/GCSH/GCSH-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion'
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9858752
  qualifier: located_in
  review:
    summary: >-
      Reactome-traceable matrix localization associated with the lipoyl-transfer reaction from
      lipoyl-GCSH to DLAT (moonlighting lipoylation role). Correct compartment.
    action: ACCEPT
    reason: >-
      GCSH-mediated lipoyl transfer to DLAT occurs in the mitochondrial matrix; correct and
      specific localization.
    supported_by:
    - reference_id: file:human/GCSH/GCSH-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion'
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6793590
  qualifier: located_in
  review:
    summary: >-
      Reactome-traceable matrix localization associated with the LIPT2 octanoyl-transfer
      reaction generating octanoyl-GCSH. Correct compartment.
    action: ACCEPT
    reason: >-
      Lipoyl-cofactor biogenesis on GCSH occurs in the mitochondrial matrix; correct and
      specific localization.
    supported_by:
    - reference_id: file:human/GCSH/GCSH-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Mitochondrion'
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: TAS
  original_reference_id: PMID:3348809
  qualifier: located_in
  review:
    summary: >-
      Author-traceable annotation from the human H-protein cloning paper. Correct compartment;
      less specific than the matrix annotations.
    action: ACCEPT
    reason: >-
      Consistent with all other localization evidence; foundational reference for GCSH identity.
    supported_by:
    - reference_id: PMID:3348809
      supporting_text: a constituent of the glycine cleavage
- term:
    id: GO:0005960
    label: glycine cleavage complex
  evidence_type: TAS
  original_reference_id: PMID:3348809
  qualifier: part_of
  review:
    summary: >-
      Author-traceable annotation establishing GCSH (H-protein) as a constituent of the glycine
      cleavage system. Core complex-membership annotation.
    action: ACCEPT
    reason: >-
      Core annotation, directly supported by the cloning paper that identifies GCSH as an
      H-protein constituent of the glycine cleavage system.
    supported_by:
    - reference_id: PMID:3348809
      supporting_text: a constituent of the glycine cleavage
- term:
    id: GO:0031405
    label: lipoic acid binding
  evidence_type: IDA
  original_reference_id: PMID:1671321
  qualifier: enables
  review:
    summary: >-
      GCSH binds one lipoic acid (lipoate) cofactor covalently on Lys107 (N6-lipoyllysine), via
      its lipoyl-binding domain. This covalently bound lipoyl group is the swinging arm that
      carries the reaction intermediate through the glycine cleavage cycle; lipoic acid binding
      is the informative molecular function of this otherwise non-catalytic carrier protein.
    action: NEW
    reason: >-
      GOA lists only bare protein binding as a molecular function. The lipoyl-carrier role is
      GCSH's defining molecular activity and is directly supported by the covalent (R)-lipoate
      cofactor (PMID:1671321), the N6-lipoyllysine modification at position 107, and the
      lipoyl-binding (biotinyl/lipoyl attachment) domain in UniProt. GO:0031405 lipoic acid
      binding is the appropriate, informative term. Proposed as a new molecular-function
      annotation.
    supported_by:
    - reference_id: file:human/GCSH/GCSH-uniprot.txt
      supporting_text: Binds 1 lipoyl cofactor covalently.
    - reference_id: file:human/GCSH/GCSH-uniprot.txt
      supporting_text: N6-lipoyllysine
    - reference_id: PMID:36190515
      supporting_text: >-
        Lipoate is also a critical cofactor of the glycine cleavage enzyme system (GCS), where
        the H-protein itself is the lipoate carrier of this enzyme complex.
core_functions:
- description: >-
    Lipoyl-carrier (H-protein) function in the glycine cleavage system: GCSH bears a covalently
    attached lipoyl cofactor whose swinging arm shuttles the aminomethyl reaction intermediate
    between the P-, T- and L-proteins, making GCSH essential to glycine decarboxylation via the
    glycine cleavage complex in the mitochondrial matrix.
  molecular_function:
    id: GO:0031405
    label: lipoic acid binding
  directly_involved_in:
  - id: GO:0019464
    label: glycine decarboxylation via glycine cleavage system
  in_complex:
    id: GO:0005960
    label: glycine cleavage complex
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  supported_by:
  - reference_id: PMID:36190515
    supporting_text: >-
      Lipoate is also a critical cofactor of the glycine cleavage enzyme system (GCS), where
      the H-protein itself is the lipoate carrier of this enzyme complex.
  - reference_id: file:human/GCSH/GCSH-uniprot.txt
    supporting_text: 'The H protein (GCSH) shuttles the methylamine group of glycine'
proposed_new_terms: []
suggested_questions:
- question: >-
    Is there a dedicated GO molecular-function term for the lipoyl-swinging-arm/substrate-carrier
    role of GCSH-type H-proteins, distinct from the generic lipoic acid binding, that would
    better capture its aminomethyl-carrier activity within the glycine cleavage complex?
- question: >-
    How should GCSH's moonlighting role as a lipoyl donor for DLAT/DLST (protein lipoylation) be
    represented relative to its core carrier role in the GCS, e.g. via protein lipoylation
    (GO:0009249)?
suggested_experiments:
- hypothesis: >-
    The swinging lipoyl arm of GCSH protects and transfers the aminomethyl intermediate during
    glycine cleavage, a carrier mechanism separable from its lipoyl-donor role.
  description: >-
    Structural and kinetic characterization of the swinging lipoyl arm (e.g. the role of Ser67 in
    protecting the aminomethyl group) to define GCSH's carrier mechanism in the human GCS.
  experiment_type: structural biology / enzyme kinetics
- hypothesis: >-
    GCSH's contributions to glycine cleavage and to E2-enzyme lipoylation are genetically
    separable moonlighting activities.
  description: >-
    Quantify the relative contribution of GCSH to glycine cleavage versus E2-enzyme lipoylation in
    human cells (e.g. using separation-of-function GCSH variants) to clarify the two activities.
  experiment_type: cell biology / biochemistry