id: P48728
gene_symbol: AMT
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  AMT is the T-protein (aminomethyltransferase, EC 2.1.2.10) of the mitochondrial
  glycine cleavage system (GCS), a four-protein multienzyme complex (P-protein GLDC,
  T-protein AMT, L-protein DLD, H-protein GCSH) that catalyses the reversible oxidative
  degradation of glycine. AMT is a tetrahydrofolate (THF)-dependent enzyme that carries
  out the third step of glycine cleavage: it acts on the aminomethyl moiety of glycine
  that, following decarboxylation, is carried on the reduced lipoate arm of H-protein
  (the aminomethyl-dihydrolipoyl-GCSH intermediate), releases ammonia (NH3), and
  transfers the remaining one-carbon (methylene) unit to tetrahydrofolate to form
  (6R)-5,10-methylenetetrahydrofolate, leaving H-protein in its dihydrolipoyl (reduced
  lipoate) form for reoxidation by the L-protein (DLD). This reaction couples glycine
  catabolism to one-carbon/folate metabolism. The protein is nuclear-encoded, synthesised
  as a precursor with an N-terminal mitochondrial transit peptide and localises to the
  mitochondrial matrix. It adopts a three-domain cloverleaf fold with a central
  folate-binding cavity and belongs to the GcvT family. Deficiency of AMT causes
  nonketotic hyperglycinemia (glycine encephalopathy), a severe neonatal-onset metabolic
  disorder with high glycine in body fluids; AMT (T-protein) defects are the second most
  common cause of the disease after GLDC (P-protein).
alternative_products:
- name: '1'
  id: P48728-1
- name: '2'
  id: P48728-2
  sequence_note: VSP_042557
- name: '3'
  id: P48728-3
  sequence_note: VSP_043288
- name: '4'
  id: P48728-4
  sequence_note: VSP_045418
existing_annotations:
- term:
    id: GO:0004047
    label: aminomethyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Aminomethyltransferase activity is the core molecular function of AMT, the T-protein
      of the glycine cleavage system, supported here by a phylogenetic (IBA) inference
      across the GcvT family. It is corroborated by experimental (EXP/IMP) and
      EC/RHEA-based annotations on the same protein.
    action: ACCEPT
    reason: >-
      Correct and specific molecular function for the GcvT-family T-protein. The IBA sits
      at the appropriate level of specificity and matches the experimentally established
      activity (EC 2.1.2.10; RHEA:16945).
    supported_by:
    - reference_id: PMID:16051266
      supporting_text: >-
        T-protein, a component of the glycine cleavage system, catalyzes the formation
    - reference_id: file:human/AMT/AMT-uniprot.txt
      supporting_text: "EC=2.1.2.10"
- 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: >-
      AMT participates in glycine degradation via the glycine cleavage system. This
      phylogenetic (IBA) process annotation matches the well-established role of the
      T-protein in the GCS and is corroborated by an experimental IMP on the same protein.
    action: ACCEPT
    reason: >-
      Directly reflects the T-protein's role in the multienzyme glycine cleavage reaction.
      Appropriate biological process for the core function.
    supported_by:
    - reference_id: PMID:16051266
      supporting_text: >-
        T-protein, a component of the glycine cleavage system, catalyzes the formation
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      AMT is active in the mitochondrion. This phylogenetic (IBA) localisation is
      consistent with the N-terminal mitochondrial transit peptide and with multiple
      experimental localisation annotations on the human protein.
    action: ACCEPT
    reason: >-
      The GCS operates in the mitochondrial matrix; the more specific matrix term is also
      annotated (GO:0005759). Correct compartment for the enzyme's activity.
    supported_by:
    - reference_id: file:human/AMT/AMT-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion"
- term:
    id: GO:0004047
    label: aminomethyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Automated (IEA) assignment of aminomethyltransferase activity derived from
      InterPro/EC/RHEA mapping (EC 2.1.2.10, RHEA:16945). This reproduces the experimentally
      established molecular function.
    action: ACCEPT
    reason: >-
      The EC and RHEA identifiers correspond exactly to the T-protein reaction; the mapping
      is correct and appropriately specific.
    supported_by:
    - reference_id: file:human/AMT/AMT-uniprot.txt
      supporting_text: "Xref=Rhea:RHEA:16945"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Automated (IEA) mitochondrion localisation from the UniProt Subcellular Location
      mapping (SL-0173). Consistent with the curated subcellular location and the transit
      peptide.
    action: ACCEPT
    reason: >-
      Correct compartment; agrees with experimental IDA/HTP/IC annotations and the
      UniProt-asserted mitochondrial location.
    supported_by:
    - reference_id: file:human/AMT/AMT-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: >-
      AMT (T-protein) is a component of the glycine cleavage complex, the four-protein
      GCS multienzyme system (P/GLDC, T/AMT, L/DLD, H/GCSH). This InterPro-based (IEA)
      part_of annotation is correct.
    action: ACCEPT
    reason: >-
      The T-protein is by definition a constituent of the glycine cleavage complex; the
      complex composition is documented in UniProt and Reactome.
    supported_by:
    - reference_id: file:human/AMT/AMT-uniprot.txt
      supporting_text: >-
        The glycine cleavage system is composed of four proteins: P,
    - reference_id: Reactome:R-HSA-6783984
      supporting_text: >-
        comprising dimeric P protein (GLDC), T protein (AMT, GCST), dimeric L protein (DLD)
        and H protein (GCSH)
- term:
    id: GO:0006546
    label: glycine catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Automated (IEA) assignment of glycine catabolic process from ARBA/InterPro. AMT is
      a bona fide component of the glycine catabolic (glycine cleavage) pathway.
    action: ACCEPT
    reason: >-
      Correct process. This is a parent/related view of the more specific
      GO:0019464 (glycine decarboxylation via glycine cleavage system) and is well supported.
    supported_by:
    - reference_id: Reactome:R-HSA-6783984
      supporting_text: >-
        The simplest amino acid, glycine, is catabolised by several different pathways.
        The major pathway is via the glycine cleavage system
- term:
    id: GO:0006546
    label: glycine catabolic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6783984
  qualifier: involved_in
  review:
    summary: >-
      Reactome (TAS) annotation placing AMT in glycine degradation. The Reactome pathway
      "Glycine degradation" describes the glycine cleavage system in which AMT is the
      T-protein.
    action: ACCEPT
    reason: >-
      Author-traceable statement that correctly assigns AMT to glycine catabolism via the
      GCS. Consistent with all other process annotations.
    supported_by:
    - reference_id: Reactome:R-HSA-6783984
      supporting_text: >-
        The major pathway is via the glycine cleavage system, comprising dimeric P protein
        (GLDC), T protein (AMT, GCST), dimeric L protein (DLD) and H protein (GCSH)
- term:
    id: GO:0004047
    label: aminomethyltransferase activity
  evidence_type: EXP
  original_reference_id: PMID:16051266
  qualifier: enables
  review:
    summary: >-
      Experimental (EXP) support for aminomethyltransferase activity from the crystal
      structure and biochemical characterisation of human T-protein, which demonstrated
      the reaction converting the H-protein-bound aminomethyl moiety to ammonia and
      5,10-methylenetetrahydrofolate.
    action: ACCEPT
    reason: >-
      Directly experimentally established core molecular function. Disease-causing variants
      (e.g. N145I, R320H) abolish this activity, further confirming it.
    supported_by:
    - reference_id: PMID:16051266
      supporting_text: >-
        T-protein, a component of the glycine cleavage system, catalyzes the formation
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Direct immunofluorescence (IDA, Human Protein Atlas) localises AMT to the
      mitochondrion, consistent with its function in the mitochondrial glycine cleavage
      system.
    action: ACCEPT
    reason: >-
      Experimental localisation agreeing with the curated subcellular location and the
      N-terminal mitochondrial transit peptide.
    supported_by:
    - reference_id: file:human/AMT/AMT-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 (HTP) detection of AMT in the high-confidence human
      mitochondrial proteome (MitoCoP), supporting mitochondrial localisation.
    action: ACCEPT
    reason: >-
      Consistent with all other localisation evidence; MitoCoP is a stringently curated
      mitochondrial proteome. Non-core relative to the enzymatic function but correct.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: >-
        We defined a human mitochondrial high-confidence proteome (MitoCoP) of 1,134
        protein-coding genes
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IC
  original_reference_id: PMID:16051266
  qualifier: located_in
  review:
    summary: >-
      Curator inference (IC) of mitochondrial localisation based on the enzyme's role in
      the mitochondrial glycine cleavage system (from GO:0019464).
    action: ACCEPT
    reason: >-
      Reasonable inference consistent with direct experimental localisation and the
      curated UniProt subcellular location.
    supported_by:
    - reference_id: file:human/AMT/AMT-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion"
- term:
    id: GO:0004047
    label: aminomethyltransferase activity
  evidence_type: IMP
  original_reference_id: PMID:16051266
  qualifier: enables
  review:
    summary: >-
      Mutational (IMP) evidence for aminomethyltransferase activity: disease-associated
      substitutions and site-directed mutations (e.g. Asp129, N145I, R320H) abolish or
      decrease AMT catalytic activity, confirming this molecular function.
    action: ACCEPT
    reason: >-
      Loss-of-function mutations that specifically eliminate aminomethyltransferase
      activity are strong evidence for the core molecular function.
    supported_by:
    - reference_id: PMID:16051266
      supporting_text: >-
        Several mutations in the
        human T-protein gene cause non-ketotic hyperglycinemia
    - reference_id: file:human/AMT/AMT-uniprot.txt
      supporting_text: "Loss of aminomethyltransferase activity"
- term:
    id: GO:0019464
    label: glycine decarboxylation via glycine cleavage system
  evidence_type: IMP
  original_reference_id: PMID:16051266
  qualifier: involved_in
  review:
    summary: >-
      Mutational (IMP) evidence that AMT functions in glycine cleavage: variants that
      impair T-protein activity cause nonketotic hyperglycinemia, a block of the glycine
      cleavage system.
    action: ACCEPT
    reason: >-
      Correct and specific biological process for the T-protein; loss-of-function mutations
      disrupt glycine cleavage, causing the disease phenotype.
    supported_by:
    - reference_id: PMID:16051266
      supporting_text: >-
        Several mutations in the
        human T-protein gene cause non-ketotic hyperglycinemia
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5693977
  qualifier: located_in
  review:
    summary: >-
      Reactome (TAS) localises the AMT-catalysed reaction to the mitochondrial matrix,
      where the glycine cleavage system operates. This is the most precise localisation
      annotation.
    action: ACCEPT
    reason: >-
      Correct and more specific than the generic mitochondrion term; the GCS is a
      matrix-localised multienzyme system.
    supported_by:
    - reference_id: Reactome:R-HSA-5693977
      supporting_text: >-
        the decarboxylated moiety
        from glycine decarboxylation attached to H protein (GCSH:SAMDLL) is further degraded
        by mitochondrial aminomethyltransferase (AMT, GCST, T protein) to ammonia (NH3)
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: TAS
  original_reference_id: PMID:8188235
  qualifier: located_in
  review:
    summary: >-
      Author statement (TAS) that AMT is the mitochondrial T-protein of the glycine
      cleavage system, supporting mitochondrial localisation.
    action: ACCEPT
    reason: >-
      Correct compartment; corroborated by direct experimental localisation and the
      curated subcellular location.
    supported_by:
    - reference_id: PMID:8188235
      supporting_text: >-
        The gene for human aminomethyltransferase (AMT), also known as the T-protein of
        the glycine cleavage system
- term:
    id: GO:0006546
    label: glycine catabolic process
  evidence_type: TAS
  original_reference_id: PMID:9600239
  qualifier: involved_in
  review:
    summary: >-
      Author statement (TAS) that AMT (T-protein) is a component of the glycine cleavage
      multienzyme system whose loss causes nonketotic hyperglycinemia, placing AMT in
      glycine catabolism.
    action: ACCEPT
    reason: >-
      Correct process; T-protein enzyme deficiency in patients establishes AMT's role in
      glycine degradation.
    supported_by:
    - reference_id: PMID:9600239
      supporting_text: >-
        Nonketotic hyperglycinemia (NKH) is caused by a mutation in the genes encoding
        the components of the glycine cleavage multi-enzyme system
    - reference_id: PMID:9600239
      supporting_text: >-
        Enzymatic analysis revealed that T-protein activity was deficient in the liver
        specimen from one propositus
core_functions:
- description: >-
    Aminomethyltransferase (T-protein) activity of the glycine cleavage system: a
    tetrahydrofolate-dependent reaction that degrades the aminomethyl-dihydrolipoyl moiety
    carried on H-protein (GCSH), releasing ammonia and transferring the one-carbon
    (methylene) unit to tetrahydrofolate to form 5,10-methylenetetrahydrofolate.
  molecular_function:
    id: GO:0004047
    label: aminomethyltransferase activity
  directly_involved_in:
  - id: GO:0019464
    label: glycine decarboxylation via glycine cleavage system
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  in_complex:
    id: GO:0005960
    label: glycine cleavage complex
  supported_by:
  - reference_id: PMID:16051266
    supporting_text: >-
      T-protein, a component of the glycine cleavage system, catalyzes the formation
  - reference_id: Reactome:R-HSA-5693977
    supporting_text: >-
      Tetrahydrofolate (THF) is required for this reaction
      and accepts the methyl group to form 5,10MTHF
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: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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:16051266
  title: Crystal structure of human T-protein of glycine cleavage system at 2.0 A
    resolution and its implication for understanding non-ketotic hyperglycinemia.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. 2.0 A crystal structure of human T-protein (AMT); establishes the
      aminomethyltransferase reaction (ammonia + 5,10-methylene-THF from the H-protein
      aminomethyl-lipoate moiety), substrate/folate binding, and disease-variant effects.
- 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; supports the HTP mitochondrial
      localisation of AMT.
- id: PMID:8188235
  title: Structure and chromosomal localization of the aminomethyltransferase gene
    (AMT).
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Genomic characterisation of AMT; explicitly identifies AMT as the mitochondrial
      T-protein of the glycine cleavage system.
- id: PMID:9600239
  title: A missense mutation (His42Arg) in the T-protein gene from a large Israeli-Arab
    kindred with nonketotic hyperglycinemia.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      T-protein (AMT) missense variant causing NKH; enzymatic deficiency confirmed in
      liver, tying AMT to glycine catabolism via the GCS.
- id: file:human/AMT/AMT-uniprot.txt
  title: UniProtKB entry P48728 (GCST_HUMAN), Aminomethyltransferase, mitochondrial
  findings: []
- id: Reactome:R-HSA-5693977
  title: AMT transfers NH2CH2 from GCSH:SAMDLL to THF
  findings: []
- id: Reactome:R-HSA-6783984
  title: Glycine degradation
  findings: []