Details for: AMT

Gene ID: 275

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: AMT

Ensembl ID: ENSG00000145020

Description: aminomethyltransferase

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • neural crest cell CL0011012
    CSI 4.01
    rCSI 3.17%
    PRS 97.87
  • renal alpha-intercalated cell CL0005011
    CSI 3.79
    rCSI 5.07%
    PRS 99.03
  • transit amplifying cell of colon CL0009011
    CSI 3.08
    rCSI 3.62%
    PRS 99.07
  • ciliated epithelial cell CL0000067
    CSI 2.91
    rCSI 2.56%
    PRS 95.82
  • astrocyte of the cerebral cortex CL0002605
    CSI 2.01
    rCSI 4.5%
    PRS 95.62
  • cardiac muscle cell CL0000746
    CSI 2
    rCSI 2.87%
    PRS 95.76
  • kidney connecting tubule epithelial cell CL1000768
    CSI 1.82
    rCSI 4.62%
    PRS 97.61
  • dopaminergic neuron CL0000700
    CSI 1.31
    rCSI 7.4%
    PRS 94.54

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

Loading network (please wait)...

Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary Aminomethyltransferase, encoded by the [AMT](/details-gene/275) gene, is a critical mitochondrial enzyme that functions as the T-protein component of the glycine cleavage system (GCS). This system is central to glycine catabolism in the mitochondrial matrix. Functionally, [AMT](/details-gene/275) catalyzes the transfer of a methylamine group from the H-protein of the GCS to tetrahydrofolate, a key step in amino acid metabolism. Deficiencies in [AMT](/details-gene/275) function are causally linked to nonketotic hyperglycinemia ([238310](https://omim.org/entry/238310)), a severe autosomal recessive inborn error of metabolism characterized by the accumulation of glycine in body fluids, leading to profound neurological dysfunction [Link](https://doi.org/10.1007/bf00201565). Expression data indicates its high significance in metabolically active and developing cells, including [neural crest cells](/details-cell/CL0011012) and various specialized epithelial cells, consistent with its fundamental role in cellular metabolism. ## Cellular Roles and Expression Landscape The expression profile of [AMT](/details-gene/275) highlights its importance in a diverse set of specialized cell types, suggesting a role in fundamental metabolic processes beyond simple housekeeping. **Overall**, the gene shows the highest significance in [neural crest cells](/details-cell/CL0011012) (CSI: 4.01), which are multipotent embryonic cells critical for the development of the nervous system, craniofacial skeleton, and pigment cells. This is consistent with the severe neurological phenotype of its associated disorder. High significance is also observed in several renal and epithelial cell types, including [renal alpha-intercalated cells](/details-cell/CL0005011) (CSI: 3.79), [transit amplifying cells of the colon](/details-cell/CL0009011) (CSI: 3.08), and [ciliated epithelial cells](/details-cell/CL0000067) (CSI: 2.91). This pattern suggests a crucial role for glycine metabolism in tissues involved in secretion, absorption, and maintenance of homeostasis. Furthermore, its notable significance in terminally differentiated cells such as [astrocytes of the cerebral cortex](/details-cell/CL0002605) (CSI: 2.01), [cardiac muscle cells](/details-cell/CL0000746) (CSI: 2.00), and [dopaminergic neurons](/details-cell/CL0000700) (CSI: 1.31) underscores the ongoing importance of the glycine cleavage system in tissues with high energy demands throughout life. ## Pathways and Molecular Function The function of [AMT](/details-gene/275) is well-defined within the context of amino acid metabolism. As a core component of the [glycine cleavage complex](/details-go/GO:0005960) located in the [mitochondrial matrix](/details-go/GO:0005759), it executes [aminomethyltransferase activity](/details-go/GO:0004047). This function is integral to the [glycine catabolic process](/details-go/GO:0006546), specifically [glycine decarboxylation via the glycine cleavage system](/details-go/GO:0019464). This molecular role places [AMT](/details-gene/275) centrally in several key metabolic pathways annotated by Reactome, including [Glycine degradation](/details-reactome/R-HSA-6783984) and the broader [Metabolism of amino acids and derivatives](/details-reactome/R-HSA-71291). The gene product's ability to participate in [protein binding](/details-go/GO:0005515) is essential for its interaction with other components of the glycine cleavage system to form a functional enzymatic complex. The crystal structure of the human T-protein has provided detailed insights into its catalytic mechanism and the structural basis for disease-causing mutations [Link](https://doi.org/10.1016/j.jmb.2005.06.056). ## Research Directions The established role of [AMT](/details-gene/275) in nonketotic hyperglycinemia (NKH) provides a clear clinical context, but the cell-type-specific consequences of its dysfunction remain an area for further investigation. The high expression in specific neuronal and renal cell types points toward new research avenues. **Testable Hypotheses:** 1. The high significance of [AMT](/details-gene/275) in [dopaminergic neurons](/details-cell/CL0000700) suggests that glycine accumulation from [AMT](/details-gene/275) deficiency may selectively impair dopaminergic signaling or survival, contributing to the motor and developmental deficits observed in NKH. 2. Given its high expression in [renal alpha-intercalated cells](/details-cell/CL0005011), which are critical for acid-base homeostasis, impaired [AMT](/details-gene/275) function may lead to subtle but chronic renal tubular stress or dysfunction, representing an underappreciated aspect of NKH pathology. **Proposed Experimental Approach:** To test the hypothesis regarding dopaminergic neurons, a robust *in vitro* model could be developed. Human induced pluripotent stem cells (iPSCs) derived from NKH patients with confirmed [AMT](/details-gene/275) mutations could be differentiated into [dopaminergic neurons](/details-cell/CL0000700) alongside isogenic, CRISPR-Cas9 corrected controls. A multi-omics analysis combining proteomics and metabolomics on these differentiated neurons would quantify glycine accumulation and its downstream effects on the proteome and other metabolic pathways. Functional assessments, such as measuring dopamine release, mitochondrial respiration rates (e.g., via Seahorse assay), and susceptibility to oxidative stress, would directly test whether [AMT](/details-gene/275) deficiency compromises the specific function and viability of this neuronal subtype. **Therapeutic Potential:** As nonketotic hyperglycinemia is a loss-of-function monogenic disorder, [AMT](/details-gene/275) is a target for **restoration or replacement**, not inhibition. The primary challenge is delivering a functional copy of the gene to the central nervous system across the blood-brain barrier. Gene therapy using adeno-associated virus (AAV) vectors capable of CNS delivery represents a promising, albeit complex, therapeutic strategy. Alternatively, therapies aimed at reducing substrate (glycine) levels or enhancing the function of residual mutant enzyme could be explored. However, the mitochondrial localization of the enzyme makes conventional enzyme replacement therapy extremely challenging.

Genular Protein ID: 2095740534

Symbol: GCST_HUMAN

Name: N/A

UniProtKB Accession Codes:

P48728 A8K3I5 B4DE61 B4DJQ0 E9PBG1 Q96IG6

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 2 Bgee 1 BioCyc 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 4 CTD 1 ChEBI 5 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 4 EC 1 EMBL 8 Ensembl 4 EvolutionaryTrace 1 ExpressionAtlas 1 GO 8 Gene3D 3 GeneCards 1 GeneReviews 1 GeneTree 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 6 KEGG 1 MANE-Select 1 MIM 3 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 NCBIfam 1 OMA 1 OpenTargets 1 Orphanet 3 OrthoDB 1 PANTHER 2 PDB 2 PDBsum 2 PIR 1 PIRSF 1 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 4 RNAct 1 Reactome 1 RefSeq 4 Rhea 3 SABIO-RK 1 SIGNOR 1 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 7916605

Title: Isolation and sequence determination of cDNA encoding human T-protein of the glycine cleavage system.

PubMed ID: 7916605

DOI: 10.1006/bbrc.1993.1480

PubMed ID: 8188235

Title: Structure and chromosomal localization of the aminomethyltransferase gene (AMT).

PubMed ID: 8188235

DOI: 10.1006/geno.1994.1007

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 16641997

Title: The DNA sequence, annotation and analysis of human chromosome 3.

PubMed ID: 16641997

DOI: 10.1038/nature04728

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 28244183

Title: Nonketotic Hyperglycinemia: functional assessment of missense variants in GLDC to understand phenotypes of the disease.

PubMed ID: 28244183

DOI: 10.1002/humu.23208

PubMed ID: 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.

PubMed ID: 16051266

DOI: 10.1016/j.jmb.2005.06.056

PubMed ID: 8005589

Title: Identification of the mutations in the T-protein gene causing typical and atypical nonketotic hyperglycinemia.

PubMed ID: 8005589

DOI: 10.1007/bf00201565

PubMed ID: 9600239

Title: A missense mutation (His42Arg) in the T-protein gene from a large Israeli-Arab kindred with nonketotic hyperglycinemia.

PubMed ID: 9600239

DOI: 10.1007/s004390050716

PubMed ID: 9621520

Title: A one-base deletion (183delC) and a missense mutation (D276H) in the T-protein gene from a Japanese family with nonketotic hyperglycinemia.

PubMed ID: 9621520

DOI: 10.1007/s100380050055

PubMed ID: 10873393

Title: Biochemical and molecular investigations of patients with nonketotic hyperglycinemia.

PubMed ID: 10873393

DOI: 10.1006/mgme.2000.3000

PubMed ID: 11286506

Title: Recurrent mutations in P- and T-proteins of the glycine cleavage complex and a novel T-protein mutation (N145I): a strategy for the molecular investigation of patients with nonketotic hyperglycinemia (NKH).

PubMed ID: 11286506

DOI: 10.1006/mgme.2001.3158

PubMed ID: 26371980

Title: A novel AMT gene mutation in a newborn with nonketotic hyperglycinemia and early myoclonic encephalopathy.

PubMed ID: 26371980

DOI: 10.1016/j.ejpn.2015.08.008

Sequence Information:

  • Length: 403
  • Mass: 43946
  • Checksum: 218DC9EEADFA9102
  • Sequence:
    • MQRAVSVVAR LGFRLQAFPP ALCRPLSCAQ EVLRRTPLYD FHLAHGGKMV AFAGWSLPVQ 
YRDSHTDSHL HTRQHCSLFD VSHMLQTKIL GSDRVKLMES LVVGDIAELR PNQGTLSLFT 
NEAGGILDDL IVTNTSEGHL YVVSNAGCWE KDLALMQDKV RELQNQGRDV GLEVLDNALL 
ALQGPTAAQV LQAGVADDLR KLPFMTSAVM EVFGVSGCRV TRCGYTGEDG VEISVPVAGA 
VHLATAILKN PEVKLAGLAA RDSLRLEAGL CLYGNDIDEH TTPVEGSLSW TLGKRRRAAM 
DFPGAKVIVP QLKGRVQRRR VGLMCEGAPM RAHSPILNME GTKIGTVTSG CPSPSLKKNV 
AMGYVPCEYS RPGTMLLVEV RRKQQMAVVS KMPFVPTNYY TLK