Details for: AGXT

Gene ID: 189

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: AGXT

Ensembl ID: ENSG00000172482

Description: alanine--glyoxylate aminotransferase

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • centrilobular region hepatocyte CL0019029
    CSI 8.17
    rCSI 21.32%
    PRS 97.42
  • hepatocyte CL0000182
    CSI 7.62
    rCSI 13.63%
    PRS 98.06
  • midzonal region hepatocyte CL0019028
    CSI 5.5
    rCSI 12.91%
    PRS 97.85
  • intrahepatic cholangiocyte CL0002538
    CSI 4.26
    rCSI 10.22%
    PRS 98.88
  • Kupffer cell CL0000091
    CSI 4.05
    rCSI 9.26%
    PRS 99.2
  • hepatic stellate cell CL0000632
    CSI 4
    rCSI 14.97%
    PRS 98.51
  • periportal region hepatocyte CL0019026
    CSI 3.7
    rCSI 14.37%
    PRS 97.71
  • epithelial cell of proximal tubule CL0002306
    CSI 3.55
    rCSI 8.67%
    PRS 96.97
  • extravillous trophoblast CL0008036
    CSI 2.53
    rCSI 3.13%
    PRS 98.4
  • cholangiocyte CL1000488
    CSI 1.74
    rCSI 10.42%
    PRS 97.95

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.

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  • Node Color (Target Cell CSI, relative to current network):
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  • Shared Pathway Edge (ONTOLOGY)

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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 [AGXT](/details-gene/189), or Alanine--glyoxylate aminotransferase, is a peroxisomal enzyme critical for amino acid metabolism. Its primary function is the detoxification of glyoxylate by catalyzing its conversion to glycine. The gene exhibits highly specific and significant expression in liver cells, particularly [hepatocytes](/details-cell/CL0000182), and to a lesser extent in the [epithelial cells of the proximal tubule](/details-cell/CL0002306) in the kidney. Loss-of-function mutations in [AGXT](/details-gene/189) are the cause of Primary Hyperoxaluria Type 1 ([259900](https://omim.org/entry/259900)), a severe autosomal recessive disorder characterized by the overproduction of oxalate, leading to recurrent kidney stones and progressive renal failure. ## Cellular Roles and Expression Landscape The expression profile of [AGXT](/details-gene/189) points to a highly specialized role in hepatic and renal metabolism. **Overall**, the gene's significance is most pronounced in the liver, with the highest Cell Significance Index (CSI) scores observed in [centrilobular region hepatocyte](/details-cell/CL0019029) (CSI: 8.17), general [hepatocyte](/details-cell/CL0000182) (CSI: 7.62), and [midzonal region hepatocyte](/details-cell/CL0019028) (CSI: 5.50). Its substantial expression is also noted in other liver-resident cells, including [intrahepatic cholangiocytes](/details-cell/CL0002538), [Kupffer cells](/details-cell/CL0000091), and [hepatic stellate cells](/details-cell/CL0000632). Beyond the liver, [AGXT](/details-gene/189) shows significant expression in the kidney, specifically within the [epithelial cell of proximal tubule](/details-cell/CL0002306) (CSI: 3.55). This dual expression in the primary metabolic organ (liver) and the primary excretory organ (kidney) underscores its central role in managing metabolic byproducts. The highly restricted expression pattern suggests that its function is tailored to the unique metabolic demands of these tissues and is not a general housekeeping role. ## Pathways and Molecular Function Functionally, [AGXT](/details-gene/189) encodes a pyridoxal-phosphate-dependent enzyme that operates primarily as a homodimer. It possesses both [alanine-glyoxylate transaminase activity](/details-go/GO:0008453) and [L-serine-pyruvate transaminase activity](/details-go/GO:0004760). This dual activity places it at the intersection of several metabolic pathways. Its most critical role is in the [glyoxylate catabolic process](/details-go/GO:0009436), as detailed in the Reactome pathway [Glyoxylate metabolism and glycine degradation](/details-pathway/R-HSA-389661). By converting glyoxylate to glycine, AGT prevents its oxidation to oxalate, a toxic and poorly soluble compound. The enzyme also participates in the metabolism of amino acids, including the [L-alanine catabolic process](/details-go/GO:0042853) and [L-serine metabolic process](/details-go/GO:0006563) ([Link](https://doi.org/10.1074/jbc.274.23.16028)). The subcellular localization of the AGT protein is crucial to its function. It is predominantly found in the [peroxisome](/details-go/GO:0005777), specifically the [peroxisomal matrix](/details-go/GO:0005782). A common pathogenic mechanism in Primary Hyperoxaluria Type 1 involves mutations that cause the AGT protein to be mistargeted from the peroxisome to the mitochondrion, where it is unable to access its substrate, glyoxylate, leading to functional deficiency despite being catalytically active ([Link](https://doi.org/10.1083/jcb.111.6.2341), [Link](https://doi.org/10.1016/0300-9084(93)90091-6)). ## Research Directions Given that [AGXT](/details-gene/189) deficiency is a well-characterized monogenic disorder, research is primarily focused on understanding the molecular basis of the disease and developing targeted therapies. **Testable Hypotheses:** 1. *Pharmacological Chaperoning:* The observation that some [AGXT](/details-gene/189) mutations lead to protein misfolding and aggregation ([Link](https://pubmed.ncbi.nlm.nih.gov/8101040/)) suggests that small molecule chaperones could stabilize mutant AGT protein conformations, thereby restoring correct peroxisomal targeting and partial enzymatic function in [hepatocytes](/details-cell/CL0000182). 2. *Metabolic Crosstalk:* The dual substrate specificity of AGT for glyoxylate and pyruvate suggests that metabolic states affecting the intracellular concentration of L-alanine or L-serine in the liver could modulate the enzyme's glyoxylate detoxification capacity. It is hypothesized that nutritional interventions that increase the availability of the L-alanine amino donor could enhance the residual activity of certain hypomorphic [AGXT](/details-gene/189) mutants. **Proposed Experiment:** To test the first hypothesis regarding pharmacological chaperoning, a high-throughput screening approach could be employed. A library of approved small molecules could be screened for their ability to restore the correct peroxisomal localization of a known mistargeting mutant of [AGXT](/details-gene/189) (e.g., G170R) fused to a fluorescent reporter in a human [hepatocyte](/details-cell/CL0000182) cell line. Hits would be identified by automated high-content imaging, quantifying the shift of fluorescence from a mitochondrial to a peroxisomal pattern, and subsequently validated for their ability to restore enzymatic activity and reduce oxalate production in patient-derived cells. **Therapeutic Potential:** [AGXT](/details-gene/189) represents a prime candidate for therapeutic intervention aimed at **restoration of function**. Because the disease pathology is primarily restricted to the liver, hepatocyte-targeted therapies are highly attractive. Key strategies include: * **Gene Therapy:** Using adeno-associated virus (AAV) vectors to deliver a correct copy of the [AGXT](/details-gene/189) cDNA specifically to [hepatocytes](/details-cell/CL0000182). * **Pharmacological Chaperoning:** As outlined above, developing small molecules that correct the folding or trafficking of specific mutant proteins. This approach would be tailored to patients with specific genotypes ([Link](https://doi.org/10.1016/s0022-2836(03)00791-5)). * **mRNA Therapy:** Delivering lipid nanoparticle-formulated mRNA encoding functional AGT, allowing for transient but repeatable restoration of enzyme activity in the liver. Inhibition of [AGXT](/details-gene/189) is not a therapeutic goal; rather, strategies that enhance its activity or bypass its deficiency are the focus of current and future research.

Genular Protein ID: 1927770238

Symbol: AGT1_HUMAN

Name: N/A

UniProtKB Accession Codes:

P21549 Q53QU6

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 2 Bgee 1 BindingDB 1 BioCyc 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChEBI 9 ChEMBL 1 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 7 EC 2 EMBL 8 Ensembl 1 EvolutionaryTrace 1 GO 19 Gene3D 2 GeneCards 1 GeneReviews 1 GeneTree 1 GeneWiki 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 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PDB 17 PDBsum 17 PIR 1 PIRSF 1 PRO 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 2 RefSeq 1 Rhea 4 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 2253628

Title: Cloning and nucleotide sequence of cDNA encoding human liver serine-pyruvate aminotransferase.

PubMed ID: 2253628

DOI: 10.1111/j.1432-1033.1990.tb19420.x

PubMed ID: 1703535

Title: Identification of mutations associated with peroxisome-to-mitochondrion mistargeting of alanine/glyoxylate aminotransferase in primary hyperoxaluria type 1.

PubMed ID: 1703535

DOI: 10.1083/jcb.111.6.2341

PubMed ID: 2363689

Title: Human peroxisomal L-alanine: glyoxylate aminotransferase. Evolutionary loss of a mitochondrial targeting signal by point mutation of the initiation codon.

PubMed ID: 2363689

DOI: 10.1042/bj2680517

PubMed ID: 2045108

Title: Characterization and chromosomal mapping of a genomic clone encoding human alanine:glyoxylate aminotransferase.

PubMed ID: 2045108

DOI: 10.1016/0888-7543(91)90481-s

PubMed ID: 14702039

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

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 15815621

Title: Generation and annotation of the DNA sequences of human chromosomes 2 and 4.

PubMed ID: 15815621

DOI: 10.1038/nature03466

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: 10347152

Title: Flux of the L-serine metabolism in rabbit, human, and dog livers. Substantial contributions of both mitochondrial and peroxisomal serine:pyruvate/alanine:glyoxylate aminotransferase.

PubMed ID: 10347152

DOI: 10.1074/jbc.274.23.16028

PubMed ID: 24275569

Title: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome.

PubMed ID: 24275569

DOI: 10.1016/j.jprot.2013.11.014

PubMed ID: 12899834

Title: Crystal structure of alanine:glyoxylate aminotransferase and the relationship between genotype and enzymatic phenotype in primary hyperoxaluria type 1.

PubMed ID: 12899834

DOI: 10.1016/s0022-2836(03)00791-5

PubMed ID: 2039493

Title: Primary hyperoxaluria type I due to a point mutation of T to C in the coding region of the serine:pyruvate aminotransferase gene.

PubMed ID: 2039493

DOI: 10.1016/0006-291x(91)90396-o

PubMed ID: 1349575

Title: A glycine-to-glutamate substitution abolishes alanine:glyoxylate aminotransferase catalytic activity in a subset of patients with primary hyperoxaluria type 1.

PubMed ID: 1349575

DOI: 10.1016/0888-7543(92)90225-h

PubMed ID: 1301173

Title: A serine-to-phenylalanine substitution leads to loss of alanine:glyoxylate aminotransferase catalytic activity and immunoreactivity in a patient with primary hyperoxaluria type 1.

PubMed ID: 1301173

DOI: 10.1093/hmg/1.8.643

PubMed ID: 8101040

Title: Enzymological and mutational analysis of a complex primary hyperoxaluria type 1 phenotype involving alanine:glyoxylate aminotransferase peroxisome-to-mitochondrion mistargeting and intraperoxisomal aggregation.

PubMed ID: 8101040

PubMed ID: 8507692

Title: Primary hyperoxaluria type 1 and peroxisome-to-mitochondrion mistargeting of alanine:glyoxylate aminotransferase.

PubMed ID: 8507692

DOI: 10.1016/0300-9084(93)90091-6

PubMed ID: 9192270

Title: Primary hyperoxaluria type 1: a cluster of new mutations in exon 7 of the AGXT gene.

PubMed ID: 9192270

DOI: 10.1136/jmg.34.6.489

PubMed ID: 9604803

Title: Identification of new mutations in primary hyperoxaluria type 1 (PH1).

PubMed ID: 9604803

PubMed ID: 10394939

Title: Gene symbol: AGXT. Disease: primary hyperoxaluria type I.

PubMed ID: 10394939

DOI: 10.1007/s004390050984

PubMed ID: 10453743

Title: Molecular analysis of hyperoxaluria type 1 in Italian patients reveals eight new mutations in the alanine: glyoxylate aminotransferase gene.

PubMed ID: 10453743

DOI: 10.1007/s004390050998

PubMed ID: 10541294

Title: Primary hyperoxaluria type I: a model for multiple mutations in a monogenic disease within a distinct ethnic group.

PubMed ID: 10541294

DOI: 10.1681/asn.v10112352

PubMed ID: 10862087

Title: Identification of 5 novel mutations in the AGXT gene.

PubMed ID: 10862087

DOI: 10.1002/1098-1004(200006)15:6<577::aid-humu9>3.0.co;2-#

PubMed ID: 10960483

Title: Functional synergism between the most common polymorphism in human alanine:glyoxylate aminotransferase and four of the most common disease-causing mutations.

PubMed ID: 10960483

DOI: 10.1074/jbc.m006693200

PubMed ID: 12559847

Title: The AGT gene in Africa: a distinctive minor allele haplotype, a polymorphism (V326I), and a novel PH1 mutation (A112D) in Black Africans.

PubMed ID: 12559847

DOI: 10.1016/s1096-7192(02)00204-4

PubMed ID: 12777626

Title: Primary hyperoxaluria type 1 in the Canary Islands: a conformational disease due to I244T mutation in the P11L-containing alanine:glyoxylate aminotransferase.

PubMed ID: 12777626

DOI: 10.1073/pnas.1131968100

PubMed ID: 15253729

Title: Clinical implications of mutation analysis in primary hyperoxaluria type 1.

PubMed ID: 15253729

DOI: 10.1111/j.1523-1755.2004.00796.x

PubMed ID: 15849466

Title: Implications of genotype and enzyme phenotype in pyridoxine response of patients with type I primary hyperoxaluria.

PubMed ID: 15849466

DOI: 10.1159/000085411

PubMed ID: 15961946

Title: Intra-familial clinical heterogeneity: absence of genotype-phenotype correlation in primary hyperoxaluria type 1 in Israel.

PubMed ID: 15961946

DOI: 10.1159/000086357

PubMed ID: 15963748

Title: The major allele of the alanine:glyoxylate aminotransferase gene: nine novel mutations and polymorphisms associated with primary hyperoxaluria type 1.

PubMed ID: 15963748

DOI: 10.1016/j.ymgme.2005.05.005

PubMed ID: 16971151

Title: Consequences of missense mutations for dimerization and turnover of alanine:glyoxylate aminotransferase: study of a spectrum of mutations.

PubMed ID: 16971151

DOI: 10.1016/j.ymgme.2006.07.013

PubMed ID: 17495019

Title: Selected exonic sequencing of the AGXT gene provides a genetic diagnosis in 50% of patients with primary hyperoxaluria type 1.

PubMed ID: 17495019

DOI: 10.1373/clinchem.2006.084434

PubMed ID: 24055001

Title: Gly161 mutations associated with primary hyperoxaluria type I induce the cytosolic aggregation and the intracellular degradation of the apo-form of alanine:glyoxylate aminotransferase.

PubMed ID: 24055001

DOI: 10.1016/j.bbadis.2013.09.002

PubMed ID: 23229545

Title: Four of the most common mutations in primary hyperoxaluria type 1 unmask the cryptic mitochondrial targeting sequence of alanine:glyoxylate aminotransferase encoded by the polymorphic minor allele.

PubMed ID: 23229545

DOI: 10.1074/jbc.m112.432617

PubMed ID: 24934730

Title: Mutational analysis of AGXT in two Chinese families with primary hyperoxaluria type 1.

PubMed ID: 24934730

DOI: 10.1186/1471-2369-15-92

PubMed ID: 26149463

Title: Misfolding caused by the pathogenic mutation G47R on the minor allele of alanine:glyoxylate aminotransferase and chaperoning activity of pyridoxine.

PubMed ID: 26149463

DOI: 10.1016/j.bbapap.2015.07.002

Sequence Information:

  • Length: 392
  • Mass: 43010
  • Checksum: 2987DDE85B2470B4
  • Sequence:
    • MASHKLLVTP PKALLKPLSI PNQLLLGPGP SNLPPRIMAA GGLQMIGSMS KDMYQIMDEI 
KEGIQYVFQT RNPLTLVISG SGHCALEAAL VNVLEPGDSF LVGANGIWGQ RAVDIGERIG 
ARVHPMTKDP GGHYTLQEVE EGLAQHKPVL LFLTHGESST GVLQPLDGFG ELCHRYKCLL 
LVDSVASLGG TPLYMDRQGI DILYSGSQKA LNAPPGTSLI SFSDKAKKKM YSRKTKPFSF 
YLDIKWLANF WGCDDQPRMY HHTIPVISLY SLRESLALIA EQGLENSWRQ HREAAAYLHG 
RLQALGLQLF VKDPALRLPT VTTVAVPAGY DWRDIVSYVI DHFDIEIMGG LGPSTGKVLR 
IGLLGCNATR ENVDRVTEAL RAALQHCPKK KL