Author: Francesca Bertolini
Date: 09/07/2013



AGxT gene is located on chromosomes 2q37.3 and encodes for a AGXT an omodimeric 392 aa transaminase of 86 kDa.
It is an hepatic alanine-glyoxylate aminotransferase that plays an important role in glioxilate and oxalate metabolism. (Assay of alanine:glyoxylate aminotransferase in human liver by its serine: glyoxylate aminotransferase activity,2009).
The intracellular localization of AGXT is species-dependent: it is found in peroxisomes in humans; mitochondria in carnivores and in both organelles in rodents. (Human peroxisomal L-alanine:glyoxylate aminotransferase.Evolutionary loss of a mitochondrial targeting signal by point mutation of the initiation codon,1990).
The primary hyperoxaluria type 1 is caused by functional deficiency of this enzyme.


AGxT gene is located at the telomeric end of the short harm of cromosome 2 in band 2q37.3 (Characterization and chromosomal mapping of a genomic clone encoding human alanine:glyoxylate aminotransferase,1991). The gene contain 11 exon.

Other Designations: AGT; AGT1; AGXT1; PH1; SPAT; SPT; TLH6

Primer extension experiments have identified a major transcription start site located at c.-45bp and a secondary site to c.-115. An analysis of the deletion in the 5'UTR has indicated that the region from c.-65 is important for the expression of AGxT in human liver cells and that the region from c.-440 to c.-700 is potentially important for enhancer elements. (Functional analysis of the 5'-flanking region of the human alanine:glyoxylate aminotransferase gene AGXT,2002).



In AGxT gene is present with a frequency of 10-20% in the Caucasian population a series of esonic and intronic polymorphisms in linkage disequilibrium.
The main polymorphism that characterizes it, is the replacement p.P11L (c.32C>T) (Identification of mutations associated with peroxisome-to-mitochondrion mistargeting of alanine/glyoxylate aminotransferase in primary hyperoxaluria type 1,1990).
The most recent revision collects 146 different mutations; these are distributed throughout the gene, in majority (75%) are point mutations: 73 missense, 19 nonsense and 18 substitutions in the consensus splice site; 25% are insertions /deletion. (Primary hyperoxaluria type 1: update and additional mutation analysis of the AGXT gene,2009).
p.G170R is the most common mutation in all populations, is associated with a 30-60% residual catalytic activity and immunoreactivity in liver biopsies. AGXT in mitochondria is functional but is not able to detoxify the glyoxylate product in peroxisomes. (Identification of mutations associated with peroxisome-to-mitochondrion mistargeting of alanine/glyoxylate aminotransferase in primary hyperoxaluria type 1,1990).


The wide dimerization interface consists of two Alpha-helix and 5 loop. (Pyridoxal 5'-phosphate binding of a recombinant rat serine: pyruvate/alanine:glyoxylate aminotransferase,1996).
Each monomer binds one molecule of pyridoxal phosphate forming a Schiff base.
Each monomer AGXT includes an extension of the first 21 aa at N-terminal that binds the other monomer stabilizing the dimer, a large central domain and a C-terminal domain (283-392). (Crystal structure of alanine:glyoxylate aminotransferase and the relationship between genotype and enzymatic phenotype in primary hyperoxaluria type 1,2003).
Amino acids form an atypical terminal site KKL for peroxisomal targeting, which is necessary but not sufficient for import into peroxisomes by the Pex5p receptor. (Mammalian alanine/glyoxylate aminotransferase 1 is imported into peroxisomes via the PTS1 translocation pathway. Increased degeneracy and context specificity of the mammalian PTS1 motif and implications for the peroxisome-to-mitochondrion mistargeting of AGT in primary hyperoxaluria type 1,1995).

  • "Tertiary structure"

Protein Aminoacids Percentage


In humans AGXT is localized in peroxisome,in some mammal species AGXT is localized in the mitochondria, while in others, as in the rat is distributed both in the mitochondria than in peroxisomes. The protein is synthesized in hepatocytes on free polyribosomes, dimerizes and is imported into peroxisomes.
Has been hypothesized that the intracellular localization of AGXT appears from an adaptive evolution to the contribution of dietetic oxalate in the different species. In a predominantly carnivorous diet, the main precursor of glyoxylate is hydroxyproline which is formed in the mitochondria. A vegetable diet instead, set the glycolate that originates glyoxylate in peroxisomes. (Variable peroxisomal and mitochondrial targeting of alanine: glyoxylate aminotransferase in mammalian evolution and disease,1997).


AGXT catalyzes important reactions for the metabolism of glyoxylate; in detail AGXT transfers the amino Group from L-Alanine to glyoxylate with the formation of Glycine and Pyruvate.
AGXT uses the prosthetic group pyridoxal phosphate (PLP) as a cofactor, derived from pyridoxine (vitamin B6).
The reaction involves two steps summarized here:

1) Alanine + PLP-AGXT↔ pyruvate + AGXT-PMP (PMP = pyridoxamine phosphate)

2) Glyoxylate + PMP-AGXT ↔ glycine +PLP-AGXT.

AGXT deficiency results in a lack of detoxification of glyoxylate which is oxidized by the enzyme GO or reduced to glycolate by GR (glycolate reductase).
Glycolate and L-glycerate are not harmful because soluble, but their assay is useful to confirm the diagnosis of primary hyperoxaluria and discriminate between the type I and II.


The functional deficiency of alanine-glyoxylate aminotransferase (AGXT) causes a rare autosomal recessive genetic disorder: primary hyperoxaluria type 1.
In the absence of AGXT, the glyoxylate is oxidized in the peroxisome in oxalate otherwise is reduced to oxidized glycolate or oxalate in the cytoplasm. Glyoxylate accumulation in the cytosol is readily transformed by lactate dehydrogenase in oxalate, a dicarboxylic acid which can not be metabolized by mammals. This cytoplasmatic product is then released into the bloodstream, in which forming calcium oxalate crystals giving rise to the clinical picture of disease. (Primary hyperoxalurias: disorders of glyoxylate detoxification,2012).

PHI is an extremely heterogeneous pathology; the first symptoms are those related to the presence of kidney stones, such as colic, hematuria, and / or recurrent infections of the urinary tract. (Primary hyperoxaluria type 1: AGT mistargeting highlights the fundamental differences between the peroxisomal and mitochondrial protein import pathways,2006).

Diagnosis And Gene Therapy

The primary hyperoxaluria diagnosis is based on clinical evidence, metabolic, genetic and enzymatic. The metabolic diagnosis expected the dosage of oxalate, of the glycolate (PHI) in urine and in plasma; the genetics diagnosis foresees the search of mutations in both alleles in the gene AGxT (PHI).
Finally, in the enzymatic diagnosis is metered residual catalytic activity of AGXT on liver biopsy.

For the treatment of PH1 are used, in addition to conservative and classic treatments, new therapeutic strategies. One of these is the gene therapy: a small fraction of functional AGXT is sufficient to detoxify glyoxylate in each liver cell.
A carrier of null mutation on one allele and haplotype has on the lower catalytic activity of 30% compared to normal but not affection. However, because gene therapy may lead to an effective reduction of the latter, it is necessary to transduce a large percentage of hepatocytes with the AGxT gene. (Primary hyperoxaluria: from gene defects to designer drugs?,2005).

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