Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.6.1.44 (AGT)
 770 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Primary hyperoxaluria Type 1 (PH1) is caused by a functional deficiency of a liver enzyme, serine:pyruvate/alanine:glyoxylate aminotransferase (SPT/AGT), which catalyzes transamination between L-serine or l-alanine as an amino acid substrate and glyoxylate or pyruvate as an alpha-keto acid substrate. A high affinity for glyoxylate is a notable feature of this enzyme, suggesting a role in glyoxylate metabolism in vivo. Another conspicuous feature of SPT/AGT is its species-specific and food habit-dependent subcellular distribution. Thus, the enzyme is located in peroxisomes in herbivores and man, largely in mitochondria in carnivores, and in both the organelles in rodents. The mechanism of the species-specific dual organelle localization of SPT/AGT is either transcription of the gene from two different start sites or loss of the upstream translation initiation ATG codon by mutations. It appears that the mitochondrial versus peroxisomal distribution of SPT/AGT in different animal species is indispensable in meeting the metabolic needs caused by their respective food habits. As for the peroxisomal localization, glycolate is contained in plants much more than in animal tissues, and when ingested, it is converted to glyoxylate, an immediate precursor of oxalate, in liver peroxisomes. Therefore, peroxisomal localization of SPT/AGT may be indispensable for herbivores to convert the glyoxylate formed in peroxisomes into glycine in situ rather than forming oxalate. On the other hand, our recent studies showed that SPT/AGT contributed substantially to serine metabolism in rabbit, human, and dog livers; i.e., irrespective of its mitochondrial or peroxisomal localization. Thus, the mitochondrial localization of SPT/AGT was not a prerequisite for the metabolism of L-serine. Another source of glyoxylate is the metabolism of L-hydroxyproline, and in this case, the enzyme responsible for the glyoxylate formation has been reported to be a mitochondrial matrix enzyme. Collagen accounts for about 30% of total animal proteins and contains about 13% (w/w) hydroxyproline. It is therefore possible that both mitochondrial and peroxisomal SPT/AGT contribute to the metabolism of glyoxylate and serine, but the subcellular site for glyoxylate metabolism is different in herbivores and carnivores.
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PMID:Oxalate synthesis in mammals: properties and subcellular distribution of serine:pyruvate/alanine:glyoxylate aminotransferase in the liver. 1115

Serine:pyruvate/alanine:glyoxylate aminotransferase (SPT/AGT) is largely located in mitochondria in carnivores, whereas it is entirely found within peroxisomes in herbivores and humans. In rat liver, SPT/AGT is found in both of these organelles, and only the mitochondrial enzyme is markedly induced by glucagon. Although SPT/AGT is a bifunctional enzyme involved in the metabolism of both L-serine and glyoxylate, its contribution to L-serine metabolism is independent of mitochondrial or peroxisomal localization (Xue HH et al., J Biol Chem 274: 16028-16033, 1999). Therefore, the species-specific and food habit-dependent organelle distribution might be required for proper metabolism of glyoxylate at the subcellular site of its formation. Glyoxylate formation from glycolate and that from L-hydroxyproline have been shown to occur in peroxisomes and mitochondria, respectively. The present study found that urinary excretion of oxalate was markedly increased when a large dose of L-hydroxyproline or glycolate was administered to rats. Oxalate formation from L-hydroxyproline but not that from glycolate was significantly reduced when mitochondrial SPT/AGT had been induced by glucagon. The hydroxyproline content of collagen is 10 to 13%, and collagen accounts for about 30% of total animal protein; therefore, these results suggest that an important role of mitochondrial SPT/AGT in carnivores is to convert L-hydroxyproline-derived glyoxylate into glycine in situ, preventing undesirable overflow into the production of oxalate.
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PMID:Control of oxalate formation from L-hydroxyproline in liver mitochondria. 1266 Mar 28

Serine:pyruvate (or alanine:glyoxylate) aminotransferase (SPT or AGT) in the liver is unique in that its subcellular distribution is entirely peroxisomal in man and herbivores, and largely mitochondrial in carnivores. In rats, this enzyme is located in both mitochondria and peroxisomes and only the mitochondrial activity is markedly induced by glucagon. The mechanism of the species-specific dual organelle localization is either transcription of the gene from two different start sites or loss of upstream translation initiation ATG codon by mutations. In herbivores, peroxisomal localization of SPT appears to be indispensable to prevent excessive oxalate production by removing glyoxylate, an immediate precursor of oxalate, formed from glycolate in this organelle. In carnivores, its mitochondrial localization appears to be needed to metabolize glyoxylate formed from L-hydroxyproline in mitochondria. In addition, SPT contributes substantially to gluconeogenesis from serine in rabbit, human and dog livers, irrespective of its mitochondrial or peroxisomal localization. (Communicated by Shigetada Nakanishi, M.J.A.).
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PMID:Studies on a unique organelle localization of a liver enzyme, serine:pyruvate (or alanine:glyoxylate) aminotransferase. 2155 62

Primary hyperoxaluria type 1 (PH1) and type 2 (PH2) are rare genetic diseases that result from deficiencies in glyoxylate metabolism. The increased oxalate synthesis that occurs can lead to kidney stone formation, deposition of calcium oxalate in the kidney and other tissues, and renal failure. Hydroxyproline (Hyp) catabolism, which occurs mainly in the liver and kidney, is a prominent source of glyoxylate and could account for a significant portion of the oxalate produced in PH. To determine the sensitivity of mouse models of PH1 and PH2 to Hyp-derived oxalate, animals were fed diets containing 1% Hyp. Urinary excretions of glycolate and oxalate were used to monitor Hyp catabolism and the kidneys were examined to assess pathological changes. Both strains of knockout (KO) mice excreted more oxalate than wild-type (WT) animals with Hyp feeding. After 4 wk of Hyp feeding, all mice deficient in glyoxylate reductase/hydroxypyruvate reductase (GRHPR KO) developed severe nephrocalcinosis in contrast to animals deficient in alanine-glyoxylate aminotransferase (AGXT KO) where nephrocalcinosis was milder and with a lower frequency. Plasma cystatin C measurements over 4-wk Hyp feeding indicated no significant loss of renal function in WT and AGXT KO animals, and significant and severe loss of renal function in GRHPR KO animals after 2 and 4 wk, respectively. These data suggest that GRHPR activity may be vital in the kidney for limiting the conversion of Hyp-derived glyoxylate to oxalate. As Hyp catabolism may make a major contribution to the oxalate produced in PH patients, Hyp feeding in these mouse models should be useful in understanding the mechanisms associated with calcium oxalate deposition in the kidney.
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PMID:Hydroxyproline metabolism in mouse models of primary hyperoxaluria. 2249 66