Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

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

Primary hyperoxaluria type 1 (PH1) is a rare inherited metabolic disorder in which deficiency of the liver enzyme AGT leads to renal failure and systemic oxalosis. Timely, combined cadaveric liver-kidney transplantation (LKT) is recommended for end-stage renal failure (ESRF) caused by PH1; however, the shortage of cadaveric organs has generated enthusiasm for living-related transplantation in years. Recently, successful sequential LKT from the same living donor has been reported in a child with PH1. We present a sister-to-brother simultaneous LKT in a pediatric patient who suffered from PH1 with ESRF. Twelve months after transplantation, his daily urine oxalate excretion was decreased from 160 mg to 19.5 mg with normal liver and renal allograft functions. In addition to the well-known advantages of living organ transplantation, simultaneous LKT may facilitate early postoperative hemodynamic stability and may induce immunotolerance and allow for low-dose immunosuppression.
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PMID:Primary hyperoxaluria: simultaneous combined liver and kidney transplantation from a living related donor. 1268 98

Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder caused by a deficiency of alanine-glyoxylate aminotransferase (AGT), which is encoded by a single copy gene (AGXT). Molecular diagnosis was used in conjunction with clinical, biochemical and enzymological data to evaluate genotype-phenotype correlation. Patients can present a severe form of PH1, an adult form and a mild to moderate decrease in renal function. Biochemical diagnosis is made by plasma, urine and dialyzate oxalate and glycolate assays, and by liver AGT activity and pyridoxine responsitivity. Molecular genetic diagnosis can be made using different techniques, for example, the single strand conformation polymorphism technique (SSCP), followed by the sequencing of the 11 AGXT exons. The disease is clinically and genetically classified as highly heterogeneous. Mutant alleles can be recognised in 80- 90% of chromosomes, depending on the techniques used. Mutations in exons 1, 2, 4 and 10 are more frequent in Italian patients. Normalized AGT activity seems to be lower in the severe form than in the adult form. Double heterozygous patients present a lower age at disease onset and they were more frequent in the more severe than in mild severe disease. The 444T>C mutation was more frequent in the severe form, while the opposite was observed for 630G>A. 630G>A mutation homozygotes had a higher AGT residual activity. The presence of allelic heterogeneity of the AGXT could be responsible, to some extent, for the phenotypic heterogeneity in PH1. Homozygous genotypes were more frequent than expected and were associated with a less severe form of the disease.
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PMID:Primary hyperoxaluria: genotype-phenotype correlation. 1276 81

Primary hyperoxaluria (PH1) is a condition caused by a hepatic-based enzyme defect which can lead to renal failure due to oxalate stone disease, obstructive uropathy and nephrocalcinosis. It has been shown that the underlying metabolic defect can be corrected by liver transplantation and in most cases (renal failure having already occurred) is accompanied by a kidney graft. This paper describes the current results of 127 liver transplants performed in 117 patients over a 20-year period from 1984 to 2004 in 35 European centres. The mean age at onset of symptoms was 5.6 +/- 7.8 years and the mean age at which a diagnosis was made was 8.8 +/- 9.5 years. The diagnosis was confirmed by liver biopsy proven decreased AGT activity in 68% of cases, hyperoxaluria in 74%, hyperglycolicaciduria in 37% and hyperoxalaemia in 50%. Patients were transplanted at a mean age of 16.5 +/- 11.4 years following a period of dialysis of 3.2 +/- 3.2 years (range 0-14.4 years). 1-, 5- and 10-year patient survival values were 86, 80 and 69%, respectively, and liver graft survival rates of 80, 72 and 60% at the same time intervals. There have been 27 deaths and 10 liver retransplants have been carried out. Patient outcomes are improved when prolonged periods on dialysis and the complications of systemic oxalosis have not occurred.
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PMID:A 20-year experience of combined liver/kidney transplantation for primary hyperoxaluria (PH1): the European PH1 transplant registry experience 1984-2004. 1596 48

In primary hyperoxaluria the deficiency or mistargeting of hepatic alanine-glyoxylate aminotransferase (AGT) leads to the overproduction of oxalate resulting in hyperoxaluria and renal damage due to urolithiasis and/or nephrocalcinosis. Presently, the cure of the metabolic defect can be achieved only by liver transplantation. While for patients with end-stage renal disease combined hepatorenal transplantation is recommended, the concept of preemptive liver transplantation (PLTX), i.e. cure of the metabolic defect before renal damage occurs, has received considerable attention. Due to the heterogenous clinical course in PH1, optimal timing of PLTX is a matter of debate. Advocators of PLTX would consider a patient with a slowly declining GFR, reaching levels of 40-60 ml/min/1.73 m(2), as an ideal candidate, while others would continue medical treatment in these patients and opt for rapid combined liver-kidney transplantation if GFR reaches even lower levels. This review will discuss the background and rationale of PLTX and gives an update on 11 patients with PLTX who have been reported in the literature to date.
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PMID:The role of preemptive liver transplantation in primary hyperoxaluria type 1. 1628 78

Failure to detoxify the intermediary metabolite glyoxylate in human hepatocytes underlies the metabolic pathology of two potentially lethal hereditary calcium oxalate kidney stone diseases, PH (primary hyperoxaluria) types 1 and 2. In order to define more clearly the roles of enzymes involved in the metabolism of glyoxylate, we have established singly, doubly and triply transformed CHO (Chinese-hamster ovary) cell lines, expressing all combinations of normal human AGT (alanine:glyoxylate aminotransferase; the enzyme deficient in PH1), GR/HPR (glyoxylate/hydroxypyruvate reductase; the enzyme deficient in PH2), and GO (glycolate oxidase). We have embarked on the preliminary metabolic analysis of these transformants by studying the indirect toxicity of glycolate as a simple measure of the net intracellular production of glyoxylate. Our results show that glycolate is toxic only to those cells expressing GO and that this toxicity is diminished when AGT and/or GR/HPR are expressed in addition to GO. This finding indicates that we have been able to reconstruct the glycolate-->glyoxylate, glyoxylate-->glycine, and glyoxylate-->glycolate metabolic pathways, catalysed by GO, AGT, and GR/HPR respectively, in cells that do not normally express them. These results are compatible with the findings in PH1 and PH2, in which AGT and GR/HPR deficiencies lead to increased oxalate synthesis, due to the failure to detoxify its immediate precursor glyoxylate. These CHO cell transformants have a potential use as a cell-based bioassay for screening small molecules that stabilize AGT or GR/HPR and might have use in the treatment of PH1 or PH2.
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PMID:Reconstruction of human hepatocyte glyoxylate metabolic pathways in stably transformed Chinese-hamster ovary cells. 1630 82

Genetic disorders of mineral metabolism cause urolithiasis, renal disease, and osteodystrophy. Most are rare, such that the full spectrum of clinical expression is difficult to appreciate. Diagnosis is further complicated by overlap of clinical features. Dent's disease and primary hyperoxaluria, inherited causes of calcium urolithiasis, are both associated with nephrocalcinosis and urolithiasis in early childhood and renal failure that can occur at any age but is seen more often in adulthood. Bone disease is an inconsistent feature of each. Dent's disease is caused by mutations of the CLCN-5 gene with impaired kidney-specific CLC-5 chloride channel expression in the proximal tubule, thick ascending limb of Henle, and the collecting ducts. Resulting hypercalciuria and proximal tubule dysfunction, including phosphate wasting, are primarily responsible for the clinical manifestations. Low-molecular-weight proteinuria is characteristic. Definitive diagnosis is made by DNA mutation analysis. Primary hyperoxaluria, type I, is due to mutations of the AGXT gene leading to deficient hepatic alanine-glyoxylate aminotransferase activity. Marked overproduction of oxalate by hepatic cells results in the hyperoxaluria responsible for clinical features. Definitive diagnosis is by liver biopsy with measurement of enzyme activity, with DNA mutation analysis used increasingly as mutations and their frequency are defined. These disorders of calcium urolithiasis illustrate the value of molecular medicine for diagnosis and the promise it provides for innovative and more effective future treatments.
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PMID:Stones, bones, and heredity. 1680 Nov 62

Glyoxylate is a 2 carbon aldo acid that is formed in hepatic tissue from glycolate. Once formed, the molecule can be converted to glycine by alanine-glyoxylate aminotransferase (AGAT). In defects of AGAT, glyoxylate is transformed to oxalate, resulting in high levels of oxalate in the body. The objective of this study was 2-fold. First, it was to determine, if akin to D-glucose, D-fructose or DL-glyceraldehyde, glyoxylate was susceptible to non-enzymatic attack by amino containing molecules such as lysine, arginine or glucosamine. Second, if by virtue of its molecular structure and size, glyoxylate was as reactive a reagent in non-enzymatic reactions as DL-glyceraldehyde; i.e., a glycose that we previously demonstrated to be a more effective glycating agent than D-glucose or D-fructose. Using capillary electrophoresis (CE), high performance liquid chromatography and UV and fluorescence spectroscopy, glyoxylate was found to be a highly reactive precursor of advanced glycation like end products (AGLEs) and a more effective promoter of non-enzymatic end products than D-glucose, D-fructose or DL-glyceraldehyde.
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PMID:Non-enzymatic interactions of glyoxylate with lysine, arginine, and glucosamine: a study of advanced non-enzymatic glycation like compounds. 1697 Sep 75

PH1 is a metabolic disorder characterized by urolithiasis and the accumulation of oxalate crystals in the kidneys and other organs. Although patients often first present with renal failure, PH1 results from a deficiency of the hepatic peroxisomal enzyme AGT. Ultimately only liver transplantation will cure the underlying metabolic defect. Herein, we report the case of a three-month-old male infant diagnosed with PH and treated using a combined liver and en bloc-kidney transplant from a single donor. At the time of transplant, the patient was 11 months old and weighed 7.9 kg. He received a full size liver graft and en bloc kidneys from a two-yr-old donor. At 36 months post-transplant, the patient is steadily growing with normal renal and hepatic function. This is one of the first reports of successful liver and en bloc-kidney transplantation with abdominal compartment expansion by PTFE for the infantile form of PH1 in a high risk child before one yr of age. Prompt diagnosis and early referral to a specialized center for liver and kidney replacement offer the best chance for survival for infants with this otherwise fatal disease.
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PMID:Successful outcome after early combined liver and en bloc-kidney transplant in an infant with primary hyperoxaluria type 1: a case report. 1968 42

PH1 (primary hyperoxaluria type 1) is a severe inborn disorder of glyoxylate metabolism caused by a functional deficiency of the peroxisomal enzyme AGXT (alanine-glyoxylate aminotransferase), which converts glyoxylate into glycine using L-alanine as the amino-group donor. Even though pre-genomic studies indicate that other human transaminases can convert glyoxylate into glycine, in PH1 patients these enzymes are apparently unable to compensate for the lack of AGXT, perhaps due to their limited levels of expression, their localization in an inappropriate cell compartment or the scarcity of the required amino-group donor. In the present paper, we describe the cloning of eight human cytosolic aminotransferases, their recombinant expression as His6-tagged proteins and a comparative study on their ability to transaminate glyoxylate, using any standard amino acid as an amino-group donor. To selectively quantify the glycine formed, we have developed and validated an assay based on bacterial GO (glycine oxidase); this assay allows the detection of enzymes that produce glycine by transamination in the presence of mixtures of potential amino-group donors and without separation of the product from the substrates. We show that among the eight enzymes tested, only GPT (alanine transaminase) and PSAT1 (phosphoserine aminotransferase 1) can transaminate glyoxylate with good efficiency, using L-glutamate (and, for GPT, also L-alanine) as the best amino-group donor. These findings confirm that glyoxylate transamination can occur in the cytosol, in direct competition with the conversion of glyoxylate into oxalate. The potential implications for the treatment of primary hyperoxaluria are discussed.
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PMID:Recombinant production of eight human cytosolic aminotransferases and assessment of their potential involvement in glyoxylate metabolism. 1954 38


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