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)

We examine the suitability of a rapid and sensitive liquid chromatographic technique to determine L-alanine:glyoxylate aminotransferase (AGT) activity in human liver. Homogenised tissue was incubated for 30 min in the presence of substrates and the generated pyruvate was converted into the corresponding phenylhydrazone which was determined using reversed-phase high-performance liquid chromatography (HPLC). The procedure allowed the detection of the enzyme activity expressed by 10 micrograms of liver protein and was rapid enough resulting more sensitive and less time-consuming than the previous colorimetric one. We found that AGT activity in two hyperoxaluria type 1 patients was reduced as compared with controls. Also, cirrhotic patients had very low enzyme activities, even in the absence of detectable disorders of oxalate metabolism and this was ascribed to abnormal liver morphology. This may represent a misleading drawback if diagnosis of type 1 primary hyperoxaluria (PH1) uniquely relies on AGT assay.
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PMID:High-performance liquid chromatographic microassay for L-alanine:glyoxylate aminotransferase activity in human liver. 149 37

Primary hyperoxaluria type 1 (PH 1), an inborn error of glyoxylate metabolism characterized by excessive synthesis of oxalate and glycolate, is caused by a defect in serine:pyruvate/alanine:glyoxylate aminotransferase (SPT/AGT). This enzyme is peroxisomal in human liver. Recently, we cloned SPT/AGT-cDNA from a PH 1 case, and demonstrated a point mutation of T to C in the coding region of the SPT/AGT gene encoding a Ser to Pro substitution at residue 205 (Nishiyama, K., T. Funai, R. Katafuchi, F. Hattori, K. Onoyama, and A. Ichiyama. 1991. Biochem. Biophys. Res. Commun. 176:1093-1099). In the liver of this patient, SPT/AGT was very low with respect to not only activity but also protein detectable on Western blot and immunoprecipitation analyses. Immunocytochemically detectable SPT/AGT labeling was also low, although it was detected predominantly in peroxisomes. On the other hand, the level of translatable SPT/AGT-mRNA was higher than normal, indicating that SPT/AGT had been synthesized in the patient's liver at least as effectively as in normal liver. Rapid degradation of the mutant SPT/AGT was then demonstrated in transfected COS cells and transformed Escherichia coli, accounting for the low level of immunodetectable mutant SPT/AGT in the patient's liver. The mutant SPT/AGT was also degraded much faster than normal in an in vitro system with a rabbit reticulocyte extract, and the degradation in vitro was ATP dependent. These results indicate that a single amino acid substitution in SPT/AGT found in the PH1 case leads to a reduced half-life of this protein. It appears that the mutant SPT/AGT is recognized in cells as an abnormal protein to be eliminated by degradation.
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PMID:ATP-dependent degradation of a mutant serine: pyruvate/alanine:glyoxylate aminotransferase in a primary hyperoxaluria type 1 case. 824 28

Considering the clinical heterogeneity of primary hyperoxaluria type I (PH1) and the fact that in many instances this diagnosis was made without enzymatic and immunohistochemical investigation, other disturbances of oxalate metabolism than those presently known can be expected in PH1. Using a gaschromatographic/mass spectrometric method that allows quantification of these acids, hyperoxaluria and hyperglycoluria was found repeatedly in two unrelated patients. The hyperoxaluria was unresponsive to pyridoxine. There was no nephrocalcinosis or urolithiasis. In the liver biopsy normal AGT activity and normal localization of this enzyme in the peroxisome was found. In one patient abnormal Km and maximal activity and mozaicism of AGT were excluded. Hyperoxaluria and hyperglycoluria were also found in other family members, suggesting autosomal dominant transmission. Although the underlying defect leading to hyperoxaluria and hyperglycoluria could not be identified in these patients, it is probable that they represent a separate type of primary hyperoxaluria.
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PMID:Hyperoxaluria with hyperglycoluria not due to alanine:glyoxylate aminotransferase defect: a novel type of primary hyperoxaluria. 891 45

The hyperoxaluria syndromes can be differentiated by the assessment of associated abnormalities in generation and urine excretion of metabolically related molecules. Based on the experience gained in our laboratory during the last decade, we have developed a comprehensive diagnostic work-up, which includes measurements of oxalate, glycolate and L-glycerate in plasma, urine and dialysis fluids, and an assay for AGT activity on liver biopsy. The availability of reliable assays for each of these parameters is indispensable for the recognition and differentiation of hyperoxalurias. Patients suspected to have abnormalities in oxalate metabolism are first screened by analysing spot urines and serum, and subsequently are subjected to more extensive studies using properly pre-treated blood samples and 24-hour urine collection. AGT activity, in the case of PH1, is assayed on few milligrams liver specimen by using a sensitive chromatographic procedure. Pertinent biochemistries will also assist in the long-term medical follow-up of these patients and in view of the choice of renal replacement or transplantation strategies.
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PMID:Biochemical approach to diagnosis and differentiation of primary hyperoxalurias: an update. 960 5

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

We describe nine novel mutations and polymorphisms occurring on the major allele of the human alanine:glyoxylate aminotransferase gene in patients with primary hyperoxaluria type 1, an autosomal recessive disease resulting from a deficiency of the liver peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT; EC 2.6.1.44). The PH1 mutations include two small frameshift mutations, 327delG and 117_118insCA, a large deletion spanning exon 9 and portions of the flanking introns, a splice junction mutation, IVS6+5G>C, and two missense mutations, G161R and S218L. Expression studies of the two missense mutations indicated very little enzymatic activity associated with either of them. Three polymorphisms in the coding sequence were also identified, I279T, A280V, and T235T. Expression studies of I279T and A280V suggested essentially normal AGT activity. I279T, found in two cases, was located on a 33_34insC allele. A280V and T235T were both located on the same allele as IVS6+5G>C. We have also identified recurrences of previously reported rare mutations, 33delC, IVS7-1G>C, and IVS4-1G>A. Five of the six novel PH1 mutations occurred in a compound heterozygous state with either of two common PH1 mutations, G170R or 33_34insC. S218L was apparently homozygous in two individuals. These findings contribute to our overall picture of heterogeneity of mutations in PH1 and the AGT major allele.
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PMID:The major allele of the alanine:glyoxylate aminotransferase gene: nine novel mutations and polymorphisms associated with primary hyperoxaluria type 1. 1596 48

We report herein a domino orthotopic liver transplantation (LT), from a 38-year-old woman undergoing liver-kidney transplantation (LKT) for primary hyperoxaluria type I (PH1) to a recipient with cirrhosis and hepatocellular carcinoma. Delayed onset of PH1 and renal failure and 10% residual alanine-glyoxylate aminotransferase (AGT) activity in domino liver justified its use for domino procedure. The clinical course after LKT was similar to that described in other series, including ours. Renal function started promptly and maintained despite sustained hyperoxaluria from dissolution of oxalotic deposits. Conversely, the domino recipient manifested severe hyperoxaluria and developed nephrolithiasis and renal insufficiency with rapid progression over 2 months. A new LT resulted in slow decrease of oxaluria and improvement of renal function. Therefore, PH1 behaved quite differently in these two patients, leading us to conclude that domino LT using livers from PH1 patients should be considered very carefully, only as a bridge to definitive LT in recipients with critical clinical conditions.
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PMID:Severe course of primary hyperoxaluria and renal failure after domino hepatic transplantation. 1609 18

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

Primary hyperoxaluria type 1 [PH1] is an autosomal recessive disorder caused by a deficiency of alanine-glyoxylate aminotransferase AGT, which is encoded by the AGXT gene. We report an Indian family with two affected siblings having a novel mutation in the AGXT gene inherited from the parents. The index case progressed to end stage renal disease at 5 months of age. His 4 month old sibling is presently under follow up with preserved renal function.
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PMID:Primary hyperoxaluria type 1 with a novel mutation. 1881 Mar 41


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