Alanine glyoxylate aminotransferase and the urinary excretion of oxalate and glycollate in hyperoxaluria type I and the Zellweger syndrome

Wanders, Ronald J. A.; Roermund, C. W. T. van; Westra, Ronald L.; Schutgens, R. B. H.; Ende, M. Van Den; Tager, J. M.; Monnens, L.A.H.; Baadenhuysen, H.; Govaerts, L.; Przyrembel, Hildegard; Wolff, Ed; Blom, W.; Huijmans, J. G. M.; Laerhoven, F.G.M. van

doi:10.1016/0009-8981(87)90176-8

Cited by 32 publications

(12 citation statements)

References 27 publications

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“…This is suggested by the fact that a third of patients with primary hyperoxaluria type 1 have disease, because AGT is redirected away from the peroxisomes toward the mitochondria (1). In addition, some patients with peroxisome biogenesis disorders, such as Zellweger syndrome, in which AGT becomes stuck in the cytosol, have marked hyperoxaluria (40,41). If the PTS1A, in addition to the PTS1, is a determinant of AGT peroxisomal import efficiency, then naturally occurring amino acid replacements in this region might be expected to affect this efficiency.…”

Section: Cell Context Dependence Of the Interaction Between Humanmentioning

confidence: 99%

Peroxisomal Import of Human Alanine:glyoxylate Aminotransferase Requires Ancillary Targeting Information Remote from Its C Terminus

Huber

Birdsey

Lumb

et al. 2005

Journal of Biological Chemistry

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Although human alanine:glyoxylate aminotransferase (AGT) is imported into peroxisomes by a Pex5p-dependent pathway, the properties of its C-terminal tripeptide (KKL) are unlike those of any other type 1 peroxisomal targeting sequence (PTS1). We have previously suggested that AGT might possess ancillary targeting information that enables its unusual PTS1 to work. In this study, we have attempted to locate this information and to determine whether or not it is a characteristic of all vertebrate AGTs. Using the two-hybrid system, we show that human AGT interacts with human Pex5p in mammalian cells, but not yeast cells. Using (immuno)fluorescence microscopic analysis of the distribution of various constructs expressed in COS cells, we show the following. 1) The putative ancillary peroxisomal targeting information (PTS1A) in human AGT is located entirely within the smaller C-terminal structural domain of 110 amino acids, with the sequence between Val-324 and Ile-345 being the most likely candidate region. 2) The PTS1A is present in all mammalian AGTs studied (human, rat, guinea pig, rabbit, and cat), but not amphibian AGT (Xenopus). 3) The PTS1A is necessary for peroxisomal import of human, rabbit, and cat AGTs, but not rat and guinea pig AGTs. We speculate that the internal PTS1A of human AGT works in concert with the C-terminal PTS1 by interacting with Pex5p indirectly with the aid of a yet-to-be-identified mammal-specific adaptor molecule. This interaction might reshape the tetratricopeptide repeat domain allosterically, enabling it to accept KKL as a functional PTS1.Alanine:glyoxylate aminotransferase (AGT, 1 EC 2.6.1.44) catalyzes the transamination of the intermediary metabolite glyoxylate to glycine. A deficiency of AGT, as occurs in the hereditary disease primary hyperoxaluria type 1, allows glyoxylate to be oxidized to oxalate instead. The resulting increased synthesis and excretion of oxalate leads to the deposition of insoluble calcium oxalate in the kidney and urinary tract and, ultimately, renal failure (1). AGT is normally peroxisomal in human liver, but in a subset of primary hyperoxaluria type 1 patients it is mistargeted to mitochondria (2). Although the molecular basis of the peroxisome-to-mitochondrion mistargeting of AGT in primary hyperoxaluria type 1 has been subjected to extensive investigation (3-6), its normal targeting to peroxisomes has received much less attention (7,8).Peroxisomal import of human AGT is dependent on the presence of the type 1 peroxisomal targeting sequence (PTS1) receptor Pex5p, but not the PTS2 receptor Pex7p (7). However, several features of the peroxisomal targeting of AGT are unusual when compared with the targeting of other peroxisomal proteins. The C-terminal tripeptide of human AGT is KKL (9), which has a two-out-of-three match with the prototypical consensus PTS1 of (S/A/C)(K/R/H)(L/M) (10, 11). KKL is necessary for peroxisomal targeting of human AGT but insufficient to direct the peroxisomal targeting of reporter proteins, such as bacterial chloramphenicol acetyl...

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Section: Cell Context Dependence Of the Interaction Between Humanmentioning

confidence: 99%

Peroxisomal Import of Human Alanine:glyoxylate Aminotransferase Requires Ancillary Targeting Information Remote from Its C Terminus

Huber

Birdsey

Lumb

et al. 2005

Journal of Biological Chemistry

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“…Ultrathin sections of Unicryl embedded samples were incubated with polyclonal antibodies against PMK (11) or the peroxisomal alanine/glyoxylate aminotransferase (AGT) (20), decorated with colloidal gold, and examined by electron microscopy as previously described (18) (19). Negative controls were incubated with normal rabbit serum.…”

Section: Immunocytochemistry Of Liver Samplesmentioning

confidence: 99%

Phosphomevalonate kinase is a cytosolic protein in humans

Hogenboom

Tuyp

Espeel

et al. 2004

Journal of Lipid Research

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In the past decade, a predominant peroxisomal localization has been reported for several enzymes functioning in the presqualene segment of the cholesterol/isoprenoid biosynthesis pathway. More recently, however, conflicting results have been reported raising doubts about the postulated role of peroxisomes in isoprenoid biosynthesis, at least in humans. In this study, we have determined the subcellular localization of human phosphomevalonate kinase using a variety of biochemical and microscopic techniques, including conventional subcellular fractionation studies, digitonin permeabilization studies, immunofluorescence, and immunoelectron microscopy. We found an exclusive cytosolic localization of both endogenously

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“…1. Figure 1 also shows the absense of cross-reactive immunological material in a patient who was earlier found to be fully deficient with regard to AGT (see 8).…”

Section: Sds Polyacrylamide Gel Electrophoresis and Immunoblot Analysismentioning

confidence: 99%

“…Subsequently, the precipitates were removed by centrifugation as described above and pyruvate and 2-oxoglutarate were measured in the supernatants, respectively. Pyruvate and 2-oxoglutarate were measured as described by Wanders et al 8 All enzyme activity measurements were carried out in quadruplicate.…”

Section: Chemicalsmentioning

confidence: 99%

Re-Evaluation of Conditions Required for Measurement of True Alanine:Glyoxylate Aminotransferase Activity in Human Liver: Implications for the Diagnosis of Hyperoxaluria Type I

Horvath

Wanders

1994

Ann Clin Biochem

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SUMMARY. In this paper we studied the glyoxy1ate-dependent transamination of Lalanine and L-glutamate in human liver homogenates in order to develop a reliable method for the determination of true alanine:glyoxylate aminotransferase activity in liver homogenates from patients suspected to suffer from hyperoxaluria type 1. Measurements were made according to two protocols described in literature in control human liver homogenates which were either untreated or treated with an antiserum raised against purified alanine:glyoxylate aminotransferase. The results obtained show that enzyme activity can best be determined at pH 8.0 as compared to pH 7.4 since the former leads to a higher sensitivity of the method. Alanine:glyoxylate aminotransferase activities measured at pH 8.0 are approximately 50070 higher compared to the enzyme activities measured at pH 7.4. Accordingly, it is proposed to measure alanine:glyoxylate aminotransferase activity at pH 8.0 using the newly determined correction factor as described in this paper.

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Alanine glyoxylate aminotransferase and the urinary excretion of oxalate and glycollate in hyperoxaluria type I and the Zellweger syndrome

Cited by 32 publications

References 27 publications

Peroxisomal Import of Human Alanine:glyoxylate Aminotransferase Requires Ancillary Targeting Information Remote from Its C Terminus

Peroxisomal Import of Human Alanine:glyoxylate Aminotransferase Requires Ancillary Targeting Information Remote from Its C Terminus

Phosphomevalonate kinase is a cytosolic protein in humans

Re-Evaluation of Conditions Required for Measurement of True Alanine:Glyoxylate Aminotransferase Activity in Human Liver: Implications for the Diagnosis of Hyperoxaluria Type I

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