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Chemie für Mediziner: Aminosäuren und Proteine

Oxalose (Hyperoxalurie) Typ I + II

Bei beiden autosomal-rezessiv vererbten Stoffwechsel-Krankheiten der primären Hyperoxalurie wird vermehrt Glyoxalat gebildet, das nicht weiter zu CO2 abgebaut, sondern zu Oxalat oxidiert wird. Bei Typ I ist die 2-Hydroxy-3-oxoadipat-Synthase (2-Oxoglutarat:Glyoxylat-Carboligase) betroffen, bei Typ II die D-Glycerat-Dehydrogenase. Bei normaler Nierenfunktion und reichlicher Wasserzufuhr kann die Oxalsäure über den Harn ausgeschieden werden (Oxalurie). Meist kommt es jedoch zur Bildung von Nieren- und Blasensteinen aus Calciumoxalat. Oxalat-Ablagerungen im Nieren-Parenchym können zu Niereninsuffizienz führen.

Therapie: Reichliche Flüssigkeitszufuhr und Ansäuerung des Harns (Ausschwemmung von Oxalsäure) sowie reichliche Pyridoxol-Zufuhr zur Verminderung der Oxalat-Bildung (Pyridoxol bzw. Pyridoxalphosphat ist Cofaktor der Transaminierung von Glyoxylat zu Glycin). Verboten sind Oxalat-reiche Lebensmittel, insbesondere Rhabarber, Spinat und Sauerampfer.

Abb.1

Typ I wird auch als Glycolsäure-Typ bezeichnet, weil das sich anhäufende Glyoxylat von der Glyoxylat-Reduktase reduziert und als Glycolat ausgeschieden wird.

Typ II trägt den Beinahmen L-Glycerat-Typ, da bei diesem Krankheitsbild vermehrt L-Glycerinsäure im Urin nachweisbar ist.

Eine neuere Theorie beschreibt die Typ-I-Hyperoxalurie als einen Mangel des Enzyms Alanin-Glyoxylat-Aminotrasferase und Typ II als einen Mangel von Glyoxylat-Reduktase (das zugehörige Gen GPHPR ist auch mit der Aktivität der Enzyme Hydroxypyruvat-Reduktase und D-Glycerat-Dehydrogenase verknüpft, siehe (Abb. 1) ).

Abb.2

Literatur

Karlson, P.; Gerok, W.; Groß, W. (1982): Pathobiochemie. Georg Thieme Verlag
De Pauw, L.; Toussaint, C. (1996): Primary hyperoxaluria. In: Rev. Med. Brux.. 17 (2) , 67-74
Titel des Artikels
Primary hyperoxaluria
Abstract
Primary hyperoxaluria is a rare hereditary disease. Two types have been identified. Type 1 is due to the deficiency of the liver-specific peroxisomal enzyme alanine:glyoxylate aminotransferase/serine: pyruvate amino-transferase whereas, in type 2, the deficiency concerns the glyoxylate reductase/D-glycerate dehydrogenase, a cytosolic enzyme present in the leucocytes and hepatocytes. In the elapsed decade, important progress in molecular biology led to the introduction of new strategies in the diagnosis and treatment of type 1 primary hyperoxaluria. However, the greater rarity of type 2 has so far prevented similar development. The present review recalls the normal metabolism of oxalic acid, details its deviations and their clinical consequences, and describes the methods of diagnosis and treatment to be presently recommended in primary hyperoxaluria.
Giafi, C. F.; Rumsby, G. (1998): Kinetic analysis and tissue distribution of human D-glycerate dehydrogenase/glyoxylate reductase and its relevance to the diagnosis of primary hyperoxaluria type 2.. In: Ann. Clin. Biochem.. 35 (5) , 688
Titel des Artikels
Kinetic analysis and tissue distribution of human D-glycerate dehydrogenase/glyoxylate reductase and its relevance to the diagnosis of primary hyperoxaluria type 2.
Abstract
The enzyme D-glycerate dehydrogenase (D-GDH; EC 1.1.1.29), which is also believed to have glyoxylate reductase (GR; EC 1.1.1.26/79) activity, plays a role in serine catabolism and glyoxylate metabolism and deficiency of this enzyme is believed to be the cause of primary hyperoxaluria type 2 (PH2). The pH optima and kinetic parameters of D-GDH and GR in human liver have been determined and assays developed for their measurement. Maximal activities were observed at pH 6.0, 8.0 and 7.6 for the D-GDH forward, D-GDH reverse and GR reactions, respectively. The apparent Km values for the substrates in these reactions were as follows: D-GDH forward reaction, 0.5 mmol/L hydroxypyruvate and 0.08 mmol/L NADPH; D-GDH reverse reaction, 20 mmol/L D-glycerate and 0.03 mmol/L NADP and for the GR reaction 1.25 mmol/L glyoxylate and 0.33 mmol/L NADPH. The forward D-GDH and GR assays were adopted for routine use, the low activity of the reverse D-GDH reaction being of little use for routine analyses. D-GDH and GR activity in 13 normal livers ranged from 350-940 nmol per min per mg protein (median 547) and 129-209 nmol per min per mg protein (median 145), respectively. D-GDH activity in kidney, lymphocytes and fibroblasts fell within the range of values seen in the liver but GR activity was approximately 30% in the kidney and barely detectable in lymphocytes and fibroblasts. Analysis of liver and lymphocyte samples from patients with PH2 showed that GR activity was either very low or undetectable while D-GDH activity was reduced in liver but within the normal range in lymphocytes. These results suggest that there is more than one enzyme with D-GDH activity in human tissues but only one of these has significant GR activity. We conclude that a definitive diagnosis of PH2 requires measurement of GR and D-GDH in a liver biopsy.
Cregeen, D. P.; Williams, E. L.; Hulton, S.; Rumsby, G. (2003): Molecular analysis of the glyoxylate reductase (GRHPR) gene and description of mutations underlying primary hyperoxaluria type 2.. In: Hum. Mutat.. 22 (6) , 497
Titel des Artikels
Molecular analysis of the glyoxylate reductase (GRHPR) gene and description of mutations underlying primary hyperoxaluria type 2.
Abstract
Primary hyperoxaluria type 2, an inherited autosomal recessive disorder of endogenous oxalate overproduction, is caused by mutations in the GRHPR gene encoding the glyoxylate/hydroxypyruvate reductase enzyme. The GRHPR genes from nineteen unrelated patients with PH2 were analysed for mutations using a combination of PCR-SSCP and sequence analysis of genomic and cDNA. Eleven mutations were identified, seven of which are novel. The mutations included five point mutations: c.84-2A>G, c.295C>T (R99X), c.494G>A (G165D), and c.904C>T (R302C) as well as six minor deletions: c.103delG, c.375delG, c.403_405+2 delAAGT, c.540delT, c.608_609delCT and a more complex mutation in intron 1: c.84-13_c.84-12del; c.84-8_c.84-5del. Aberrant transcripts were demonstrated in hepatic mRNA as a result of the c.403_405+2 delAAGT and c.84-2A>G mutations. In addition, a splice variant lacking 28 bp of exon 1 was expressed in a number of tissues but is of unknown function. Two polymorphisms, c.579A>G in exon 6 and a (CT)(n) microsatellite in intron 8 were identified. Expression studies showed that the G165D and R302C mutants had glyoxylate reductase activity 1.5 and 5.6% respectively of the wild type protein. Both mutant proteins were unstable on purification. Although there is wide expression of the GRHPR mRNA demonstrated by northern blot analysis, our study shows that GRHPR protein distribution is predominantly hepatic and concludes that PH2, like the related type 1 disease, is primarily a disorder affecting hepatic glyoxylate metabolism.

Schema des Glyoxylat-Metabolismus bei Kegg Pathway

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