Disease relevance of GRHPR

• The gene encoding hydroxypyruvate reductase (GRHPR) is mutated in patients with primary hyperoxaluria type II [1].
• Hyperoxaluria is discussed relative to mutations in AGXT and GRHPR [2].
• One of the key enzymes in this pathway is glyoxylate reductase/hydroxypyruvate reductase (GRHPR) whose dysfunction in human causes primary hyperoxaluria type 2, a disease resulting in oxalate accumulation and formation of kidney stones [3].

High impact information on GRHPR

• We identified a glyoxylate reductase/hydroxypyruvate reductase (GRHPR) cDNA clone from a human liver expressed sequence tag (EST) library [1].
• The genomic structure of the human GRHPR gene was determined and contains nine exons and eight introns and spans approximately 9 kb pericentromeric on chromosome 9 [1].
• Human glyoxylate reductase/hydroxypyruvate reductase (GRHPR) is a D-2-hydroxy-acid dehydrogenase that plays a critical role in the removal of the metabolic by-product glyoxylate from within the liver [4].
• GRHPR has an unusual substrate specificity, preferring glyoxylate and hydroxypyruvate, but not pyruvate [4].
• This first crystal structure of a human GRHPR enzyme also explains the deleterious effects of naturally occurring missense mutations of this enzyme that lead to PH2 [4].

Chemical compound and disease context of GRHPR

• Molecular analysis of the glyoxylate reductase (GRHPR) gene and description of mutations underlying primary hyperoxaluria type 2 [5].

Biological context of GRHPR

• The cDNA (GLXR) is 1235 bp and consists of a predicted open reading frame of 987 bp with a 225-bp 3'-untranslated region [6].
• Because of this high proportion of homozygotes, we have used microsatellite markers in close linkage with the GRHPR gene to investigate the possibility that the patients are the offspring of related individuals [7].

Associations of GRHPR with chemical compounds

• The potential roles of LDH isoforms and GRHPR in oxalate synthesis are discussed [8].
• 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 [5].
• Glyoxylate reductase (GRHPR) has a potentially protective role metabolising glyoxylate to the less reactive glycolate [8].
• GRHPR had a higher affinity for NADPH than NADH (K(M) 0.011 mM vs. 2.42 mM) [8].

Other interactions of GRHPR

• METHODS: Polymerase chain reaction (PCR) was used to detect three common mutations in the AGXT gene (c.33_34insC, c.508G>A, and c.731T>C) and one, c.103delG, in the GRHPR gene in DNA samples from 365 unrelated individuals referred for diagnosis of PH1 and/or PH2 by liver enzyme analysis [9].
• A preliminary account of the properties of recombinant human Glyoxylate reductase (GRHPR), LDHA and LDHB with glyoxylate, and their potential roles in its metabolism [8].
• The Km values and specificity constants (Kcat/K(M)) of purified recombinant human LDHA, LDHB and GRHPR were determined for the reduction of glyoxylate and hydroxypyruvate [8].

Analytical, diagnostic and therapeutic context of GRHPR

• This was confirmed by the presence of immunoreactive GRHPR protein by western blot analysis [10].
• Novel mutation in the GRHPR gene in a Chinese patient with primary hyperoxaluria type 2 requiring renal transplantation from a living related donor [11].
• 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 [5].

References