Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.1.2.13 (aldolase)
 3,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Perturbations in glyoxylate metabolism lead to the accumulation of oxalate and give rise to primary hyperoxalurias, recessive disorders characterized by kidney stone disease. Loss-of-function mutations in HOGA1 (formerly DHDPSL) are responsible for primary hyperoxaluria type III. HOGA1 is a mitochondrial 4-hydroxy-2-oxoglutarate aldolase catalyzing the fourth step in the hydroxyproline pathway. We investigated hydroxyproline metabolites in the urine of patients with primary hyperoxaluria type III using gas chromatography-mass spectroscopy. Significant increases in concentrations of 4-hydroxy-2-oxoglutarate and its precursor and derivative 4-hydroxyglutamate and 2,4-dihydroxyglutarate, respectively, were found in all patients as compared to carriers of the corresponding mutations or healthy controls. Despite a functional block in the conversion of hydroxyproline to glyoxylate--the immediate precursor of oxalate--the production of oxalate increases. To explain this apparent contradiction, we propose a model of glyoxylate compartmentalization in which cellular glyoxylate is normally prevented from contact with the cytosol where it can be oxidized to oxalate. We propose that HOGA1 deficiency results in the accumulation of 4-hydroxy-2-oxoglutarate in the mitochondria and its transport into the cytosol where it is converted to glyoxylate by a different cytosolic aldolase. In human hepatocyte cell lines, we detected a cytosolic 4-hydroxy-2-oxoglutarate aldolase activity not due to HOGA1. These studies provide a diagnostic tool for primary hyperoxaluria type III and shed light on glyoxylate metabolism and the pathogenesis of primary hyperoxalurias.
 ...
PMID:Primary hyperoxaluria type III--a model for studying perturbations in glyoxylate metabolism. 2272 92

Primary hyperoxaluria (PH) is a very rare genetic disorder; it is characterized by total or partial deficiency of the enzymes related to the metabolism of glyoxylate, with an overproduction of calcium oxalate that is deposited in different organs, mainly the kidney, leading to recurrent lithiasis, nephrocalcinosis and end stage renal disease (ESRD). In patients with ESRD that receive kidney transplantation alone, the disease has a relapse of 100%, with graft loss in a high percentage of patients in the first 5 years of transplantation. Three molecular disorders have been described in PH: mutation of the gene alanin glioxalate aminotransferase (AGXT); glyoxalate reductase/hydroxy pyruvate reductase (GRHPR) and 4-OH-2-oxoglutarate aldolase (HOGA1). We present two cases of patients with a history of renal lithiasis who were diagnosed with primary hyperoxaluria in the post-transplant period, manifested by early graft failure, with evidence of calcium oxalate crystals in renal biopsy, hyperoxaluria, hyperoxalemia, and genetic test compatible; they were managed with proper diet, abundant oral liquids, pyridoxine, hydrochlorothiazide and potassium citrate; however, they had slow but progressive deterioration of their grafts function until they reached end-stage chronic renal disease.
 ...
PMID:Primary hiperoxaluria diagnosed after kidney transplantation: report of 2 cases and literature review. 2931 75