Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.2.1.31 (beta-glucuronidase)
 7,680 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Klotho gene mutation leads to a syndrome strangely resembling chronic kidney disease patients undergoing dialysis with multiple accelerated age-related disorders, including hypoactivity, sterility, skin thinning, muscle atrophy, osteoporosis, vascular calcifications, soft-tissue calcifications, defective hearing, thymus atrophy, pulmonary emphysema, ataxia, and abnormalities of the pituitary gland, as well as hypoglycemia, hyperphosphatemia, and paradoxically high-plasma calcitriol levels. Conversely, mice overexpressing klotho show an extended existence and a slow aging process through a mechanism that may involve the induction of a state of insulin and oxidant stress resistance. Two molecules are produced by the klotho gene, a membrane bound form and a circulating form. However, their precise biological roles and molecular functions have been only partly deciphered. Klotho can act as a circulating factor or hormone, which binds to a not yet identified high-affinity receptor and inhibits the intracellular insulin/insulin-like growth factor-1 (IGF-1) signaling cascade; klotho can function as a novel beta-glucuronidase, which deglycosylates steroid beta-glucuronides and the calcium channel transient receptor potential vallinoid-5 (TRPV5); as a cofactor essential for the stimulation of fibroblast growth factor (FGF) receptor by FGF23. The two last functions have propelled klotho to the group of key factors regulating mineral and vitamin D metabolism, and have also stimulated the interest of the nephrology community. The purpose of this review is to provide a nephrology-oriented overview of klotho and its potential implications in normal and altered renal function states.
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PMID:Klotho: an antiaging protein involved in mineral and vitamin D metabolism. 2241 41

Phosphate homeostasis is central to diverse physiologic processes including energy homeostasis, formation of lipid bilayers, and bone formation. Reduced phosphate levels due to excessive renal loss cause hypophosphatemic rickets, a disease characterized by prominent bone defects; conversely, hyperphosphatemia, a major complication of renal failure, is accompanied by parathyroid hyperplasia, hyperparathyroidism, and osteodystrophy. Here, we define a syndrome featuring both hypophosphatemic rickets and hyperparathyroidism due to parathyroid hyperplasia as well as other skeletal abnormalities. We show that this disease is due to a de novo translocation with a breakpoint adjacent to alpha-Klotho, which encodes a beta-glucuronidase, and is implicated in aging and regulation of FGF signaling. Plasma alpha-Klotho levels and beta-glucuronidase activity are markedly increased in the affected patient; unexpectedly, the circulating FGF23 level is also markedly elevated. These findings suggest that the elevated alpha-Klotho level mimics aspects of the normal response to hyperphosphatemia and implicate alpha-Klotho in the selective regulation of phosphate levels and in the regulation of parathyroid mass and function; they also have implications for the pathogenesis and treatment of renal osteodystrophy in patients with kidney failure.
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PMID:A translocation causing increased alpha-klotho level results in hypophosphatemic rickets and hyperparathyroidism. 1830 35

The discovery that two recently identified molecules, klotho and fibroblast growth factor 23 (FGF23), played an important role in calcium, phosphate, and vitamin D metabolism has transformed our traditional physiological view in which bone and mineral homeostasis was mainly regulated by parathyroid hormone, vitamin D, and calcitonin, according to mineral body needs. FGF23 is a 251-amino acid secreted protein produced by osteoblasts and osteocytes in bone following the stimulation by phosphate and vitamin D or the inhibition by dentin matrix protein 1. Originally isolated from tumoral cells of patients with tumor-induced osteomalacia and hypophosphatemia, FGF23 inhibits phosphate reabsorption in renal proximal tubular cells and 1alpha-hydroxylase activity, resulting in decreased synthesis of calcitriol. To exert these actions, FGF23 requires the conversion, by klotho, of the canonical FGF receptor 1 (IIIc) in a specific high affinity FGF23 receptor. On the other hand, klotho is a putative antiaging gene identified in 1997 when a particular mouse strain, created by random insertion mutagenesis, was found to be short-lived and displayed premature atherosclerosis, osteopenia, skin atrophy, pulmonary emphysema, hyperphosphatemia, hypercalcemia, and high serum calcitriol levels. The gene of klotho encodes a 1012-amino acid cell-surface protein with a short cytoplasmic tail and an extracellular domain that consists in tandem duplicated copies of a beta-glucuronidase-like sequence, which can be released into the circulation as soluble forms after being cleaved by metalloproteinases such as ADAM10 and ADAM17. By modulating FGF23 action, klotho regulates urinary phosphate excretion and calcitriol synthesis. By virtue of its beta-glucuronidase activity, klotho deglycosylates the calcium channel TRPV5 (transient receptor potential vallinoid-5) and regulates urinary calcium excretion. klotho also binds to Na(+),K(+)-ATPase in parathyroid cells and regulates calcium-stimulated PTH secretion. Finally, klotho extends life span via several mechanisms, including the reduction of calcitriol synthesis, serum calcium, and phosphorus levels; the induction of insulin resistance; and by increasing the resistance to oxidative stress.
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PMID:Klotho gene, phosphocalcic metabolism, and survival in dialysis. 1912 71