title: The 11 beta-hydroxysteroid dehydrogenase type II enzyme: biochemical consequences of the congenital R337C mutation.
abstract: The 11 beta-hydroxysteroid dehydrogenase type II enzyme (11 beta HSD2) converts cortisol to cortisone, allowing the non-selective mineralocorticoid receptor to bind aldosterone. When the activity of this enzyme is compromised, as occurs in licorice intoxication or in the congenital syndrome of apparent mineralocorticoid excess (AME), there is marked sodium retention, hypokalemia, and hypertension. The first proof that this enzyme was defective in AME came from the identification of the R337C mutation in a number of siblings with the syndrome. Subsequent expression studies showed that the mutant had a Km one order of magnitude higher than the wild-type enzyme while in the cell-free system it was without detectable activity. In the present work we have extended our studies on this mutant and provide evidence that the mutant protein may also partially inhibit the wild-type enzyme in heterozygotes. Furthermore, experiments incorporating the protein synthesis inhibitor cycloheximide show that the mutant enzyme is less stable than the wild-type activity in intact cells. These results suggest that mutations in the 11 beta HSD2 enzyme may have multiple consequences for the mineralocorticoid target cell.
authors: Laboratory of Molecular Hypertension, Baker Medical Research Institute, Melbourne, Australia.
authors: P
authors: P
authors: Ferrari
authors: V R
authors: VR
authors: Obeyesekere
authors: K
authors: K
authors: Li
authors: R K
authors: RK
authors: Andrews
authors: Z S
authors: ZS
authors: Krozowski
mesh_terms: D042842:11-beta-Hydroxysteroid Dehydrogenases; D000818:Animals; D002460:Cell Line / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D004795:Enzyme Stability; D005816:Genetic Complementation Test; D006579:Heterozygote; D006854:Hydrocortisone / Q000378:metabolism; D006913:Hydroxysteroid Dehydrogenases / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D009154:Mutation; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D014162:Transfection
chemical_list: D011500:Protein Synthesis Inhibitors; D003513:Cycloheximide; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases; D006854:Hydrocortisone