Ferrari P, Obeyesekere V R, Li K, Andrews R K, Krozowski Z S
Laboratory of Molecular Hypertension, Baker Medical Research Institute, Melbourne, Australia.
Steroids. 1996 Apr;61(4):197-200. doi: 10.1016/0039-128x(96)00013-x.
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.
11β-羟类固醇脱氢酶2型（11βHSD2）可将皮质醇转化为可的松，使非选择性盐皮质激素受体能够结合醛固酮。当该酶的活性受损时，如在甘草中毒或先天性假性醛固酮增多症（AME）综合征中发生的那样，会出现明显的钠潴留、低钾血症和高血压。该酶在AME中存在缺陷的首个证据来自于对多名患有该综合征的兄弟姐妹中R337C突变的鉴定。随后的表达研究表明，在无细胞系统中，该突变体的米氏常数（Km）比野生型酶高一个数量级，且无检测到的活性。在本研究中，我们扩展了对该突变体的研究，并提供证据表明突变蛋白在杂合子中也可能部分抑制野生型酶。此外，加入蛋白质合成抑制剂环己酰亚胺的实验表明，在完整细胞中，突变酶的稳定性低于野生型活性。这些结果表明，11βHSD2酶的突变可能对盐皮质激素靶细胞产生多种影响。
