Enzymatic interconversion of the oxysterols 7β,25-dihydroxycholesterol and 7-keto,25-hydroxycholesterol by 11β-hydroxysteroid dehydrogenase type 1 and 2
Enzymatic interconversion of the oxysterols 7β,25-dihydroxycholesterol and 7-keto,25-hydroxycholesterol by 11β-hydroxysteroid dehydrogenase type 1 and 2
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DOI：
10.1016/j.jsbmb.2019.03.011
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发表时间：
2019-06-01
影响因子：
4.1
通讯作者：
Odermatt, Alex
中科院分区：
文献类型：
--
作者：
Beck, Katharina R.;Kanagaratnam, Sharavan;Odermatt, Alex
氧化甾醇是通过自氧化或酶促过程产生的胆固醇代谢物。它们由一个与多种病理进展相关的生物活性脂类大家族组成。为了揭示与氧化甾醇有关的（病理）生理机制，阐明氧化甾醇的形成和降解是至关重要的。11种β -羟基类固醇脱氢酶（11 β - hsds）通过催化7-酮胆固醇（7kC）和7- β -羟基胆固醇（7 β OHC）的相互转化在氧甾醇代谢中的作用已经有报道。本研究探讨了11 β - hsd1在7-酮- 25-羟基胆固醇（7k25OHC）酶促生成7 β，25-二羟基胆固醇（7 β 25OHC）中的作用，并测试了11 β - hsd2是否能够催化该逆反应。利用重组酶首次证实了胆固醇25-羟化酶（CH25H）将7kC转化为7k25OHC，并通过人和小鼠11 β - hsd1进一步立体定向氧化还原为7 β - 25OHC。此外，利用人11 β - hsd2进行的实验表明，7 β - 25OHC被氧化为7k25OHC。分子模型解释了7 β 25OHC和7k25OHC的立体定向相互转化。Epstein-Barr病毒诱导的基因2 （EBI2）配体7 β - 25OHC在11 β - hsd1攻毒组织中的7k25OHC产生可能在炎症中很重要。总之，这些结果证明了一种新的糖皮质激素非依赖性受体前调节由11 β - hsd介导。
Oxysterols are cholesterol metabolites derived through either autoxidation or enzymatic processes. They consist of a large family of bioactive lipids that have been associated with the progression of multiple pathologies. In order to unravel (patho-)physiological mechanisms involving oxysterols, it is crucial to elucidate the underlying formation and degradation of oxysterols. A role of 11 beta-hydroxysteroid dehydrogenases (11 beta-HSDs) in oxysterol metabolism by catalyzing the interconversion of 7-ketocholesterol (7kC) and 7 beta-hydroxycholesterol (7 beta OHC) has already been reported. The present study addresses a function of 11 beta-HSD1 in the enzymatic generation of 7 beta,25-dihydroxycholesterol (7 beta 25OHC) from 7-keto,25-hydroxycholesterol (7k25OHC) and tested whether 11 beta-HSD2 is able to catalyze the reverse reaction. For the first time, using recombinant enzymes, the formation of 7k25OHC from 7kC by cholesterol 25-hydroxylase (CH25H) and further stereospecific oxoreduction to 7 beta 25OHC by human and mouse 11 beta-HSD1 could be demonstrated. Additionally, experiments using human 11 beta-HSD2 showed the oxidation of 7 beta 25OHC to 7k25OHC. Molecular modeling provided an explanation for the stereospecific interconversion of 7 beta 25OHC and 7k25OHC. Production of the Epstein-Barr virus-induced gene 2 (EBI2) ligand 7 beta 25OHC from 7k25OHC in challenged tissue by 11 beta-HSD1 may be important in inflammation. In conclusion, these results demonstrate a novel glucocorticoid-independent pre-receptor regulation mediated by 11 beta-HSDs.