Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea.
Mol Cell. 2012 Jun 8;46(5):584-94. doi: 10.1016/j.molcel.2012.05.030.
Certain members of the peroxiredoxin (Prx) family undergo inactivation through hyperoxidation of the catalytic cysteine to sulfinic acid during catalysis and are reactivated by sulfiredoxin; however, the physiological significance of this reversible regulatory process is unclear. We now show that PrxIII in mouse adrenal cortex is inactivated by H(2)O(2) produced by cytochrome P450 enzymes during corticosterone production stimulated by adrenocorticotropic hormone. Inactivation of PrxIII triggers a sequence of events including accumulation of H(2)O(2), activation of p38 mitogen-activated protein kinase, suppression of steroidogenic acute regulatory protein synthesis, and inhibition of steroidogenesis. Interestingly, levels of inactivated PrxIII, activated p38, and sulfiredoxin display circadian oscillations. Steroidogenic tissue-specific ablation of sulfiredoxin in mice resulted in the persistent accumulation of inactive PrxIII and suppression of the adrenal circadian rhythm of corticosterone production. The coupling of CYP11B1 activity to PrxIII inactivation provides a feedback regulatory mechanism for steroidogenesis that functions independently of the hypothalamic-pituitary-adrenal axis.
某些过氧化物酶（Prx）家族成员在催化过程中，其催化半胱氨酸被过氧化物氧化为亚磺酸而失活，随后被硫氧还蛋白（sulfiredoxin）重新激活；然而，这种可逆调节过程的生理意义尚不清楚。我们现在发现，在促肾上腺皮质激素刺激下产生的皮质酮过程中，细胞色素 P450 酶产生的 H2O2 使小鼠肾上腺皮质中的 PrxIII 失活。PrxIII 的失活引发了一系列事件，包括 H2O2 的积累、p38 丝裂原活化蛋白激酶的激活、类固醇生成急性调节蛋白合成的抑制以及类固醇生成的抑制。有趣的是，失活的 PrxIII、激活的 p38 和硫氧还蛋白的水平呈现出昼夜节律性波动。在小鼠中，类固醇生成组织特异性敲除硫氧还蛋白导致失活的 PrxIII 持续积累，并抑制了肾上腺皮质酮生成的昼夜节律。CYP11B1 活性与 PrxIII 失活的偶联为类固醇生成提供了一种独立于下丘脑-垂体-肾上腺轴的反馈调节机制。
