Copper regulates cyclic-AMP-dependent lipolysis.
Copper regulates cyclic-AMP-dependent lipolysis.
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DOI：
10.1038/nchembio.2098
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发表时间：
2016-08
影响因子：
14.8
通讯作者：
Chang CJ
中科院分区：
文献类型：
--
作者：
Krishnamoorthy L;Cotruvo JA Jr;Chan J;Kaluarachchi H;Muchenditsi A;Pendyala VS;Jia S;Aron AT;Ackerman CM;Wal MN;Guan T;Smaga LP;Farhi SL;New EJ;Lutsenko S;Chang CJ
细胞信号传导广泛依赖于氧化还原非活性金属离子（如钠、钾、钙和锌）的动态池，但它们的氧化还原活性过渡金属对应物（如铜和铁）主要作为静态酶辅因子进行研究。在这里，我们报告说，铜是一种内源性调节剂的脂肪分解，脂肪分解，这是一个重要的过程，在维持身体的重量和能量储存。利用遗传性铜失调的小鼠模型，结合铜状态的药理学改变和3 T3-L1白色脂肪细胞模型中的成像研究，我们证明了铜通过改变cAMP降解磷酸二酯酶PDE 3B的活性，在第二信使环腺苷（cAMP）的水平上调节脂解。铜-PDE 3B相互作用的生化研究确立了酶活性的铜依赖性抑制，并确定了PDE 3特异性环内的关键保守半胱氨酸残基，该残基对于观察到的铜依赖性脂解表型至关重要。
Cell signaling relies extensively on dynamic pools of redox-inactive metal ions such as sodium, potassium, calcium, and zinc, but their redox-active transition metal counterparts such as copper and iron have been studied primarily as static enzyme cofactors. Here we report that copper is an endogenous regulator of lipolysis, the breakdown of fat, which is an essential process in maintaining the body's weight and energy stores. Utilizing a murine model of genetic copper misregulation, in combination with pharmacological alterations in copper status and imaging studies in a 3T3-L1 white adipocyte model, we demonstrate that copper regulates lipolysis at the level of the second messenger, cyclic AMP (cAMP), by altering the activity of the cAMP-degrading phosphodiesterase PDE3B. Biochemical studies of the copper-PDE3B interaction establish copper-dependent inhibition of enzyme activity and identify a key conserved cysteine residue within a PDE3-specific loop that is essential for the observed copper-dependent lipolytic phenotype.