脂解
铜
化学
磷酸二酯酶
生物化学
铜缺乏
酶
细胞生物学
生物
脂肪组织
有机化学
作者
Lakshmi Krishnamoorthy,Joseph A. Cotruvo,Jefferson Chan,Harini Kaluarachchi,Abigael Muchenditsi,Venkata Pendyala,Shang Jia,Allegra T. Aron,Cheri M. Ackerman,Mark N. Vander Wal,Timothy Guan,Lukas P. Smaga,Samouil L. Farhi,Elizabeth J. New,Svetlana Lutsenko,Christopher J. Chang
标识
DOI:10.1038/nchembio.2098
摘要
Biochemical analysis, and imaging using a copper-sensitive fluorescent sensor, demonstrate that copper regulates cAMP-mediated lipolysis by inhibiting the activity of the cAMP-degrading phosphodiesterase PDE3B. 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 body weight and energy stores. Using a mouse model of genetic copper misregulation, in combination with pharmacological alterations in copper status and imaging studies in a 3T3-L1 white adipocyte model, we found 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 in a PDE3-specific loop that is essential for the observed copper-dependent lipolytic phenotype.
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