Prigge S T, Kolhekar A S, Eipper B A, Mains R E, Amzel L M
Department of Biophysics and Biophysical Chemistry, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Science. 1997 Nov 14;278(5341):1300-5. doi: 10.1126/science.278.5341.1300.
Many neuropeptides and peptide hormones require amidation at the carboxyl terminus for activity. Peptidylglycine alpha-amidating monooxygenase (PAM) catalyzes the amidation of these diverse physiological regulators. The amino-terminal domain of the bifunctional PAM protein is a peptidylglycine alpha-hydroxylating monooxygenase (PHM) with two coppers that cycle through cupric and cuprous oxidation states. The anomalous signal of the endogenous coppers was used to determine the structure of the catalytic core of oxidized rat PHM with and without bound peptide substrate. These structures strongly suggest that the PHM reaction proceeds via activation of substrate by a copper-bound oxygen species. The mechanistic and structural insight gained from the PHM structures can be directly extended to dopamine beta-monooxygenase.
许多神经肽和肽类激素需要在羧基末端进行酰胺化才能发挥活性。肽基甘氨酸α-酰胺化单加氧酶（PAM）催化这些多种生理调节因子的酰胺化反应。双功能PAM蛋白的氨基末端结构域是一种肽基甘氨酸α-羟化单加氧酶（PHM），含有两个通过铜离子和亚铜离子氧化态循环的铜离子。利用内源性铜离子的异常信号确定了结合和未结合肽底物的氧化大鼠PHM催化核心的结构。这些结构有力地表明，PHM反应是通过与铜结合的氧物种激活底物来进行的。从PHM结构中获得的机理和结构见解可直接扩展到多巴胺β-单加氧酶。
