Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee , 3210 N. Cramer Street, Milwaukee, Wisconsin 53211-3209, United States.
J Am Chem Soc. 2013 Sep 18;135(37):13980-7. doi: 10.1021/ja407384h. Epub 2013 Sep 5.
Renalase is a protein hormone secreted into the blood by the kidney that is reported to lower blood pressure and slow heart rate. Since its discovery in 2005, renalase has been the subject of conjecture pertaining to its catalytic function. While it has been widely reported that renalase is the third monoamine oxidase (monoamine oxidase C) that oxidizes circulating catecholamines such as epinephrine, there has been no convincing demonstration of this catalysis in vitro. Renalase is a flavoprotein whose structural topology is similar to known oxidases, lysine demethylases, and monooxygenases, but its active site bears no resemblance to that of any known flavoprotein. We have identified the catalytic activity of renalase as an α-NAD(P)H oxidase/anomerase, whereby low equilibrium concentrations of the α-anomer of NADPH and NADH initiate rapid reduction of the renalase flavin cofactor. The reduced cofactor then reacts with dioxygen to form hydrogen peroxide and releases nicotinamide dinucleotide product in the β-form. These processes yield an apparent turnover number (0.5 s(-1) in atmospheric dioxygen) that is at least 2 orders of magnitude more rapid than any reported activity with catechol neurotransmitters. This highly novel activity is the first demonstration of a role for naturally occurring α-NAD(P)H anomers in mammalian physiology and the first report of a flavoprotein catalyzing an epimerization reaction.
肾酶是一种由肾脏分泌到血液中的蛋白质激素，据报道可降低血压和心率。自 2005 年发现以来，肾酶的催化功能一直是人们猜测的主题。虽然广泛报道肾酶是第三种单胺氧化酶（单胺氧化酶 C），可氧化循环中的儿茶酚胺，如肾上腺素，但尚未在体外对此催化作用进行令人信服的证明。肾酶是一种黄素蛋白，其结构拓扑与已知的氧化酶、赖氨酸去甲基酶和单加氧酶相似，但它的活性位点与任何已知的黄素蛋白都没有相似之处。我们已经确定了肾酶的催化活性为 α-NAD(P)H 氧化酶/差向异构酶，其中 α-NADPH 和 NADH 的低平衡浓度会迅速还原肾酶黄素辅因子。然后，还原的辅因子与氧气反应形成过氧化氢，并以 β-形式释放烟酰胺二核苷酸产物。这些过程产生的表观周转率（在大气氧气中为 0.5 s(-1)）比任何报道的儿茶酚神经递质活性至少快 2 个数量级。这种高度新颖的活性首次证明了天然存在的 α-NAD(P)H 差向异构体在哺乳动物生理学中的作用，并且首次报道了一种黄素蛋白催化差向异构化反应。
