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首页> 外文期刊>Biochemistry >Kinetics and Equilibria of the Reductive and Oxidative Half-Reactions of Human Renalase with α?NADPH
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Kinetics and Equilibria of the Reductive and Oxidative Half-Reactions of Human Renalase with α?NADPH

机译：人肾素酶与α？NADPH的还原和氧化半反应的动力学和平衡

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Renalase is a recently discovered flavoprotein that has been reported to be a hormone produced by the kidney to down-modulate blood pressure and heart rate. The consensus belief has been that renalase oxidizes circulating catecholamine neurotransmitters thereby attenuating vascular tone. However, a convincing in vitro demonstration of this activity has not been made. We have recently discovered that renalase has α-NAD(P)H oxidase/anomerase activity. Unlike most naturally occurring nucleotides, NAD(P)H can accumulate small amounts of the α-anomers that once oxidized are configurationally stable and unable to participate in cellular activity. Thus, anomerization of NAD(P)H would result in a continual loss of cellular redox currency. As such, it appears that the root purpose of renalase is to return α-anomers of nicotinamide dinucleotides to the β-anomer pool. In this article, we measure the kinetics and equilibria of renalase in turnover with α-NADPH. Renalase is selective for the α-anomer, which binds with a dissociation constant of ～20 ± 3 μM. This association precedes monophasic two-electron reduction of the FAD cofactor with a rate constant of 40.2 ± 1.3 s~(?1). The reduced enzyme then delivers both electrons to dioxygen in a second-order reaction with a rate constant of ～2900 M~(?1) s~(?1). Renalase has modest affinity for its β-NADP~+ product (K_d = 2.2 mM), and the FAD cofactor has a reduction potential of ?155 mV that is unaltered by saturating β-NADP~+. Together these data suggest that the products are formed and released in a kinetically ordered sequence (β-NADP~+ then H_2O_2), however, the reoxidation of renalase is not contingent on the dissociation of β-NADP~+. Neither the oxidized nor the reduced form of renalase is able to catalyze anomerization, implying that the redox and anomerization chemistries are inextricably linked through a common intermediate.
机译：肾病酶是最近发现的一种黄素蛋白，据报道是一种由肾脏产生的激素，可下调血压和心率。公认的信念是肾酶氧化循环的儿茶酚胺神经递质，从而减弱血管张力。但是，还没有令人信服的体外证明这种活性。我们最近发现，肾酶具有α-NAD（P）H氧化酶/异构酶活性。与大多数天然存在的核苷酸不同，NAD（P）H可以积累少量的α-异头物，一旦被氧化，它们的构型就稳定并且无法参与细胞活性。因此，NAD（P）H的异构化将导致细胞氧化还原货币的持续损失。这样，看来肾酶的根本目的是使烟酰胺二核苷酸的α-端基异构体返回到β-端基异构体库中。在本文中，我们测量了α-NADPH转化过程中肾酶的动力学和平衡。肾病酶对α-端基异构体具有选择性，该端基的解离常数为〜20±3μM。这种结合在FAD辅因子的单相两电子还原之前，速率常数为40.2±1.3 s〜（？1）。被还原的酶然后以〜2900 M〜（？1）s〜（？1）的速率常数将两个电子同时传递给双氧。肾病酶对其β-NADP〜+产物具有适度的亲和力（K_d = 2.2 mM），FAD辅因子的还原电位约为155 mV，这不会因饱和β-NADP〜+而改变。这些数据一起表明，产物是以动力学有序的顺序形成和释放的（β-NADP〜+，然后是H_2O_2），但是，肾酶的再氧化并不取决于β-NADP〜+的解离。肾酶的氧化形式或还原形式均不能催化异构化，这意味着氧化还原和异构化化学物质通过共同的中间体密不可分地相连。

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