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首页> 外文期刊>Biochemistry >Bacterial Renalase: Structure and Kinetics of an Enzyme with 2-and 6-Dihydro-beta-NAD(P) Oxidase Activity from Pseudomonas phaseolicola
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Bacterial Renalase: Structure and Kinetics of an Enzyme with 2-and 6-Dihydro-beta-NAD(P) Oxidase Activity from Pseudomonas phaseolicola

机译：细菌肾病酶：具有Pseudomonas phaseolicola的2-和6-dihydro-beta-NAD（P）氧化酶活性的酶的结构和动力学

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Despite a lack of convincing in vitro evidence and a number of sound refutations, it is widely accepted that renalase is an enzyme unique to animals that catalyzes the oxidative degradation of catecholamines in blood in order to lower vascular tone. Very recently, we identified isomers of beta-NAD(P)H as substrates for renalase (Beaupre, B. A. et al. (2015) Biochemistry, 54, 795806). These molecules carry the hydride equivalent on the 2 or 6 position of the nicotinamide base and presumably arise in nonspecific redox reactions of nicotinamide dinucleotides. Renalase serves to rapidly oxidize these isomers to form beta-NAD(P)(+) and then pass the electrons to dioxygen, forming H2O2. We have also shown that these substrate molecules are highly inhibitory to dehydrogenase enzymes and thus have proposed an intracellular metabolic role for this enzyme. Here, we identify a renalase from an organism without a circulatory system. This bacterial form of renalase has the same substrate specificity profile as that of human renalase but, in terms of binding constant (K-d), shows a marked preference for substrates derived from beta-NAD(+). 2-dihydroNAD(P) substrates reduce the enzyme with rate constants (k(red)) that greatly exceed those for 6-dihydroNAD(P) substrates. Taken together, k(red)/K-d values indicate a minimum 20-fold preference for 2DHNAD. We also offer the first structures of a renalase in complex with catalytically relevant ligands beta-NAD(+) and beta-NADH (the latter being an analogue of the substrate(s)). These structures show potential electrostatic repulsion interactions with the product and a unique binding orientation for the substrate nicotinamide base that is consistent with the identified activity.
机译：尽管缺乏令人信服的体外证据和许多合理的反驳，但肾病酶是动物特有的酶，可催化血液中儿茶酚胺的氧化降解以降低血管张力。最近，我们确定了β-NAD（P）H的异构体是肾酶的底物（Beaupre，B. A.等人（2015）Biochemistry，54，795806）。这些分子在烟酰胺碱基的2或6位带有氢化物当量，并可能在烟酰胺二核苷酸的非特异性氧化还原反应中出现。肾素酶用于迅速氧化这些异构体以形成β-NAD（P）（+），然后将电子传递给双氧，形成H2O2。我们还显示了这些底物分子对脱氢酶具有高度抑制作用，因此提出了该酶的细胞内代谢作用。在这里，我们从没有循环系统的生物体中鉴定出一种肾脏酶。这种细菌形式的肾酶具有与人肾酶相同的底物特异性特征，但是就结合常数（K-d）而言，显示出对衍生自β-NAD（+）的底物的明显偏好。 2-dihydroNAD（P）底物可降低酶的速率常数（k（red）），该常数大大超过6-dihydroNAD（P）底物的速率常数。总而言之，k（红色）/ K-d值表示2DHNAD的最小20倍偏好。我们还提供了具有催化相关配体β-NAD（+）和β-NADH（后者是底物的类似物）的复合酶中肾酶的第一个结构。这些结构显示出与产物的潜在静电排斥相互作用，以及底物烟酰胺碱的独特结合方向，与确定的活性一致。

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