β-nicotinamide adenine dinucleotide reduced

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - （5'->5'）-二核苷酸
• 英文名称: β-nicotinamide adenine dinucleotide reduced
• 英文别名: 1,6-NADH；2-hydro-beta-NAD(2-)；[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-oxidophosphoryl] [(2R,3S,4R,5R)-5-(3-carbamoyl-2H-pyridin-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate
• 化学式: C₂₁H₂₇N₇O₁₄P₂
• 分子量: 663.431
• InChiKey: TVJJIHUATXWSJG-NNYOXOHSSA-L

计算性质

• 辛醇/水分配系数(LogP)：
  -6
• 重原子数：
  44
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  323
• 氢给体数：
  6
• 氢受体数：
  19

反应信息

• 作为反应物：
  描述：

  β-nicotinamide adenine dinucleotide reduced 、 氢(+1)阳离子 、 氧气 生成 双氧水 、 nicotinamide adenine dinucleotide
  参考文献：
  名称：

  人类肾病酶的代谢功能：抑制主要代谢的β-NAD（P）H异构形式的氧化。

  摘要：

  肾病酶是最近鉴定出的黄素蛋白，与许多生理疾病有关。仍然普遍认为肾酶起着激素的作用，通过氧化循环的儿茶酚胺（主要是肾上腺素）而对血管紧张度和心率产生影响。然而，尚未在体外令人信服地证明该活性，也未显示该转化的化学计量。在现有的工作，我们证实β-NAD（P）H的解决方案（博普雷，BA等人的低级别的污染物的那renalase诱导快速氧化（2013）。生物化学52，8929-8937;博普雷，BA等人，（2013）J.化学会会志。135，13980–13987）。缓慢的β-NAD（P）H的水物种形成导致肾酶底物分子的产生，其底物的分光光度特性和平衡分数积累与NAD（P）H的α-端基异构体报道的相近。这些基材的短暂特性使结构分配无法进行。在这里，我们在结构上分配并确定了肾脏酶的两种底物。这些分子是2-和6-dihydroNAD（P）的β-NAD（P）H的异构体，其通过β-NAD（P）+的非特异性还原

  DOI：

  10.1021/bi5013436
• 作为产物：
  描述：

  nicotinamide adenine dinucleotide 在 [(η⁶-benzene)Ru(N-(2-aminoethyl)-4-(trifluoromethyl)benzenesulfonamide(1-))Cl] 、 sodium formate 作用下， 以 氘代甲醇-d 、 重水 为溶剂， 生成 β-nicotinamide adenine dinucleotide reduced 、 NADH
  参考文献：
  名称：

  Improved Catalytic Activity of Ruthenium–Arene Complexes in the Reduction of NAD⁺

  摘要：

  A series of neutral Ru-II half-sandwich complexes of the type [(eta(6)-arene)Ru(N,N')Cl] where the arene is para-cymene (p-cym), hexamethylbenzene (hmb), biphenyl (bip), or benzene (bn) and N,N' is N-(2-aminoethyl) -4-(trifluoromethyl)benzenesulfonamide (TfEn), N-(2-aminoethyl)-4-toluenesulfonamide (TsEn), or N-(2-aminoethyl)-methylenesulfonamide (MsEn) were synthesized and characterized. X-ray crystal structures of [(p-cym)Ru(MsEn)Cl] (1), [(hmb)Ru(TsEn)Cl] (5), [(hmb)Ru(TfEn)Cl] (6), [(bip)Ru(MsEn)Cl] (7), and [(bip)Ru(TsEn)Cl] (8) have been determined. The complexes can regioselectively catalyze the transfer hydrogenation of NAD(+) to give 1,4-NADH in the presence of formate. The turnover frequencies (TOF) when the arene is varied decrease in the order bn > bip > p-cym > hmb for complexes with the same N,N' chelating ligand. The TOF decreased with variation in the N,N' chelating ligand in the order TfEn > TsEn > MsEn for a given arene. [(bn)Ru(TfEn)Cl] (12) was the most active, with a TOP of 10.4 h(-1). The effects of NAD(+) and formate concentration on the reaction rates were determined for [(p-cym)Ru(TsEn)Cl] (2). Isotope studies implicated the formation of [(arene)Ru(N,N')(H)] as the rate-limiting step. The coordination of formate and subsequent CO2 elimination to generate the hydride were modeled computationally by density functional theory (DFT). CO2 elimination occurs via a two-step process with the coordinated formate first twisting to present its hydrogen toward the metal center. The computed barriers for CO2 release for arene = benzene follow the order MsEn > TsEn > TfEn, and for the Ms En system the barrier followed bn < hmb, both consistent with the observed rates. The effect of methanol on transfer hydrogenation rates in aqueous solution was investigated. A study of pH dependence of the reaction in D2O gave the optimum pH* as 7.2 with a TOF of 1.58 h(-1) for 2. The series of compounds reported here show an improvement in the catalytic activity by an order of magnitude compared to the ethylenediamine analogues.

  DOI：

  10.1021/om3006307

文献信息

• Bacterial Renalase: Structure and Kinetics of an Enzyme with 2- and 6-Dihydro-β-NAD(P) Oxidase Activity from <i>Pseudomonas phaseolicola</i>
  作者：Matthew R. Hoag、Joseph Roman、Brett A. Beaupre、Nicholas R. Silvaggi、Graham R. Moran

  DOI：10.1021/acs.biochem.5b00451

  日期：2015.6.23

  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 β-NAD(P)H as substrates for renalase (Beaupre, B. A. et al. (2015) Biochemistry, 54, 795–806). 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 β-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 (Kd), shows a marked preference for substrates derived from β-NAD+. 2-dihydroNAD(P) substrates reduce the enzyme with rate constants (kred) that greatly exceed those for 6-dihydroNAD(P) substrates. Taken together, kred/Kd values indicate a minimum 20-fold preference for 2DHNAD. We also offer the first structures of a renalase in complex with catalytically relevant ligands β-NAD+ and β-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.

  尽管缺乏令人信服的体外证据和大量有力的反驳，但肾素酶是动物特有的酶，可催化血液中儿茶酚胺的氧化降解，从而降低血管张力，这一点已得到广泛认可。最近，我们确定了β-NAD(P)H异构体作为肾素酶的底物（Beaupre, B. A.等人，2015年，《生物化学》，54，795-806）。这些分子在烟酰胺碱的2或6位上带有氢化物当量，可能是在烟酰胺二核苷酸的非特异性氧化还原反应中产生的。肾素酶的作用是快速氧化这些异构体，形成β-NAD(P)+，然后将电子传递给双氧，形成H2O2。我们还发现这些底物分子对脱氢酶具有高度抑制作用，因此提出了这种酶在细胞内代谢中的作用。在这里，我们从没有循环系统的生物体中鉴定出一种肾素酶。这种细菌形式的肾素酶具有与人类肾素酶相同的底物特异性，但在结合常数（Kd）方面，它对来自β-NAD+的底物表现出明显的偏好。2-二氢NAD(P)底物的酶还原速率常数（kred）大大超过6-二氢NAD(P)底物的酶还原速率常数。综合来看，kred/K
• Renalase Is an α-NAD(P)H Oxidase/Anomerase
  作者：Brett A. Beaupre、Brenton R. Carmichael、Matthew R. Hoag、Dhara D. Shah、Graham R. Moran

  DOI：10.1021/ja407384h

  日期：2013.9.18

  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 alpha-NAD(P)H oxidase/anomerase, whereby low equilibrium concentrations of the alpha-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 beta-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 a-NAD(P)H anomers in mammalian physiology and the first report of a flavoprotein catalyzing an epimerization reaction.
• Improved Catalytic Activity of Ruthenium–Arene Complexes in the Reduction of NAD⁺
  作者：Joan J. Soldevila-Barreda、Pieter C. A. Bruijnincx、Abraha Habtemariam、Guy J. Clarkson、Robert J. Deeth、Peter J. Sadler

  DOI：10.1021/om3006307

  日期：2012.8.27

  A series of neutral Ru-II half-sandwich complexes of the type [(eta(6)-arene)Ru(N,N')Cl] where the arene is para-cymene (p-cym), hexamethylbenzene (hmb), biphenyl (bip), or benzene (bn) and N,N' is N-(2-aminoethyl) -4-(trifluoromethyl)benzenesulfonamide (TfEn), N-(2-aminoethyl)-4-toluenesulfonamide (TsEn), or N-(2-aminoethyl)-methylenesulfonamide (MsEn) were synthesized and characterized. X-ray crystal structures of [(p-cym)Ru(MsEn)Cl] (1), [(hmb)Ru(TsEn)Cl] (5), [(hmb)Ru(TfEn)Cl] (6), [(bip)Ru(MsEn)Cl] (7), and [(bip)Ru(TsEn)Cl] (8) have been determined. The complexes can regioselectively catalyze the transfer hydrogenation of NAD(+) to give 1,4-NADH in the presence of formate. The turnover frequencies (TOF) when the arene is varied decrease in the order bn > bip > p-cym > hmb for complexes with the same N,N' chelating ligand. The TOF decreased with variation in the N,N' chelating ligand in the order TfEn > TsEn > MsEn for a given arene. [(bn)Ru(TfEn)Cl] (12) was the most active, with a TOP of 10.4 h(-1). The effects of NAD(+) and formate concentration on the reaction rates were determined for [(p-cym)Ru(TsEn)Cl] (2). Isotope studies implicated the formation of [(arene)Ru(N,N')(H)] as the rate-limiting step. The coordination of formate and subsequent CO2 elimination to generate the hydride were modeled computationally by density functional theory (DFT). CO2 elimination occurs via a two-step process with the coordinated formate first twisting to present its hydrogen toward the metal center. The computed barriers for CO2 release for arene = benzene follow the order MsEn > TsEn > TfEn, and for the Ms En system the barrier followed bn < hmb, both consistent with the observed rates. The effect of methanol on transfer hydrogenation rates in aqueous solution was investigated. A study of pH dependence of the reaction in D2O gave the optimum pH* as 7.2 with a TOF of 1.58 h(-1) for 2. The series of compounds reported here show an improvement in the catalytic activity by an order of magnitude compared to the ethylenediamine analogues.
• Metabolic Function for Human Renalase: Oxidation of Isomeric Forms of β-NAD(P)H that Are Inhibitory to Primary Metabolism
  作者：Brett A. Beaupre、Matt R. Hoag、Joseph Roman、F. Holger Försterling、Graham R. Moran

  DOI：10.1021/bi5013436

  日期：2015.1.27

  molecules are 2- and 6-dihydroNAD(P), isomeric forms of β-NAD(P)H that arise either by nonspecific reduction of β-NAD(P)+ or by tautomerization of β-NAD(P)H (4-dihydroNAD(P)). The pure preparations of these molecules induce rapid reduction of the renalase flavin cofactor (230 s–1 for 6-dihydroNAD, 850 s–1 for 2-dihydroNAD) but bind only a few fold more tightly than β-NADH. We also show that 2- and 6-dihydroNAD(P)

  肾病酶是最近鉴定出的黄素蛋白，与许多生理疾病有关。仍然普遍认为肾酶起着激素的作用，通过氧化循环的儿茶酚胺（主要是肾上腺素）而对血管紧张度和心率产生影响。然而，尚未在体外令人信服地证明该活性，也未显示该转化的化学计量。在现有的工作，我们证实β-NAD（P）H的解决方案（博普雷，BA等人的低级别的污染物的那renalase诱导快速氧化（2013）。生物化学52，8929-8937;博普雷，BA等人，（2013）J.化学会会志。135，13980–13987）。缓慢的β-NAD（P）H的水物种形成导致肾酶底物分子的产生，其底物的分光光度特性和平衡分数积累与NAD（P）H的α-端基异构体报道的相近。这些基材的短暂特性使结构分配无法进行。在这里，我们在结构上分配并确定了肾脏酶的两种底物。这些分子是2-和6-dihydroNAD（P）的β-NAD（P）H的异构体，其通过β-NAD（P）+的非特异性还原