NG，N'G-二甲基-L-精氨酸二（对羟基偶氮苯-p'-磺酸盐） | 102783-24-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: NG，N'G-二甲基-L-精氨酸二（对羟基偶氮苯-p'-磺酸盐）
• 英文名称: 4-Azaniumyl-4-carboxy-N-[(dimethylamino)(iminio)methyl]butan-1-aminide
• 英文别名: [(1S)-4-[[amino(dimethylamino)methylidene]amino]-1-carboxybutyl]azanium
• CAS: 102783-24-4
• 化学式: C8H19N4O2+
• 分子量: 203.26
• InChiKey: YDGMGEXADBMOMJ-LURJTMIESA-O

物化性质

• 熔点：
  >209°C (dec.)
• 溶解度：
  甲醇（微溶）、水（微溶）

计算性质

• 辛醇/水分配系数(LogP)：
  -3.6
• 重原子数：
  14
• 可旋转键数：
  6
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  107
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  水 、 NG，N'G-二甲基-L-精氨酸二（对羟基偶氮苯-p'-磺酸盐） 生成 dimethylammonium 、 L-瓜氨酸
  参考文献：
  名称：

  Leiper J.M.; Santa Maria J.; Chubb A., Biochem J, 1999, 0264-6021, 209-14

  摘要：

  DOI：

文献信息

• Ogawa T.; Kimoto M.; Sasaoka K., J Biol Chem, 1989, 0021-9258, 10205-9
  作者：Ogawa T.、Kimoto M.、Sasaoka K.

  DOI：——

  日期：——
• Characterization of Dimethylargininase from Bovine Brain:  Evidence for a Zinc Binding Site
  作者：Ralf Bogumil、Markus Knipp、Sibylle M. Fundel、Milan Vašák

  DOI：10.1021/bi972312t

  日期：1998.4.1

  Dimethylargininase (EC 3.5.3.18) is involved in the regulation of the levels of the natural occurring free arginine derivatives L-N-omega,N-omega-dimethylarginine and L-N-omega-methylarginine, which are reversible inhibitors of nitric oxide synthase. A dimethylargininase has been isolated from bovine brain tissue and was characterized by using immunological, kinetic, and spectroscopic techniques. Western blot analysis using polyclonal antibodies revealed that the enzyme is widely distributed in bovine with the highest relative concentrations found in brain and kidney tissue. A similar tissue distribution has also been reported for the other so far isolated dimethylargininase from rat kidney [Ogawa, T., Kimoto M., and Sasaoka, K. (1989) J. Biol. Chem. 264, 10205-10209], The bovine enzyme is a monomeric, globular protein (molecular mass approximate to 31.2 kDa) containing one tightly bound Zn2+ ion, which can be removed by dialysis against 1,10-phenanthroline. The determination of kinetic constants for both the native (holo-protein) and the zinc-depleted (apo-protein) enzyme at 37 degrees C established that the dimethylargininase is not a zinc hydrolase. The specific activity was 0.66 unit/mg for the hole-protein and 0.19 unit/mg for the apo-protein. The secondary structure determination of the native enzyme by circular dichroism revealed 41% alpha-helix and 32% beta-sheet and beta-turn structure. In the ape-enzyme, a small, but significant decrease in the alpha-helical content (5%) was observed, consistent with a marked decrease in enzymatic activity to 30%. Upon preincubation of both enzyme forms at 50 degrees C, only the hold-enzyme showed a residual enzymatic activity. In thermostability studies, a 7 degrees C lower apparent T-m value was observed for the ape-enzyme compared to the 66 degrees C for the hole-enzyme, suggesting that the zinc ion has a structure-stabilizing role. Besides the tightly bound zinc, additional Zn2+ ions inhibit the enzyme competitively with a K-i value of 2.0 mu M. A possible interrelationship between dimethylargininase and nitric oxide synthase is discussed.
• Mechanism of 4-HNE Mediated Inhibition of hDDAH-1:  Implications in No Regulation
  作者：Scott P. Forbes、Lawrence J. Druhan、Jorge E. Guzman、Narasimham Parinandi、Liwen Zhang、Kari B. Green-Church、Arturo J. Cardounel

  DOI：10.1021/bi701659n

  日期：2008.2.1

  Nitric oxide synthase is inhibited by NG-methylated derivatives of arginine whose cellular levels are controlled by dimethylarginine dimethylamino-hydrolase (DDAH). DDAH-1 is a Zn(II)containing enzyme that through hydrolysis of methylated 1-arginines regulates the activity of NOS. Herein, we report the kinetic properties of hDDAH-1 and its redox-dependent regulation. Kinetic studies using recombinant enzyme demonstrated K-m values of 68.7 and 53.6 mu M and V-max values of 356 and 154 nmols/mg/min for ADMA and L-NMMA, respectively. This enzymatic activity was selective for free ADMA and L-NMMA and was incapable of hydrolyzing peptide incorporated methylarginines. Subsequent studies performed to determine the effects of reactive oxygen and reactive nitrogen species on DDAH activity demonstrated that low level oxidant exposure had little effect on enzyme activity and that concentrations approaching >= 100 mu M were needed to confer significant inhibition of DDAH activity. However, exposure of DDAH to the lipid oxidation product, 4-HNE, dose-dependently inhibited DDAH activity with 15% inhibition observed at 10 mu M, 50% inhibition at 50 mu M, and complete inhibition at 500 mu M. Mass spectrometry analysis demonstrated that the mechanism of inhibition resulted from the formation of Michael adducts on His 173, which lies within the active site catalytic triad of hDDAH-1. These studies were performed with pathophysiologicaly relevant concentrations of this lipid peroxidation product and suggest that DDAH activity can be impaired under conditions of increased oxidative stress. Because DDAH is the primary enzyme involved in methylarginine metabolism, the loss of activity of this enzyme would result in impaired NOS activity and reduced NO bioavailability.
• Developing Dual and Specific Inhibitors of Dimethylarginine Dimethylaminohydrolase-1 and Nitric Oxide Synthase: Toward a Targeted Polypharmacology To Control Nitric Oxide
  作者：Yun Wang、Arthur F. Monzingo、Shougang Hu、Tera H. Schaller、Jon D. Robertus、Walter Fast

  DOI：10.1021/bi9007098

  日期：2009.9.15

  Molecules that block nitric oxide's (NO) biosynthesis are of significant interest. For example, nitric oxide synthase (NOS) inhibitors have been suggested as antitumor therapeutics, as have inhibitors of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme that catabolizes endogenous NOS inhibitors. Dual-targeted inhibitors hold promise as more effective reagents to block NO biosynthesis than single-targeted compounds. In this study, a small set of known NOS inhibitors are surveyed as inhibitors of recombinant human DDAH-1. From these, an alkylamidine scaffold is selected for homologation. Stepwise lengthening of one substituent converts an NOS-selective inhibitor into a dual-targeted NOS/DDAH-1 inhibitor and then into a DDAH-1 selective inhibitor, as seen in the inhibition constants of N-5-(1-iminoethyl)-, N-5-(1-iminopropyl)-, N-5-(1-iminopentyl)- and N-5-(1-iminohexyl)-L-ornithine for neuronal NOS (1.7, 3, 20, > 1,900 mu M, respectively) and DDAH-1 (990, 52, 7.5, 110 mu M, respectively). A 1.9 angstrom X-ray crystal structure of the N-5-(1-iminopropyl)-L-ornithine:DDAH-1 complex indicates covalent bond formation between the inhibitor's amidino carbon and the active-site Cys274, and solution studies show reversible competitive inhibition, consistent with a reversible covalent mode of DDAH inhibition by alkylamidine inhibitors. These represent a versatile scaffold for the development of a targeted polypharmacological approach to control NO biosynthesis.