N-ε-羧甲基-L-赖氨酸 | 5746-04-3

• 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: N-ε-羧甲基-L-赖氨酸
• 中文别名: NΕ-(1-羧甲基)-L-赖氨酸
• 英文名称: N⁶-carboxymethyllysine
• 英文别名: CML；N^ε-(carboxymethyl)lysine；N^ε-(1-carboxymethyl)-L-lysine；(2S)-2-azaniumyl-6-(carboxylatomethylazaniumyl)hexanoate
• CAS: 5746-04-3
• 化学式: C₈H₁₆N₂O₄
• 分子量: 204.226
• InChiKey: NUXSIDPKKIEIMI-LURJTMIESA-N

物化性质

• 熔点：
  280°C (dec.)
• 沸点：
  428.9±45.0 °C(Predicted)
• 密度：
  1?+-.0.06 g/cm3(Predicted)
• 溶解度：
  可微溶于水（微溶、加热、超声处理）

计算性质

• 辛醇/水分配系数(LogP)：
  -5.2
• 重原子数：
  14
• 可旋转键数：
  8
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  113
• 氢给体数：
  4
• 氢受体数：
  6

ADMET

代谢

尿素毒素往往会因为饮食过量或者肾脏过滤功能不佳而在血液中积聚。大多数尿素毒素是代谢废物，通常通过尿液或粪便排出。

Uremic toxins tend to accumulate in the blood either through dietary excess or through poor filtration by the kidneys. Most uremic toxins are metabolic waste products and are normally excreted in the urine or feces.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 毒性总结

尿毒症毒素如羧甲基赖氨酸通过有机离子转运体（尤其是OAT3）积极运输到肾脏中。尿毒症毒素水平的增加可以刺激活性氧种类的产生。这似乎是通过尿毒症毒素直接结合或抑制NADPH氧化酶酶（尤其是肾脏和心脏中丰富的NOX4）（A7868）来介导的。活性氧种类可以诱导几种不同的DNA甲基转移酶（DNMTs），这些酶参与沉默一种名为KLOTHO的蛋白质。KLOTHO已被确定在抗衰老、矿物质代谢和维生素D代谢中具有重要作用。许多研究表明，在急性或慢性肾脏疾病中，由于局部活性氧种类水平升高，KLOTHO mRNA和蛋白质水平会降低（A7869）。

Uremic toxins such as carboxymethyllysine are actively transported into the kidneys via organic ion transporters (especially OAT3). Increased levels of uremic toxins can stimulate the production of reactive oxygen species. This seems to be mediated by the direct binding or inhibition by uremic toxins of the enzyme NADPH oxidase (especially NOX4 which is abundant in the kidneys and heart) (A7868). Reactive oxygen species can induce several different DNA methyltransferases (DNMTs) which are involved in the silencing of a protein known as KLOTHO. KLOTHO has been identified as having important roles in anti-aging, mineral metabolism, and vitamin D metabolism. A number of studies have indicated that KLOTHO mRNA and protein levels are reduced during acute or chronic kidney diseases in response to high local levels of reactive oxygen species (A7869).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 致癌物分类

对人类不具有致癌性（未被国际癌症研究机构IARC列名）。

No indication of carcinogenicity to humans (not listed by IARC).

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 健康影响

长期暴露于尿毒症毒素可能会导致多种疾病，包括肾脏损伤、慢性肾病和心血管疾病。

Chronic exposure to uremic toxins can lead to a number of conditions including renal damage, chronic kidney disease and cardiovascular disease.

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 暴露途径

内源性的，摄入，皮肤（接触）

Endogenous, Ingestion, Dermal (contact)

来源:Toxin and Toxin Target Database (T3DB)

毒理性

• 症状

作为尿毒症毒素，这种化合物可以引起尿毒症综合征。尿毒症综合征可能影响身体的任何部位，并可能导致恶心、呕吐、食欲丧失和体重减轻。它还可能引起精神状态的变化，如混乱、意识减退、躁动、精神疾病、癫痫和昏迷。还可能出现异常出血，例如在非常轻微的损伤后自发或大量出血。心脏问题，如心律不齐、心脏包膜（心包炎）炎症和心脏压力增加，也可能出现在尿毒症综合征患者身上。由于肺部和胸壁之间（胸腔积液）的液体积聚导致的呼吸急促也可能出现。

As a uremic toxin, this compound can cause uremic syndrome. Uremic syndrome may affect any part of the body and can cause nausea, vomiting, loss of appetite, and weight loss. It can also cause changes in mental status, such as confusion, reduced awareness, agitation, psychosis, seizures, and coma. Abnormal bleeding, such as bleeding spontaneously or profusely from a very minor injury can also occur. Heart problems, such as an irregular heartbeat, inflammation in the sac that surrounds the heart (pericarditis), and increased pressure on the heart can be seen in patients with uremic syndrome. Shortness of breath from fluid buildup in the space between the lungs and the chest wall (pleural effusion) can also be present.

来源:Toxin and Toxin Target Database (T3DB)

安全信息

• 海关编码：
  2922499990
• 储存条件：
  -20°C，密闭保存，干燥conditions

制备方法与用途

Nε-(1-羧甲基)-L-赖氨酸（CML）是一种晚期糖基化终产物（AGE），它在氧化应激过程中由糖基化的蛋白质发生氧化修饰而产生。

反应信息

• 作为反应物：
  描述：

  N-ε-羧甲基-L-赖氨酸 、 1-((4-(氟-18F)苯甲酰基)氧基)-2,5-吡咯烷二酮 在 碳酸氢钠 、 sodium carbonate 作用下， 反应 0.33h， 生成
  参考文献：
  名称：

  一种18F-SFB-CML的用途及检测动脉粥样硬 化的方法

  摘要：

  本发明涉及核医学技术领域，涉及一种 18 F‑SFB‑CML的用途及检测动脉粥样硬化的方法；首先，本发明提供了一种 18 F‑SFB‑CML在制备检测动脉粥样硬化疾病产品中的用途，并提供一种检测动脉粥样硬化的方法，所述方法为采用 18 F‑SFB‑CML作为显像剂，通过分子成像扫描获取动脉粥样硬化斑块位置、大小和血管腔狭窄程度的信息；本发明所述的 18 F‑SFB‑CML作为显影剂，能够准确的反映出斑块的大小和血管腔狭窄程度，并且可有效示踪动脉粥样硬化斑块。

  公开号：

  CN109453401B
• 作为产物：
  描述：

  L-赖氨酸甲酸盐 在 盐酸 、 sodium hydroxide 、 乙酸酐 作用下， 反应 40.5h， 生成 N-ε-羧甲基-L-赖氨酸
  参考文献：
  名称：

  Identification of the Carboxymethyllysine Residue in the Advanced Stage of Glycated Human Serum Albumin.

  摘要：

  作为糖化的高级阶段，糖化人血清白蛋白（G-HSA；葡萄糖含量为2mol的5-羟甲基糠醛当量/mol的HSA）在37°C的0.2M磷酸盐缓冲液（pH 7.4）中与100 μM Fe3+一起孵育长达30天。孵育30天后的G-HSA（G-HSA-30(Fe)）随后在6N HCl中于110°C水解24小时。在水解产物中，通过与合成的CML在氨基酸分析仪上共同色谱，识别出了N2-羧甲基赖氨酸（CML）。HSA的等电点（pI）从4.8变为G-HSA的4.5。在G-HSA-30(Fe)中出现了一个更酸性的部分，pI为4.3。HSA和G-HSA中的CML含量（CML的摩尔数与HSA的摩尔数之比）如下：HSA中为0，HSA-30(Fe)中为0.2，G-HSA中为0.4，在G-HSA-30(Fe)的pI 4.3中为1.5。随着反应的进行，氨基酸组成在赖氨酸、精氨酸和酪氨酸方面也发生了变化。

  DOI：

  10.1248/cpb.40.705

文献信息

• AMINO ACID AMIDES OF PHENOXYBUTYRIC ACID DERIVATIVES
  申请人：LALEZARI IRAJ

  公开号：US20120232120A1

  公开（公告）日：2012-09-13

  A compound of the formula: where X is phenyl substituted at the 3, 4 and 5 positions with R1, R2 or R3 which are selected from hydrogen, chloro, lower alkyl of 1 to 5 carbons, phenoxy, phenyl, naphthyl, or phenyl (lower) alkyl where the lower alkyl group has 1-5 carbon atoms and m is 0 or 1; Y is —CONH— or —NHCONH— where the nitrogen atoms are unsubstituted or substituted with other phenoxyisobutyric acid derivatives, or the residue of a phenoxyisobutyric acid and n is 0 or 1; Z is unsubstituted phenyl when m is 1 and n is 1; when Y is 0, X is 0; Z is also substituted.

  式的化合物： 其中X是苯基，取代在3、4和5位与R1、R2或R3，它们从氢、氯、1至5个碳原子的低烷基、苯氧基、苯基、萘基或苯基（低）烷基中选择，其中低烷基基团有1-5个碳原子，m为0或1；Y为—CONH—或—NHCONH—，其中氮原子未取代或取代为其他苯氧异丁酸衍生物，或苯氧异丁酸的残基，n为0或1；当m为1且n为1时，Z为未取代的苯基；当Y为0时，X为0；Z也被取代。
• 13C-Nuclear Magnetic Resonance spectroscopy as a probe of enzyme environment—II
  作者：Ian J.G. Climie、David A. Evans

  DOI：10.1016/0040-4020(82)80213-5

  日期：1982.1

  proton-decoupled 13C-nuclear magnetic resonance spectra have been determined and in almost all cases, each carbon resonance has been unambiguously assigned by a combination of off-resonance and specific decoupling techniques. The effect of solvent and pH on chemical shifts is discussed. The objective of these studies is to provide models relevant to the use of 13C-labelled electrophilic inhibitors as probes of enzyme

  报道了氨基和羧基保护的赖氨酸，丝氨酸和半胱氨酸以及两个三肽的侧链衍生物的合成和表征。已确定了宽带质子去耦的13 C核磁共振波谱，并且在几乎所有情况下，通过共振和特定的去耦技术的组合，每个碳共振都得到了明确的分配。讨论了溶剂和pH值对化学位移的影响。这些研究的目的是提供与使用13 C标记的亲电子抑制剂作为酶活性位点环境探针有关的模型。
• Biocatalytic Reversal of Advanced Glycation End Product Modification
  作者：Nam Y. Kim、Tyler N. Goddard、Seungjung Sohn、David A. Spiegel、Jason M. Crawford

  DOI：10.1002/cbic.201900158

  日期：2019.9.16

  Advanced glycation end products (AGEs) are a heterogeneous group of molecules that emerge from the condensation of sugars and proteins through the Maillard reaction. Despite a significant number of studies showing strong associations between AGEs and the pathologies of aging-related illnesses, it has been a challenge to establish AGEs as causal agents primarily due to the lack of tools in reversing

  高级糖基化终产物（AGEs）是通过梅拉德反应从糖和蛋白质的缩合中出现的一种异质分子。尽管大量研究表明AGEs与衰老相关疾病的病理之间有很强的联系，但由于缺乏在分子水平上逆转AGE修饰的工具，将AGEs确立为病因一直是一个挑战。在这里，我们显示MnmC，一种参与细菌tRNA修饰途径的酶，能够将AGEs羧乙基赖氨酸（CEL）和羧甲基赖氨酸（CML）还原回其天然赖氨酸结构。结合结构同源性分析，定点诱变和蛋白质结构域解剖研究，我们产生了一种MnmC变体，其游离氨基酸形式对CEL具有改进的催化性能。我们表明，这种酶变异体对CEL修饰的拟肽和已建立为AGEs（RAGE）受体的真正配体的含AGE肽也具有活性。我们的数据表明，MnmC变体是有望发展AGE逆转工具和更好地了解AGE生物学的主要催化剂。
• Age Inhibitors
  申请人：Potier Pierre

  公开号：US20080249030A1

  公开（公告）日：2008-10-09

  The invention relates to a compound having general formula I, wherein: X represents CH 2 , C═O, C═S or CHOH, X represents CH 2 , C═O, C═S or CHOH, R 1 represents an amino acid which is optionally substituted by one or more halogen atoms, preferably fluorine, or by one or more CF 3 groups and n=0.1 or 2, or X represents CH 2 , C═O, C═S, CHOH, R 1 represents a peptide containing two amino acids, each amino acid being optionally substituted by one or more halogen atoms, preferably fluorine, or by one or more CF 3 groups and n=0 or 1, or XR 1 represent PO 3 H or SO 3 H and n=0.1 or 2; R 2 represents H, XR 1 , an alkyl group at C 1 -C 6 , an aralkyl group at C 1 -C 6 or an aryl group, whereby the alkyl, aralkyl and aryl groups can be substituted by an amine NH 2 , a carboxylic group COOH, one or more halogen atoms, preferably fluorine, or one or more CF 3 groups; or the pharmaceutically-acceptable addition salts, isomers, enantiomers and diastereoisomers of said compound, mixtures thereof, and pharmaceutical or cosmetic compositions comprising same and the use thereof as an AGE-inhibitor drug that traps reactive carbonyl compounds.

  该发明涉及一种具有一般式I的化合物，其中：X代表CH2、C═O、C═S或CHOH，X代表CH2、C═O、C═S或CHOH，R1代表一种氨基酸，该氨基酸可以选择性地被一个或多个卤素原子（优选为氟）或一个或多个CF3基团取代，n=0.1或2，或者X代表CH2、C═O、C═S、CHOH，R1代表含有两个氨基酸的肽，每个氨基酸可以选择性地被一个或多个卤素原子（优选为氟）或一个或多个CF3基团取代，n=0或1，或者XR1代表PO3H或SO3H，n=0.1或2；R2代表H、XR1、C1-C6的烷基、C1-C6的芳基烷基或芳基，其中烷基、芳基烷基和芳基可以被氨基NH2、羧基COOH、一个或多个卤素原子（优选为氟）或一个或多个CF3基团取代；或者所述化合物的药学上可接受的加合盐、异构体、对映体和二对映异构体，其混合物，以及包含其的制药或化妆品组合物及其作为捕捉反应性羰基化合物的AGE抑制剂药物的用途。
• Novel α-Oxoamide Advanced-Glycation Endproducts within the <i>N</i>⁶-Carboxymethyl Lysine and <i>N</i>⁶-Carboxyethyl Lysine Reaction Cascades
  作者：Tim Baldensperger、Tobias Jost、Alexander Zipprich、Marcus A. Glomb

  DOI：10.1021/acs.jafc.7b05813

  日期：2018.2.28

  either glyoxal or methylglyoxal were used to further elucidate the underlying mechanisms of the N6-carboxymethyl lysine and N6-carboxyethyl lysine reaction cascades. After independent synthesis of the authentic reference standards, we were able to detect N6-glyoxylyl lysine and N6-pyruvoyl lysine for the first time by HPLC-MS2 analyses. These two novel amide advanced-glycation endproducts were exclusively

  高反应性的α-二羰基化合物乙二醛和甲基乙二醛是体内翻译后蛋白质修饰的主要前体。的模型孵育Ñ 2 -吨-Boc赖氨酸和任一乙二醛或甲基乙二醛被用来进一步阐明的基本机制Ñ 6 -carboxymethyl赖氨酸和Ñ 6羧乙基赖氨酸反应级联。的可信参考标准独立合成后，我们能够检测Ñ 6 -glyoxylyl赖氨酸和Ñ 6通过HPLC-MS -pyruvoyl赖氨酸首次2分析。这两种新的酰胺高级糖化终产物仅在充气条件下形成，表明它们是氧化应激的有效标志物。类似于众所周知的从氨基酸到Strecker酸的Strecker降解途径，烯胺中间体的氧化被认为是关键的机械步骤。开发了一种用于测定组织中AGEs的高度灵敏的检测方法。为了支持我们的假设，水平ñ 6 -glyoxylyl赖氨酸和ñ 6 -pyruvoyl赖氨酸在大鼠肝脏确实有肝硬化和老化有关。