专肽生物_定制多肽合成服务_多肽合成定制服务_多肽合成厂家_多肽合成公司

内啡肽(Endorphin)的定义

内啡肽是由身体产生的小神经肽，用于减轻疼痛，因此被称为内啡肽（内源性吗啡的缩写）。术语“脑啡肽”（字面意思是“在头部”）也适用于内啡肽，但通常是指具有止痛特性的较小分子【1】。

Endorphins are small neuropeptides that are produced by the body and act to reduce pain hence, the name endorphin (a shortened version of endogenous morphine). The term "enkephalin" (meaning literally "in the head") is also applied to endorphins, but usually refers to smaller molecules that have pain-relieving properties【1】.

内啡肽(Endorphin)的3种相关多肽

Enkephalins: Met- and Leu-
Endorphins
Dynorphins

内啡肽是长度为2至39个氨基酸的神经肽。神经肽是在神经系统中产生和释放的肽分子，其作用类似于递质【2】。有三种不同的神经肽序列，包括脑啡肽、内啡肽和强啡肽【3】

Endorphins are neuropeptides that can range from 2 to 39 amino acids in length. Neuropeptides are peptide molecules produced and released in the nervous system that act like transmitters 【2】 There are three different neuropeptide sequences including enkephalins, endorphins, and dynorphins【3】

内啡肽(Endorphin)的发现

1975年，阿伯丁大学的John Hughes和Hans W.Kosterlitz分离出大脑中两种与阿片受体紧密结合的天然肽，并将其命名为脑啡肽。随后从垂体中分离出内啡肽分子【4】。

In 1975, John Hughes and Hans W. Kosterlitz of the University of Aberdeen isolated two naturally occurring peptides in the brain that bound tightly to the opiate receptors and named them enkephalins. The endorphin molecule was subsequently isolated from the pituitary gland 【4】.

内啡肽(Endorphin)的结构特征

迄今为止，已鉴定出四种不同的内啡肽。它们分别被称为：α-内啡肽，一种由16个残基组成的多肽；β-内啡肽，一种由31个残基组成的多肽；γ-内啡肽，一种由17个残基组成的多肽；以及S-内啡肽，一种由27个残基组成的多肽。与所有已知的多肽激素一样，这些不同类型的内啡肽以“前体”形式合成，即一种巨大的多肽，带有信号序列和在多肽翻译后成熟过程中被切割掉的额外序列。这方面最有趣的例子是垂体多激素前体，即促阿片黑素皮质素原，它包含β-促脂素、促黑素细胞激素（MSH）、内啡肽、脑啡肽和促肾上腺皮质激素（ACTH）的序列。合成后，这种肽在垂体中被切割生成ACTH和β-促脂素，而在中枢神经系统的加工过程中则产生内啡肽和脑啡肽，以及其他一些产物【5】。

Four distinct groups of endorphins have been identified to date. They have been termed: a-endorphin, a polypeptide with 16 residues; ß-endorphin, a polypeptide with 31 residues; ?-endorphin, a polypeptide with 17 residues; and S-endorphin, a polypeptide with 27 residues. These different types of endorphins, like all known polypeptide hormones, are synthesized in a "prepro" form that is one gigantic polypeptide with a signal sequence and additional sequences that are cleaved out during posttranslational maturation of the polypeptide. The most interesting example of this is the pituitary multihormone precursor termed pro-opiomelanocortin that contains the sequences for ß-lipotropin, melanocyte-stimulating hormone (MSH), endorphins, enkephalins, and adrenocorticotropic hormone (ACTH). After synthesis, this peptide is cleaved in the pituitary to generate ACTH and ß-lipotropin, while processing in the central nervous system produces endorphins and enkephalins, along with some other products 【5】.

内啡肽(Endorphin)的作用方式

受体使内啡肽能够发挥其特定功能。阿片受体是嵌入接收神经元细胞膜半流体基质中的大分子蛋白质。受体蛋白的表面包含一个区域，其大小和形状与内啡肽分子的结构精确匹配。内啡肽分子恰好嵌入特定的受体位点。神经肽与其特定受体（阿片受体）的结合会改变受体蛋白的三维结构，从而使神经元兴奋或抑制【6】。与内啡肽的情况一样，神经元的抑制会减少P物质的释放。换言之，阿片受体将内啡肽分子结构所编码的精确信息转化为特定的生理反应。因此，受体作为一种控制机制，从而调节内啡肽的功能【7】。

Receptors enable endorphins to perform their specific function. Opioid receptors are large protein molecules embedded in the semi-fluid matrix of the cell membrane of the receiving neuron. The surface of the receptor protein contains a region that is the precise size and shape to match the structure of the endorphin molecule. The endorphin molecule precisely fits into the specific receptor site. The binding of the neuropeptide with its specific receptor (opioid receptor) alters the three-dimensional shape of the receptor protein, thereby causing a neuron to be excited or inhibited【6】. As in the case of endorphins, inhibition of the neuron will reduce the release of substance P. In other words, the opioid receptor translates the precise messages encoded by the molecular structure of the endorphin molecule into a specific physiological response. Thus, receptors act as a control mechanism thereby regulating the function of endorphins【7】.

内啡肽(Endorphin)的功能

内啡肽并不被视为神经递质分子，而是被归类为神经调质，即它们通过多种与疼痛或愉悦相关的作用来调节神经递质的作用。内啡肽具有多种与缓解疼痛相关的神经学效应。外源性内啡肽（体外制备的内啡肽）的给药会刺激许多其他激素的释放，包括催乳素、促肾上腺皮质激素释放激素（ACTH）和抗利尿激素。吗啡的镇痛作用通常被认为是由其与内啡肽受体位点的结合引起的，但关于外源性内啡肽治疗的益处报道甚少。早期关于内啡肽功能的推测认为，它们是人体产生的天然止痛剂，用于在需要个体在受伤或压力下继续发挥功能的情况下缓解疼痛。这种情况的例子可能包括分娩、运动和战斗。几种治疗慢性疼痛的方法（针灸、直接电刺激大脑甚至催眠）可能通过诱导大脑和脊髓中脑啡肽或内啡肽的释放来发挥作用。这一假设基于以下发现：这些方法治疗疼痛的有效性可通过给予纳洛酮来阻断，纳洛酮是一种特异性阻断吗啡与阿片受体1结合的药物。

Endorphins are not considered to be neurotransmitter molecules, but are instead classified as neuromodulatory, that is, they modify the action of neurotransmitters through a number of effects associated with pain or pleasure. Endorphins exhibit a number of neurological effects associated with the relief of pain. The administration of exogenous endorphins (those prepared outside the body) stimulates the release of many other hormones including prolactin, ACTH, and antidiuretic hormone. The analgesic effects of morphine are commonly believed to be caused by binding to receptor sites for endorphins, but few beneficial effects of treatment with exogenous endorphins have been reported. Early speculations concerning the function of endorphins suggested that they were natural painkillers that the body produced to alleviate pain in circumstances requiring an individual to continue functioning in spite of injury or stress. Examples of such situations might include childbirth, exercise, and combat. Several procedures that treat chronic pain (acupuncture, direct electrical stimulation of the brain and even hypnosis) may act by inducing the release of enkephalins or endorphins in the brain and spinal cord. This hypothesis is based on the finding that the effectiveness of treating pain implemented by these procedures is blocked by administration of naloxone, a drug that specifically blocks the binding of morphine to the opiate receptor 【1】.

内啡肽(Endorphin)的相关文献

Book: Textbook of Biochemistry: With Clinical Correlations by Devlin TM.
Book: Animal Physiology by Eckert R.
Book: Neurobiology by Shepherd GM.
Book: The Brain by Iverson L.
Book: Molecular Expressions: Exploring the World of Optics and Microscopy Michael WD.
Book: Neural and Integrative Animal Physiology by Prosser CL.
Book:. Neuroscience by Barker RA

脑啡肽(Enkephalins)的定义

脑啡肽是在大脑和内分泌组织中高水平发现的阿片类肽。新出现的含有脑啡肽的肽的主要种类似乎是完整的前体，前脑啡肽【1】。

Enkephalins are opioid peptides that are found at high levels in the brain and endocrine tissues. The major species of newly appearing enkephalin-containing peptide appears to be the intact precursor, proenkephalin 【1】.

脑啡肽(Enkephalins)相关肽

阿片肽构成了一大类小蛋白，它们与鸦片生物碱，吗啡和海洛因相似，能与细胞膜受体相互作用。阿片生物碱衍生物广泛用于镇痛和麻醉。最初的阿片肽家族是脑啡肽，强啡肽和内啡肽。在心脏中已经发现了来自这三个阿片肽家族的代表性肽。已克隆并测序了三种不同的阿片受体：mu（µ），delta（d）和kappa（？）【2】。

Opioid peptides constitute a large group of small proteins that interact with cell membrane receptors similarly to opiate alkaloids, morphine and heroin. Opiate alkaloid derivatives are extensively used for analgesia and anesthesia. The original opioid peptide families are enkephalins, dynorphins, and endorphins. Representative peptides from these three opioid peptide families have been found in the heart. Three different opiate receptors have been cloned and sequenced: mu (µ), delta (d), and kappa (?) 【2】.

脑啡肽(Enkephalins)的发现

Kosterlitz和Hughes在1975年发现了脑啡肽和内啡肽【3】。

Kosterlitz and Hughes discovered enkephalins and endorphins in 1975 【3】.

脑啡肽(Enkephalins)的结构特征

蛋氨酸-脑啡肽（Met-Enk）的氨基酸序列为酪氨酸-甘氨酸-甘氨酸-苯丙氨酸-蛋氨酸。前脑啡肽序列包含五肽Met-Enk的四个拷贝，leu-脑啡肽之一和Met- enk的两个扩展形式（Met- enk -arg 6 -phe 7和met- enk -arg 6 -gly 7 -leu 8）。成对的碱性氨基酸标记这些小肽从前体裂解。原脑啡肽由称为原激素转化酶的内蛋白水解酶加工，该酶在二元氨基酸位点识别并切割。最初的前脑啡肽处理开始于传输到高尔基体网络之前，并且过程很快。后续处理需要在高尔基体网络远端的酸性环境中进行。前脑啡肽对肽B具有快速裂解，而较慢的裂解产生其他中等大小的产物，其最终被裂解成五肽至八肽。在各种组织（肌肉，神经，内分泌）中发现的不同分子量的最终产物可能是由于切割序列的差异和加工所需的局部酶促条件所致【2】。

The amino acid sequence of methionine-enkephalin (Met-Enk) is tyrosine-glycine-glycine-phenylalanine-methionine. The proenkephalin sequence contains four copies of the pentapeptide Met-Enk, one of leu-enkephalin, and two extended forms of Met-enk (Met-enk-arg6-phe7 and met-enk-arg6-gly7-leu8). Pairs of basic amino acids mark these small peptides for cleavage from the precursor. Proenkephalin is processed by endoproteolytic enyzmes termed prohormone convertases, which recognize and cleave at dibasic amino acid sites. Initial proenkephalin processing starts before transport to the golgi network and are rapid. Later processing requires an acidic environment distal to the golgi network. Proenkephalin has a fast cleavage to peptide B, and slower cleavages yield other intermediate sized products that are cleaved ultimately to the penta to octapeptides. The different molecular-weight end products found in diverse tissues (muscle, neural, endocrine) may be due to variations in the cleavage sequence and local enzymatic conditions for processing【2】.

脑啡肽(Enkephalins)的作用方式

肽Met-Enk和Leu-Enk（阿片受体的内源性配体）起神经调节剂或神经递质的作用。脑啡肽在哺乳动物脑中最显着的作用是神经元放电速率的降低，并且已经表明这些肽是抑制性递质。脑啡肽抑制或增强了中枢神经元对几种假定的递质的反应，表明突触后的作用。还显示脑啡肽抑制K +诱导的去甲肾上腺素，多巴胺和乙酰胆碱从大鼠脑片的释放，表明突触前的作用。脑啡肽抑制豚鼠回肠中的肌间神经元的发射。这种抑制可能是由于脑啡肽的直接突触后作用导致神经元膜超极化【4】。为了实现其生物学功能，必须将脑啡肽从水相转运至其膜结合受体蛋白的富含脂质的环境。现已知道，Met-enk通过三种主要的亚型受体起作用，分别称为μ，d和β。-受体。虽然前两个受体亚型介导了Met-enk的经典阿片样物质作用，但据报道β受体参与了该肽的非阿片样物质作用，即对细胞生长的抑制作用【5】。

Pentapeptides Met-Enk and Leu-Enk, the endogenous ligands for the opiate receptor, function as neuromodulators or neurotransmitters. The most prominent action of enkephalins in the mammalian brain is depression of neuronal firing rate and it has been suggested that these peptides are inhibitory transmitters. The response of central neurones to several putative transmitter substances is depressed or enhanced by enkephalins, suggesting a postsynaptic action. It has also been shown that enkephalins suppress the K+-induced release of noradrenaline, dopamine and acetylcholine from rat brain slices, indicating a presynaptic effect. The firing of myenteric neurones in the guinea-pig ileum is inhibited by enkephalins. This inhibition is probably due to a direct postsynaptic action of the enkephalins resulting in a hyperpolarisation of the neuronal membrane 【4】. To achieve their biological function, enkephalins must be transported from an aqueous phase to the lipid-rich environment of their membrane bound receptor proteins. It is now known that Met-enk acts via three main subtypes of receptors referred to as µ, d and ? - receptors. While the first two receptor subtypes mediate the classic opioid effects of Met-enk, ?-receptors are reported to be involved in the non-opioid actions of the peptide, i.e. the inhibitory effect on the cell growth【5】.

脑啡肽(Enkephalins)的功能

前脑啡肽是神经肽的前体，在神经内分泌和神经系统中具有多种功能。激活后，发现T辅助淋巴细胞表达高水平的前脑啡肽mRNA，并分泌大量的Met-Enk神经肽，这可能表明了免疫系统和神经系统相互作用的轴【6】。脑啡肽引起抗伤害感受和增强的吗啡镇痛作用，但它们也阻碍了耐受性和身体依赖性的发展。除了其中枢和外周镇痛作用外，阿片类药物还可以调节免疫活性和细胞增殖。此外，众所周知，它们在不同的生理过程中具有重要作用，例如细胞分化和再生，炎症，癌症和血管生成以及镇痛作用【5】。

Proenkephalin is a precursor for neuropeptides with a variety of functions in the neuroendocrine and nervous systems. Upon activation, T-helper lymphocytes were found to express high levels of proenkephalin mRNA and to secrete large amounts of the Met-Enk neuropeptide, perhaps indicating an axis by which the immune and nervous systems interact 【6】. Enkephalins cause antinociception and potentiated morphine analgesia but they also block the development of tolerance and physical dependence. In addition to their central and peripheral antinociceptive function, opioids can modulate immune activity and cell proliferation. Moreover it is known that they have significant role in different physiological processes like cell differentiation and regeneration, inflammation, cancer and angiogenesis and analgesia effects 【5】.

脑啡肽(Enkephalins)的参考文献

1、Fleminger G, Lahm HW, Udenfriend S (1984).Changes in rat adrenal catecholamines and proenkephalin metabolism after denervation. PNAS., 81(11):3587-3590.
2、Barbara A. Barron. 2000. Cardiac Opioids. Proceedings of the Society for Experimental Biology and Medicine, 224:1-7.
2、Fratta W, Yang HY, Hong J, Costa E (1977). Stability of Met-enkephalin content in brain structures of morphine-dependent or foot shock-stressed rats. Nature, 268(5619):452-453.
4、Wouters W, Den Bercken JV (1979). Hyperpolarisation and depression of slow synaptic inhibition by enkephalin in frog sympathetic ganglion. Nature, 277:53-54.
5、Tsanova A, Dacheva D, Penchev V, Georgiev G, Pajpanova T, Golovinski E, Lalchev Z (2009). Comparative study of the interaction between synthetic methionine-enkephalin and monolayers of zwitterionic and negatively 6、charged phospholipids. Biotechnol & Biotechnol., 23:463-466.
7、Rattner A, Korner M, Rosen H, Baeuerle PA, Citri Y (1991). Nuclear factor Kappa B activates proenkephalin transcription in T lymphocytes. Molecular and Cellular Biology, 11(2):1017-1022.