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抗痛素、Antipain

一種可逆的絲氨酸和半胱氨酸蛋白酶抑制劑,其活性譜與亮肽相當(dāng)。

編號(hào):451665

CAS號(hào):37691-11-5/37682-72-7

單字母:H2N-FCORVLRH-OH

糾錯(cuò)
  • 編號(hào):451665
    中文名稱(chēng):抗痛素、Antipain
    英文名:Antipain
    CAS號(hào):37691-11-5,freebase
    37682-72-7,二鹽酸鹽
    單字母:H2N-FCORVLRH-OH
    三字母:H2N

    N端氨基

    -Phe

    苯丙氨酸

    -Cys

    半胱氨酸

    -Orn

    鳥(niǎo)氨酸

    -Arg

    精氨酸

    -Val

    纈氨酸

    -Leu

    亮氨酸

    -Arg

    精氨酸

    -His

    組氨酸

    -OH

    C端羧基

    氨基酸個(gè)數(shù):8
    分子式:C27H44N10O6
    平均分子量: 604.71
    等電點(diǎn)(PI):-
    pH=7.0時(shí)的凈電荷數(shù):4.18
    平均親水性:-0.18571428571429
    疏水性值:0.16
    消光系數(shù):-
    標(biāo)簽:氨基酸衍生物肽    抑制劑相關(guān)肽(Inhibitor Peptide)    癌癥研究肽   

  • 一種可逆的絲氨酸和半胱氨酸蛋白酶抑制劑,其活性譜與亮肽相當(dāng)。在轉(zhuǎn)染活化的H-ras癌基因后,止痛藥抑制了NIH3T3細(xì)胞的轉(zhuǎn)化(Cox等人)。Vaccari等人使用antipain來(lái)評(píng)估蛋白酶在BALB/c 3T3細(xì)胞惡性轉(zhuǎn)化過(guò)程中的作用。

    A reversible inhibitor of Ser and Cys proteases with an activity spectrum comparable to leupeptin. Antipain inhibited transformation of NIH3T3 cells after transfection with an activated H-ras oncogene (Cox et al.). Vaccari et al. used antipain for evaluating the role of proteases in the process of malignant transformation of BALB/c 3T3 cells.

    定義
    酶是用于生化反應(yīng)的非常有效的催化劑。它們通過(guò)提供較低活化能的替代反應(yīng)途徑來(lái)加快反應(yīng)速度。酶作用于底物并產(chǎn)生產(chǎn)物。一些物質(zhì)降低或什至停止酶的催化活性被稱(chēng)為抑制劑。
    發(fā)現(xiàn)
    1965年,Umezawa H分析了微生物產(chǎn)生的酶抑制劑,并分離出了抑制亮肽素和抗痛藥的胰蛋白酶和木瓜蛋白酶,乳糜蛋白酶抑制的胰凝乳蛋白酶,胃蛋白酶抑制素抑制胃蛋白酶,泛磷酰胺抑制唾液酸酶,烏藤酮抑制酪氨酸羥化酶,多巴汀抑制多巴胺3-羥硫基嘧啶和多巴胺3-羥色胺酶酪氨酸羥化酶和多巴胺J3-羥化酶。最近,一種替代方法已應(yīng)用于預(yù)測(cè)新的抑制劑:合理的藥物設(shè)計(jì)使用酶活性位點(diǎn)的三維結(jié)構(gòu)來(lái)預(yù)測(cè)哪些分子可能是抑制劑1。已經(jīng)開(kāi)發(fā)了用于識(shí)別酶抑制劑的基于計(jì)算機(jī)的方法,例如分子力學(xué)和分子對(duì)接。
    結(jié)構(gòu)特征
    已經(jīng)確定了許多抑制劑的晶體結(jié)構(gòu)。已經(jīng)確定了三種與凝血酶復(fù)合的高效且選擇性的低分子量剛性肽醛醛抑制劑的晶體結(jié)構(gòu)。這三種抑制劑全部在P3位置具有一個(gè)新的內(nèi)酰胺部分,而對(duì)胰蛋白酶選擇性最高的兩種抑制劑在P1位置具有一個(gè)與S1特異性位點(diǎn)結(jié)合的胍基哌啶基。凝血酶的抑制動(dòng)力學(xué)從慢到快變化,而對(duì)于胰蛋白酶,抑制的動(dòng)力學(xué)在所有情況下都快。根據(jù)兩步機(jī)理2中穩(wěn)定過(guò)渡態(tài)絡(luò)合物的緩慢形成來(lái)檢驗(yàn)動(dòng)力學(xué)。
    埃米爾•菲舍爾(Emil Fischer)在1894年提出,酶和底物都具有特定的互補(bǔ)幾何形狀,彼此恰好契合。這稱(chēng)為“鎖和鑰匙”模型3。丹尼爾·科什蘭(Daniel Koshland)提出了誘導(dǎo)擬合模型,其中底物和酶是相當(dāng)靈活的結(jié)構(gòu),當(dāng)?shù)孜锱c酶4相互作用時(shí),活性位點(diǎn)通過(guò)與底物的相互作用不斷重塑。
    在眾多生物活性肽的成熟過(guò)程中,需要由其谷氨酰胺(或谷氨酰胺)前體形成N末端焦谷氨酸(pGlu)。游離形式并與底物和三種咪唑衍生抑制劑結(jié)合的人QC的結(jié)構(gòu)揭示了類(lèi)似于兩個(gè)鋅外肽酶的α/β支架,但有多個(gè)插入和缺失,特別是在活性位點(diǎn)區(qū)域。幾種活性位點(diǎn)突變酶的結(jié)構(gòu)分析為針對(duì)QC相關(guān)疾病5的抑制劑的合理設(shè)計(jì)提供了結(jié)構(gòu)基礎(chǔ)。
    作用方式
    酶是催化化學(xué)反應(yīng)的蛋白質(zhì)。酶與底物相互作用并將其轉(zhuǎn)化為產(chǎn)物。抑制劑的結(jié)合可以阻止底物進(jìn)入酶的活性位點(diǎn)和/或阻止酶催化其反應(yīng)。抑制劑的種類(lèi)繁多,包括:非特異性,不可逆,可逆-競(jìng)爭(zhēng)性和非競(jìng)爭(zhēng)性??赡嬉种苿?nbsp;以非共價(jià)相互作用(例如疏水相互作用,氫鍵和離子鍵)與酶結(jié)合。非特異性抑制方法包括最終使酶的蛋白質(zhì)部分變性并因此不可逆的任何物理或化學(xué)變化。特定抑制劑 對(duì)單一酶發(fā)揮作用。大多數(shù)毒藥通過(guò)特異性抑制酶發(fā)揮作用。競(jìng)爭(zhēng)性抑制劑是任何與底物的化學(xué)結(jié)構(gòu)和分子幾何結(jié)構(gòu)非常相似的化合物。抑制劑可以在活性位點(diǎn)與酶相互作用,但是沒(méi)有反應(yīng)發(fā)生。非競(jìng)爭(zhēng)性抑制劑是與酶相互作用但通常不在活性位點(diǎn)相互作用的物質(zhì)。非競(jìng)爭(zhēng)性抑制劑的凈作用是改變酶的形狀,從而改變活性位點(diǎn),從而使底物不再能與酶相互作用而產(chǎn)生反應(yīng)。非競(jìng)爭(zhēng)性抑制劑通常是可逆的。不可逆抑制劑與酶形成牢固的共價(jià)鍵。這些抑制劑可以在活性位點(diǎn)附近或附近起作用。
    功能
    工業(yè)應(yīng)用中, 酶在商業(yè)上被廣泛使用,例如在洗滌劑,食品和釀造工業(yè)中。蛋白酶用于“生物”洗衣粉中,以加速蛋白質(zhì)在諸如血液和雞蛋等污漬中的分解。商業(yè)上使用酶的問(wèn)題包括:它們是水溶性的,這使得它們難以回收,并且一些產(chǎn)物可以抑制酶的活性(反饋抑制)。
    藥物分子,許多藥物分子都是酶抑制劑,藥用酶抑制劑通常以其特異性和效力為特征。高度的特異性和效力表明該藥物具有較少的副作用和較低的毒性。酶抑制劑在自然界中發(fā)現(xiàn),并且也作為藥理學(xué)和生物化學(xué)的一部分進(jìn)行設(shè)計(jì)和生產(chǎn)6。
    天然毒物 通常是酶抑制劑,已進(jìn)化為保護(hù)植物或動(dòng)物免受天敵的侵害。這些天然毒素包括一些已知最劇毒的化合物。
    神經(jīng)氣體( 例如二異丙基氟磷酸酯(DFP))通過(guò)與絲氨酸的羥基反應(yīng)生成酯,從而抑制了乙酰膽堿酯酶的活性位點(diǎn)。
    參考
    1、Scapin G (2006). Structural biology and drug discovery. Curr. Pharm. Des.,      12(17):2087–2097.
    2、Krishnan R, Zhang E, Hakansson K, Arni RK, Tulinsky A, Lim-Wilby MS, Levy OE, Semple JE, Brunck TK (1998). Highly selective mechanism-based thrombin inhibitors:  structures of thrombin and trypsin inhibited with rigid peptidyl aldehydes. Biochemistry, 37 (35):12094-12103.
    3、Fischer E (1894). Einfluss der configuration auf die wirkung der enzyme. Ber. Dt. Chem. Ges., 27:2985–2993.
    4、Koshland DE (1958). Application of a theory of enzyme specificity to protein synthesis. PNAS., 44 (2):98–104.
    5、Huang KF, Liu YL, Cheng WJ, Ko TP, Wang AH (2005). Crystal structures of human glutaminyl cyclase, an enzyme responsible for protein N-terminal pyroglutamate formation. PNAS., 102(37):13117-13122.
    6、Holmes CF, Maynes JT, Perreault KR, Dawson JF, James MN (2002). Molecular enzymology underlying regulation of protein phosphatase-1 by natural toxins. Curr Med Chem., 9(22):1981-1989.

     

    Definition
    Enzymes are very efficient catalysts for biochemical reactions. They speed up reactions by providing an alternative reaction pathway of lower activation energy. Enzyme acts on substrate and gives rise to a product. Some substances reduce or even stop the catalytic activities of enzymes are called inhibitors.

    Discovery
    In 1965, Umezawa H analysed enzyme inhibitors produced by microorganisms and isolated leupeptin and antipain inhibiting trypsin and papain, chymostatin inhibiting chymotrypsin, pepstatin inhibiting pepsin, panosialin inhibiting sialidases, oudenone inhibiting tyrosine hydroxylase, dopastin inhibiting dopamine 3-hydroxylase, aquayamycin and chrothiomycin inhibiting tyrosine hydroxylase and dopamine J3-hydroxylase . Recently, an alternative approach has been applied to predict new inhibitors: rational drug design uses the three-dimensional structure of an enzyme's active site to predict which molecules might be inhibitors 1. Computer-based methods for identifying inhibitor for an enzyme have been developed, such as molecular mechanics and molecular docking.

    Structural Characteristics
    The crystal structures of many inhibitors have been determined. The crystal structures of three highly potent and selective low-molecular weight rigid peptidyl aldehyde inhibitors complexed with thrombin have been determined. All the three inhibitors have a novel lactam moiety at the P3 position, while the two with greatest trypsin selectivity have a guanidinopiperidyl group at the P1 position that binds in the S1 specificity site. The kinetics of inhibition vary from slow to fast with thrombin and are fast in all cases with trypsin. The kinetics are examined in terms of the slow formation of a stable transition-state complex in a two-step mechanism 2.

    Emil Fischer in 1894 suggested that both the enzyme and the substrate possess specific complementary geometric shapes that fit exactly into one another.This is known as "the lock and key" model 3. Daniel Koshland suggested induced fit model where substrate and enzymes are rather flexible structures, the active site is continually reshaped by interactions with the substrate as the substrate interacts with the enzyme 4.

    N-terminal pyroglutamate (pGlu) formation from its glutaminyl (or glutamyl) precursor is required in the maturation of numerous bioactive peptides. The structure of human QC in free form and bound to a substrate and three imidazole-derived inhibitors reveals an alpha/beta scaffold akin to that of two-zinc exopeptidases but with several insertions and deletions, particularly in the active-site region. The structural analyses of several active-site-mutant enzymes provide a structural basis for the rational design of inhibitors against QC-associated disorders 5.

    Mode of Action
    Enzymes are proteins that catalyze chemical reactions. Enzymes interact with substrate and convert them into products. Inhibitor binding can stop a substrate from entering the enzyme's active site and/or hinder the enzyme from catalyzing its reaction. There are a variety of types of inhibitors including: nonspecific, irreversible, reversible - competitive and noncompetitive. Reversible inhibitors bind to enzymes with non-covalent interactions like hydrophobic interactions, hydrogen bonds, and ionic bonds. Non-specific methods of inhibition include any physical or chemical changes which ultimately denature the protein portion of the enzyme and are therefore irreversible. Specific Inhibitors exert their effects upon a single enzyme. Most poisons work by specific inhibition of enzymes. A competitive inhibitor is any compound which closely resembles the chemical structure and molecular geometry of the substrate. The inhibitor may interact with the enzyme at the active site, but no reaction takes place. A noncompetitive inhibitor is a substance that interacts with the enzyme, but usually not at the active site.  The net effect of a non competitive inhibitor is to change the shape of the enzyme and thus the active site, so that the substrate can no longer interact with the enzyme to give a reaction. Non competitive inhibitors are usually reversible. Irreversible Inhibitors form strong covalent bonds with an enzyme.  These inhibitors may act at, near, or remote from the active site .

    Functions
    Industrial application, enzymes are widely used commercially, for example in the detergent, food and brewing industries. Protease enzymes are used in 'biological' washing powders to speed up the breakdown of proteins in stains like blood and egg. Problems using enzymes commercially include: they are water soluble which makes them hard to recover and some products can inhibit the enzyme activity (feedback inhibition) .

    Drug molecules, many drug molecules are enzyme inhibitors and a medicinal enzyme inhibitor is usually characterized by its specificity and its potency. A high specificity and potency suggests that a drug will have fewer side effects and less toxic. Enzyme inhibitors are found in nature and are also designed and produced as part of pharmacology and biochemistry 6.

    Natural poisons are often enzyme inhibitors that have evolved to defend a plant or animal against predators. These natural toxins include some of the most poisonous compounds known.

    Nerve gases such as diisopropylfluorophosphate (DFP) inhibit the active site of acetylcholine esterase by reacting with the hydroxyl group of serine to make an ester.

    References

    Scapin G (2006). Structural biology and drug discovery. Curr. Pharm. Des.,      12(17):2087–2097.

    Krishnan R, Zhang E, Hakansson K, Arni RK, Tulinsky A, Lim-Wilby MS, Levy OE, Semple JE, Brunck TK (1998). Highly selective mechanism-based thrombin inhibitors:  structures of thrombin and trypsin inhibited with rigid peptidyl aldehydes. Biochemistry, 37 (35):12094-12103.

    Fischer E (1894). Einfluss der configuration auf die wirkung der enzyme. Ber. Dt. Chem. Ges., 27:2985–2993.

    Koshland DE (1958). Application of a theory of enzyme specificity to protein synthesis. PNAS., 44 (2):98–104.

    Huang KF, Liu YL, Cheng WJ, Ko TP, Wang AH (2005). Crystal structures of human glutaminyl cyclase, an enzyme responsible for protein N-terminal pyroglutamate formation. PNAS., 102(37):13117-13122.

    Holmes CF, Maynes JT, Perreault KR, Dawson JF, James MN (2002). Molecular enzymology underlying regulation of protein phosphatase-1 by natural toxins. Curr Med Chem., 9(22):1981-1989.

    化學(xué)預(yù)防肽是有助于預(yù)防疾?。ɡ绨┌Y或糖尿病)的發(fā)作或發(fā)展的肽。這些肽可以源自天然來(lái)源,例如大豆或牛奶,也可以來(lái)自肽模擬物的設(shè)計(jì),也可以源自使用合成肽進(jìn)行的肽篩選。據(jù)認(rèn)為,這些肽中的某些可以充當(dāng)細(xì)胞周期的調(diào)節(jié)劑,其調(diào)節(jié)使細(xì)胞通過(guò)復(fù)制周期前進(jìn)所需的蛋白質(zhì)的產(chǎn)生和功能。另外,現(xiàn)在有越來(lái)越多的證據(jù)表明特定的飲食模式,食物和飲料以及其他飲食物質(zhì)可以而且確實(shí)可以預(yù)防癌癥。越來(lái)越多的流行病學(xué)研究表明,食物,營(yíng)養(yǎng)和身體活動(dòng)在預(yù)防和改變癌癥過(guò)程中很重要。包括植物蛋白酶抑制劑,乳鐵蛋白,乳鐵蛋白,凝集素和lunasin在內(nèi)的不同類(lèi)型的食物蛋白和多肽似乎起著化學(xué)預(yù)防劑的作用。如今,蛋白質(zhì)和多肽被認(rèn)為是一組營(yíng)養(yǎng)保健品,在預(yù)防癌癥的不同階段(包括起始,促進(jìn)和進(jìn)展)方面顯示出潛力。此外,已經(jīng)發(fā)現(xiàn)在植物中發(fā)現(xiàn)的一些蛋白酶抑制劑,例如豆類(lèi)和大豆,是有效的癌發(fā)生抑制劑。致癌作用是引發(fā)和促進(jìn)癌癥的過(guò)程。 Bowman-Birk抑制劑和Kunitz胰蛋白酶抑制劑就在其中。目前,這些化合物在致癌作用中的生物學(xué)功能主要?dú)w因于抑制癌細(xì)胞的侵襲和轉(zhuǎn)移,但是,其作用機(jī)理仍不完全清楚,需要進(jìn)一步研究以充分闡明它們。

  • DOI名稱(chēng)
    10.7164/antibiotics.25.267Structure of antipain, a new Sakaguchi-positive product of streptomyces下載
  • 暫時(shí)沒(méi)有數(shù)據(jù)
  • 暫時(shí)沒(méi)有數(shù)據(jù)