单胺氧化酶抑制剂在临床方面的应用

单胺氧化酶(monoamine oxidase,MAO)是人体内天然存在的一种酶,催化单胺类物质氧化脱氨反应的酶。人体内含有两种单胺氧化酶:单胺氧化酶A和单胺氧化酶B。单胺氧化酶A主要分布在儿茶酚胺能神经元中;单胺氧化酶B主要分布在5-羟色胺能神经元、组胺能神经元和神经胶质细胞中,这两种亚型都均可以使单胺类神经递质失活。而单胺氧化酶抑制剂则能够通过抑制单胺氧化酶的对单胺类物质的氧化活性,从而达到减轻或者消除由各种原因引起的单胺类物质减少或单胺氧化酶活性过高导致的疾病。本文主要总结了近几年单胺氧化酶抑制剂在临床上用于治疗帕金森病、抑郁症和幽门螺旋杆菌方面的最新进展。     

单胺氧化酶

单胺氧化酶（monoamine oxidase,MAO）是生物体内一种十分重要的酶,它在大脑和周围神经组织中催化一些生物体产生的胺,氧化脱氨产生过氧化氢（H₂O₂）.单胺氧化酶A和B基因的克隆清楚地证明了这些酶是由不同的多肽组成的.单胺氧化酶A和B的基因定位于X染色体（Xp11.23）,都由15个外显子组成,而且它们的内含子-外显子组织是完全一致的.这些事实表明单胺氧化酶A和B的基因很可能从同一个祖先进化而来.单胺氧化酶A和B具有不同的底物和抑制剂专一性,在生物神经递质代谢和行为方面具有不同的作用.     

生物胺降解酶研究进展及其应用

生物胺是存在于发酵食品和酒精饮料中的潜在胺类危害物。如果人体摄入过量的生物胺,则会引起呼吸困难、呕吐和发烧等过敏反应。生物胺降解酶是通过将生物胺氧化成醛类物质来实现降解生物胺的一类酶。目前发现的具有降解生物胺能力的酶主要包括胺氧化酶、胺脱氢酶和多铜氧化酶。本文详细阐述了这3类主要生物胺降解酶的催化机理、底物特异性、酶学性质、应用特性和它们对生物胺的降解效果,归纳和总结了生物胺降解酶的异源表达和分子改造的研究进展,并对生物胺降解酶在基因挖掘、分子改造和表达等方面的研究趋势进行了展望,以期为研究和开发食品中生物胺的酶法降解策略提供参考。     

肼基单胺氧化酶抑制剂活性与电子结构构效关系的计算分析

采用量子化学方法,在DFT/B3LYP/6-31G*基组水平上对肼基单胺氧化酶抑制剂进行了几何构型优化和电子结构计算.根据计算结果,分析了肼基单胺氧化酶抑制剂的抑制活性与电子结构的构效关系,结果表明,肼基单胺氧化酶抑制剂衍生物的活性与最低空轨道的能量E_LUMO与最高占据轨道的能量E_HOMO的差值、分子偶极矩和苯环上5位碳原子电荷密度有显著相关性.     

一种白僵菌中MAO抑制剂的分离纯化和结构鉴定

本研究对前期筛选出的一株具有较强的单胺氧化酶(MAO)抑制活性的白僵菌菌株Ba02进行了液体培养;通过不同提取剂的提取效果比较,发现乙酸乙酯能较好地提取出该发酵液中单胺氧化酶抑制剂。通过活性指导下的色谱分离,从乙酸乙酯提取物中得到了一种深红色粉末状化合物。活性测定结果显示该化合物在15μg.mL-1时对MAO-A和MAO-B的抑制率分别为97.50%和95.34%。MS和NMR的鉴定结果表明该化合物为卵孢菌素(Oosporein)。虽然该化合物是一已知化合物,但其对单胺氧化酶的抑制活性尚属首次发现。     

靛红生物活性研究进展

靛红是一种重要的天然产物,广泛分布于动植物和人体内,具有多种生物活性,在生物体内起着重要的作用.本文对靛红在动物和人体内作用于神经系统、单胺氧化酶、利钠肽以及其抗肿瘤、抗衰老等方面的活性的研究进展进行了综述.     

植物过氧化物酶的生理作用

过氧化物酶(EC·1·11·1·7)是一种以血红素为辅基的氧化酶。生物学研究中常用的过氧化物酶(POD)为辣根过氧化物酶(HRP),该酶为糖蛋白。 POD能催化H_2O_2氧化酚类物质、细胞色素C、维生素C、亚硝酸盐、无色染料、吲哚、胺,以及无机离子,特别是碘离子。可     

腐植酸胺肥料对矿毒土中水稻根部末端氧化酶活力的影响

实验采用腐植酸铵处理在矿毒土中生长的7302晚稻,应用测压法对水稻四个发育时期(移栽期、分蘖期、分蘖盛期、孕穗期)禾苗根部的末端氧化酶进行测定,发现在四个发育时期均有细胞色素氧化酶和抗坏血酸氧化酶的存在。这两种氧化酶在不同的发育时期酶的活力也不同。实验分三组、即腐胺组,碳胺组,对照组。实验结果证明以腐胺组酶的活力最强,其中细胞色素氧化酶在禾苗分蘖盛期根部酶的活力最高,孕穗期酶活力下降。抗坏血酸氧化酶的活力也比其他两组为高,但抗坏血 酸 氧化酶在四个发育时期酶活力变化不大,远不及细胞色素氧化酶变化的那样显著。但实验结果证明腐植酸胺处理生长在矿毒土中的7302晚稻两种酶的活力都比碳酸氢铵组和对照组为高,作者认为细胞色素氧化酶在分蘖盛期表现酶的活力增强,这是由于腐植酸铵肥料处理矿毒土后,使土壤得到改良,使严重缺氧矿毒土的土壤透气性得到改善。腐植酸可使铁、铝、钙、镁等金属的不溶性盐类释放,从而被腐植酸中的过多的正电荷所吸附,作为养料。同时腐植酸分子中存在着多元酚基,它参与植物体内的氧化还原过程,腐植酸的醌—酚结构既起着氧的活化剂的作用又是氢的载体,因此在矿毒土严重缺氧的情况下更为突出。另一方面腐植酸铵能促进生物氧化还原过程,增强水稻体内氧化还原状况,促进有机物质的积累与合成,促进根系生长,以达到增产的目的,因此在我国大面积的矿毒土中施用腐植酸铵是增加生产的有力措施。     

融合表达过氧化氢酶提高多铜氧化酶稳定性及降解生物胺能力

多铜氧化酶 (Multicopper oxidase,MCO) 家族中的某些酶可以通过氧化反应降解食品中的胺类危害物生物胺。然而酶在催化时因为持续被氧化可能会影响整个反应过程中MCO的活性及稳定性,使酶的催化效率和降解生物胺的能力下降。文中成功在大肠杆菌Escherichia coli BL21(DE3) 中构建并表达了来源于发酵乳杆菌Lactobacillus fermentum的多铜氧化酶 (MCOF) 与枯草芽孢杆菌过氧化氢酶 (CAT) 的融合酶。8种融合酶对H2O2的耐受性提高了51%–68%,融合酶CAT&MCOF在降解组胺的过程中稳定性比MCOF提高了17.3%。以2,2′-联氮-双-3-乙基苯并噻唑啉-6-磺酸(2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid),ABTS)为底物时,CAT&MCOF对底物的亲和力 (Km) 提高了1.0倍,催化效率 (kcat/Km) 提高了1.7倍,摩尔比酶活提高了1.2倍,且在酸性 (pH 2.5–4.5) 和中高温 (35–55 ℃) 条件下的稳定性都有不同程度的提高。此外,CAT&MCOF对腐胺、尸胺和组胺的降解率分别为31.7%、36.0%和57.8%,分别比MCOF提高了132.5%,45.7%和38.9%。多铜氧化酶与过氧化氢酶融合表达提高酶催化稳定性和催化效率的策略将为通过酶的分子改造提高其应用特性提供参考。     

漆酶结构的研究进展

漆酶是一种含铜的多酚氧化酶,具有特异的氧化还原电位,能够催化氧化酚类和芳胺类化合物,同时伴随4个电子的传递,最终将O2还原成水。本文就近年来漆酶的结构及其特性的研究进展做扼要综述。     

Increased acetylcholinesterase activity in selected regions of rat brain after chronic (−)-Deprenyl administration

(−)-Deprenyl, 0.05, 1.0, 2.0, and 10.0 mg/kg body weight, was administered intraperitonially to Wistar rats for 30 days. The activity of acetylcholinesterase, and monoamine oxidase A and B were assayed in different brain regions. After the experimental period acetyl cholinesterase activity was found to be significantly increased in frontal cortex [P<0.001] and hippocampus [P<0.001] but not in striatum and brainstem at 0.1, 1.0, and 2.0 mg/kg dose, the maximum increase being at 0.1 mg/kg dose. Monoamine oxidase B activity was inhibited by more than 90% at 1.0, 2.0, and 10.0 mg/kg dose while 0.05 and 0.1 dose inhibited only about 55% and 70% respectively. Monoamine oxidase A activity was inhibited to more than 70% at 1.0 mg dose and to more than 90% at 2.0 and 10.0 mg/kg dose. At 0.05 and 0.1 mg/kg dose monoamine oxidase A activity was not significantly altered.     

Purification of human blood platelet monoamine oxidase

Monoamine oxidase B has been purified from human blood platelets 185-fold to a specific activity of 113 nmole/min/mg protein by a combination of Triton X-100 solubilization and ion exchange chromatography. A protein fraction corresponding to 58,000 Da on sodium dodecyl sulfate-polyacrylamide gel electrophoresis was identified as monoamine oxidase by its ability to bind [3H]Pargyline.     

Histochemical study on the distribution of some enzyme activities in the vagal and facial lobes of the goldfish, Carassius auratus.

The histochemical localization of six enzymic activities (acetylcholinesterase, pseudocholinesterase, monoamine oxidase, lactate dehydrogenase, succinate dehydrogenase and glucose-6-phosphate dehydrogenase) has been studied in the vagal and facial lobes of the goldfish, Carassius auratus. These encephalic centers are hypertrophic in Cyprinidae, corresponding to the dominance of gustatory function. Acetylcholinesterase shows a complex laminar distribution in the vagal lobes and a peculiar cellular localization in vagal motor neurons. Monoamine oxidase activity is mainly evident in fibrous tracts coming to or leaving from the lobes. Among oxidative enzymes examined, lactate dehydrogenase and succinate dehydrogenase exhibit distribution patterns respectively similar to those observed for acetylcholinesterase and monoamine oxidase. Some features on enzymes distribution in the gustatory centers of Carassius are in agreement with the enzymatic patterns well known in higher vertebrates.     

OCCURRENCE AND PROPERTIES OF MONOAMINE OXIDASE IN ADRENERGIC NEURONS

—Monoamine oxidase activity of peripheral organs of various species has been examined after surgical, chemical and immunological sympathectomy to assess the proportion of enzyme activity in adrenergic neurons and in extraneuronal cells. Significant falls in monoamine oxidase activity of vas deferens, submaxillary gland, iris and spleen were seen after sympathetic denervation although not in heart, small intestine and kidney. It was suggested that a correlation exists between the extent of the fall in monoamine oxidase activity after sympathectomy and the density of sympathetic innervation of the control organ. Studies of monoamine oxidase activity in vas deferens after inhibition with clorgyline suggested multiple forms of monoamine oxidase. Differences in inhibitor sensitivity, substrate specificity and thermal inactivation of monoamine oxidase in normal and denervated vas deferens were found and it was suggested that differences exist in the properties of the neuronal and extraneuronal monoamine oxidase.     

3D-QSAR method on indole and pyrrole inhibitors of monoamine oxidase type A

Monoamine oxidase A (MAO-A) converts norepinephrine and serotonin to an oxidative form. These monoamine neurotransmitters have important roles in depression. The MAO-A inhibitors have been discovered for neurodegenerative disease therapy. In order to design novel MAO-A inhibitors, in this study, the quantitative structure-activity relationships for the combined series of indoles and pyrroles were elucidated and the structural conditions to show good inhibitory effects on MAO-A were derived. This result can help us design new inhibitors irrespective of their specific moiety.     

Increase of monoamine oxidase-B activity in the brain of scrapie-infected hamsters

In the present study, the purpose is to determine activities of monoamine oxidases (MAO) in the brain of 263K scrapie-infected hamsters during the development of this experimental prion disease. Indeed, MAO activity modifications which have already been related in aging and neurodegenerations is suspected to be involved in the neuron loss process by elevated hydrogen peroxide formation. Monoamine oxidase type A (MAO-A) and B (MAO-B) activities were followed in the brain at different stages of the disease. MAO-A activity did not change significantly during the evolution of the disease. However, concerning the MAO-B activity, a significant increase was observed from 50 days post-infection and through the course of the disease and reached 42.9+/-5.3% at its ultimate stage. Regarding these results, MAO-B could be a potential therapeutic target then we have performed a pre-clinical treatment with irreversible (Selegiline or L-deprenyl) or and reversible (MS-9510) MAO-B inhibitors used alone or in association with an anti-scrapie drug such as MS-8209, an amphotericin B derivative. Our results show that none of the MAO-B inhibitors used was able to delay the onset of the disease. Neither these MAO-B inhibitors nor R-NMDA inhibitors (MK-801) can enhance the effects of MS-8209. The present findings clearly indicate a significant increase of cerebral MAO-B activity in scrapie-infected hamsters. Furthermore, inhibitors of MAO-B do not have any curative or palliative effect on this experimental model indicating that the raise of this activity is probably more a consequence rather than a causal event of the neurodegenerative process.     

Distribution of membrane-bound monoamine oxidase in bacteria.

The distribution of membrane-bound monoamine oxidase in 30 strains of various bacteria was studied. Monoamine oxidase was determined by using an ammonia-selective electrode; analyses were sensitive and easy to perform. The enzyme was found in some strains of the family Enterobacteriaceae, such as Klebsiella, Enterobacter, Escherichia, Salmonella, Serratia, and Proteus. Among strains of other families of bacteria tested, only Pseudomonas aeruginosa IFO 3901, Micrococcus luteus IFO 12708, and Brevibacterium ammoniagenes IAM 1641 had monoamine oxidase activity. In all of these bacteria except B. ammoniagenes, monoamine oxidase was induced by tyramine and was highly specific for tyramine, octopamine, dopamine, and norepinephrine. The enzyme in two strains oxidized histamine or benzylamine. Correlations between the distributions of membrane-bound monoamine oxidase and arylsulfatase synthesized in the presence of tyramine were discussed.     

Distribution of membrane-bound monoamine oxidase in bacteria.

The distribution of membrane-bound monoamine oxidase in 30 strains of various bacteria was studied. Monoamine oxidase was determined by using an ammonia-selective electrode; analyses were sensitive and easy to perform. The enzyme was found in some strains of the family Enterobacteriaceae, such as Klebsiella, Enterobacter, Escherichia, Salmonella, Serratia, and Proteus. Among strains of other families of bacteria tested, only Pseudomonas aeruginosa IFO 3901, Micrococcus luteus IFO 12708, and Brevibacterium ammoniagenes IAM 1641 had monoamine oxidase activity. In all of these bacteria except B. ammoniagenes, monoamine oxidase was induced by tyramine and was highly specific for tyramine, octopamine, dopamine, and norepinephrine. The enzyme in two strains oxidized histamine or benzylamine. Correlations between the distributions of membrane-bound monoamine oxidase and arylsulfatase synthesized in the presence of tyramine were discussed.     

Kinetic behaviour of acid phosphatase-albumin co-polymers in homogeneous phase and under gel-immobilized conditions.

1. Antiserum raised to purified human liver monoamine oxidase was used to characterize the monoamine oxidase from human liver, brain cortex, placenta and platelets. 2. Antibodies to monoamine oxidase were purified by adsorption with a mitochondrial preparation. 3. Monoamine oxidase was present in liver particle-free supernatant as measured by enzyme activity and immunodiffusion. 4. Multiple precipitin lines were obtained on immunodiffusion analysis against the purified liver enzyme. It is proposed that this is due to either aggregation or to differential lipid binding. 5. The results suggest that the functionally different enzymes found in liver, brain cortex, platelets and placenta are immunochemically related and may be identical.