A paramagnetic contrast agent for detecting tyrosinase activity.
A paramagnetic contrast agent for detecting tyrosinase activity.
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用于检测酪氨酸酶活性的顺磁造影剂。
DOI：
10.1002/cbic.200700157
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
BogdanovJr,Alexei
中科院分区：
文献类型：
--
作者：
Querol,Manuel;Bennett,DavidG;Sotak,Christopher;Kang,HyeWon;BogdanovJr,Alexei
许多真核生物的氧化还原酶诱导酚类化合物的氧化和寡聚化。我们以前已经表明，辣根过氧化物酶（HRP）和髓过氧化物酶（MPO）寡聚化含钆的磁共振（MR）成像造影剂（CA），承载5-羟色胺（5-羟色胺）部分。[1-4]这种低聚产生钆弛豫率的增加，即顺磁性阳离子缩短水质子弛豫时间的能力。该观察结果表明，总体弛豫率增强是两个因素的结果：1）低聚物中钆阳离子的旋转相关时间的减少; 2）由于低聚物与大分子的连接而在反应位点处的特定积累（方案1）。[3，5]然而，催化由酚类前体形成低聚物的能力并不仅限于过氧化物酶。酪氨酸酶（EC 1.14. 18.1），我们以前建议作为成像标志物蛋白，是一种3类铜金属酶，能够结合双氧。[6-8]由于酪氨酸酶在许多黑色素瘤中以高水平表达，因此能够对这种酶在外周皮肤肿瘤以及深部组织中的催化活性进行成像是重要的。众所周知，酪氨酸酶和相关酶催化单酚羟基化为邻二酚，随后形成多晶型多酚生物聚合物（黑色素）。[9-11]在黑素生成过程中，酪氨酸酶产生邻醌，邻醌参与各种亲核试剂的迈克尔加成;这导致反应性中间体，通过次级oxACHTUNGTRENNUNGiACHTUNGTRENNUNGdation产生各种黑素。[10由于与酰化单酚的结构相似性，我们预期顺磁性N-酰化酪酰胺将在酪氨酸酶催化的反应中经历转化以产生N-酰基多巴胺（NADA），类似于酪氨酸酶诱导的表皮硬化中的前体。[15]我们研究了酪氨酸酶介导的顺磁性底物的寡聚化，与过氧化物酶相反，不需要过氧化氢，是否可以应用于体外和体内酪氨酸酶活性的成像。姓名首字母缩写-[a] M。Querol，HW Kang，Dr. A.小波格丹诺夫马萨诸塞州大学医学院放射科55 Lake Avenue North，Worcester，MA 01655（USA）传真：（+ 1）508-856-1860
Many eukaryotic oxidoreductases induce oxidation and oligomerization of phenolic compounds. We have previously shown that horseradish peroxidase (HRP) and myeloperoxidase (MPO) oligomerize gadolinium-containing magnetic resonance (MR) imaging contrast agents (CAs) that bear 5-hydroxytryptamine (serotonin) moieties.[1–4] Such oligomerization yields an increase of gadolinium relaxivity, that is, the ability of paramagnetic cations to shorten relaxation times of water protons. This observation suggests that overall relaxivity enhancement is a consequence of two factors: 1) a decrease in rotational-correlation time of gadolinium cations in oligomers; 2) specific accumulation at the reaction site as a result of attachment of oligomers to macromolecules (Scheme 1).[3, 5] However, the ability to catalyze the formation of oligomers from phenolic precursors is not limited exclusively to peroxidases. Tyrosinase (EC 1.14. 18.1), which we have previously suggested as an imaging marker protein, is a class 3 copper metalloenzyme that is able to bind dioxygen.[6–8] Since tyrosinase is expressed at high levels in many melanomas it is important to be able to image the catalytic activity of this enzyme in peripheral skin tumors as well as in deep tissues. It is well known that tyrosinase and related enzymes catalyze the hydroxylation of monophenols to ortho-diphenols with the subsequent formation of polymorphous polyphenolic biopolymers (melanins).[9–11] During melanogenesis tyrosinase generates ortho-quinones that engage in Michael addition of various nucleophiles; this results in reactive intermediates that give various melanins by secondary oxACHTUNGTRENNUNGiACHTUNGTRENNUNGdations.[10, 12–14] Due to structural similarities with acylated monophenols we anticipated that paramagnetic N-acylated tyramides would undergo transformations in tyrosinase-catalyzed reactions to give N-acyl dopamines (NADA), similar to the precursors in tyrosinase-induced cuticular sclerotization.[15] We investigated whether tyrosinase-mediated oligomerization of paramagnetic substrates, which in contrast to peroxidases does not require hydrogen peroxide, could be applied to the imaging of tyrosinase activity in vitro and in vivo. Initial-[a] M. Querol, HW Kang, Dr. A. Bogdanov, Jr. Department of Radiology University of Massachusetts Medical School 55 Lake Avenue North, Worcester, MA 01655 (USA) Fax:(+ 1) 508-856-1860
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