Determination of melanin synthetic pathways.
Determination of melanin synthetic pathways.
复制标题
DOI：
10.1038/skinbio.2011.4
复制
发表时间：
2011-11-17
期刊：
影响因子：
--
通讯作者：
Hearing VJ
中科院分区：
文献类型：
--
作者：
Hearing VJ
皮肤、头发和眼睛的可见色素沉着主要取决于这些组织中黑色素的存在。黑色素是由称为黑素细胞的特定细胞产生的。不仅产生的黑色素类型很重要，而且其在组织中的最终分布也会显著影响可见颜色，这最终决定了色素的功能，如光保护（Gilchrest，2011）。显然，在特定模式的黑素细胞前体（“成黑素细胞”）发育期间的特化、迁移和分化对于成年人的最终色素沉着是必不可少的（Kawakami和Fisher，2011）。以下是一个关键的发现，导致我们目前的理解的生化途径和黑素合成的黑素因子的概要。参与合成的所有类型的黑素从初始前体酪氨酸的关键酶是酪氨酸酶（EC 1.14. 18.1）。酪氨酸酶已在许多物种中被描述，包括哺乳动物和低等动物、植物，甚至真菌;事实上，酪氨酸酶的催化功能的最早观察是在蘑菇的提取物中进行的（Bourquelot和Bertrand，1895），其至今仍被广泛用作该酶的高度富集来源。所有酪氨酸酶的催化功能都依赖于铜的结合（Lerner等人，1950; Lerch等人，1986），尽管它们的底物特异性和物理性质可以根据物种而显著不同（Lerner等人，1951年; Hearing等人，1980年）。黑色素生物合成的限速起始步骤最初被认为是酪氨酸羟基化为L-3，4-二羟基苯丙氨酸（DOPA），随后立即氧化为DOPA醌（DQ）。在黑素细胞中，形成的DQ会自发转化为橙色的中间体，称为多巴色素。在体外，多巴色素将自发地失去其羧酸基团以形成5，6-二羟基吲哚（DHI），其然后可以进一步氧化和重结晶以形成致密的、高分子量的复合物，现在称为DHI-黑色素。这最初由Raper（1926）报道，并且该途径后来由Mason（1948）改进;因此，生物合成途径通常被称为Raper-Mason途径。在整个20世纪50年代、60年代和70年代，耶鲁大学（由AB Lerner领导）和哈佛大学（由TB菲茨帕特里克领导）的合作研究小组在确定酪氨酸酶参与人类皮肤色素沉着方面发挥了关键作用（菲茨帕特里克等人，1950），其活动如何局限于黑素体以及这些细胞器如何发育（Seiji et al.，1961; Szabo等人，1969年），以及在许多皮肤色素变性中这些过程中发生的中断，
Visible pigmentation of the skin, hair, and eyes depends primarily on the presence of melanin (s) in those tissues. Melanins are produced by specific cells called melanocytes. Not only is the type of melanin produced important, but also its eventual distribution in the tissue dramatically affects visible color, which ultimately determines the functions of the pigment, such as photoprotection (Gilchrest, 2011). Clearly, the specification, migration, and differentiation during development of melanocyte precursors (“melanoblasts”) in specific patterns are essential for eventual pigmentation in adults (Kawakami and Fisher, 2011). Following is a synopsis of critical findings that have led to our current understanding of the biochemical pathways and melanogenic factors involved in melanin synthesis.The key enzyme involved in the synthesis of all types of melanins from the initial precursor tyrosine is tyrosinase (EC 1.14. 18.1). Tyrosinases have been described in many species, including mammals and lower animals, plants, and even fungi; in fact, the earliest observations of the catalytic function of tyrosinase were made in extracts of mushrooms (Bourquelot and Bertrand, 1895), which are still widely used today as a highly enriched source of that enzyme. All tyrosinases depend on the binding of copper for their catalytic function (Lerner et al., 1950; Lerch et al., 1986), although their substrate specificities and physical properties can differ dramatically depending on the species (Lerner et al., 1951; Hearing et al., 1980). The ratelimiting initial step in the biosynthesis of melanin was initially thought to be the hydroxylation of tyrosine to L-3, 4-dihydroxyphenylalanine (DOPA) and its immediate subsequent oxidation to DOPAquinone (DQ). In melanocytic cells, the DQ formed will be spontaneously converted to an orange-colored intermediate known as DOPA-chrome. In vitro, the DOPAchrome will spontaneously lose its carboxylic acid group to form 5, 6-dihydroxyindole (DHI), which can then further oxidize and polymerize to form a dense, high-molecular-weight complex now known as DHI-melanin. This was initially reported by Raper (1926), and the pathway was later refined by Mason (1948); hence, the biosynthetic pathway is frequently referred to as the Raper–Mason pathway. Throughout the 1950s, 1960s, and 1970s, the collaborative research groups at Yale (headed by AB Lerner) and Harvard (headed by TB Fitzpatrick) played key roles in defining the involvement of tyrosinase in the human skin pigmentation (Fitzpatrick et al., 1950), how its activities were confined to melanosomes and how those organelles developed (Seiji et al., 1961; Szabo et al., 1969), and the disruptions that occurred in those processes in many skin pigmentary