GENETIC REGULATION OF MELANIN BIOSYNTHESIS

描述：（改编自申请人的摘要）-黑色素是一种 一种复杂的生物聚合物，主要存在于皮肤、头发和眼睛中。 它 作为身体表面的光保护色素， 化妆品的吸引力和伪装，并参与了发展的 眼睛和视神经。 黑色素的合成始于酪氨酸， 包括一系列步骤，导致黑褐色真黑素或红黄色 褐黑素 酪氨酸酶，作为与其他色素酶的复合物的一部分 和蛋白质因子，催化黑色素合成的前两步 途径，酪氨酸酶活性的丧失与总损失有关。 黑色素细胞中的黑色素。 研究人员建议研究酪氨酸酶在调节 使用人类酪氨酸酶相关的眼皮肤白化病的黑色素合成 或者OCA 1作为模型系统。 大多数酪氨酸酶基因突变与 完全缺乏黑色素（OCA 1A），而一些与黑色素相关的 出生后在头发、皮肤和眼睛中形成一些黑色素 （OCA1B）。 研究人员假设OCA 1B突变产生酶， 他们认为，这些物质的特征 突变及其对酶结构和功能的影响将提供 对黑色素合成调节的深入了解。 研究人员提出了三个具体目标。 首先，他们会 描述OCA 1B个体的分子基因型， 他们对这种白化病的初步研究 他们将确定 通过直接DNA测序和通过mRNA检测酪氨酸酶基因突变 分析. 其次，他们将描述OCA 1B突变对 酪氨酸酶功能 个体突变将被重新创建和分析， 突变酶的表达研究。 第三，他们将执行 重组正常和突变型酪氨酸酶结构与功能研究 酵素 纯化的链霉菌酪氨酸酶和人酪氨酸酶 将用于结晶和X射线分析，以确定 3-酶的三维结构和功能结构域。 这些研究 将提供关于酪氨酸酶在 黑色素合成的调节和这种关键色素的功能 酵素 获得的知识对未来的发展至关重要， 保护皮肤免受致癌作用的有效疗法 紫外线辐射，并促进正常的眼部发育。

DESCRIPTION: (Adapted from the applicant's abstract) - Melanin pigment is a complex biopolymer found primarily in the skin, hair, and eyes. It functions as a photoprotective pigment of the body surface, provides cosmetic appeal and camouflage, and is involved in the development of the eye and the optic nerves. Melanin synthesis starts with tyrosine and involves a series of steps that lead to black-brown eumelanin or red-yellow pheomelanin. Tyrosinase, as part of a complex with other pigment enzymes and protein factors, catalyzes the first two steps in the melanin synthetic pathway, and the loss of tyrosinase activity is associated with a total loss of melanin in the melanocyte. The investigators propose to study the role of tyrosinase in the regulation of melanin synthesis using human tyrosinase-related oculocutaneous albinism or OCA1 as the model system. Most tyrosinase gene mutations are associated with a total lack of melanin (OCA1A) while a number are associated with the formation of some melanin pigment in the hair, skin, and eyes after birth (OCA1B). The investigators hypothesize that OCA1B mutations produce enzymes with residual acidity, and they feel that the characterization of these mutations and their effect on enzyme structure and function will provide insight into the regulation of melanin synthesis. The investigators propose three specific aims. First, they will characterize the molecular genotype of individuals with OCA1B to extend their initial studies of this type of albinism. They will identify responsible tyrosinase gene mutations by direct DNA sequencing and by mRNA analysis. Second, they will characterize the effects of OCA1B mutations on tyrosinase function. Individual mutations will be recreated and analyzed in expression studies of mutant enzyme. Third, they will perform structure:function studies of recombinant normal and mutant tyrosinase enzyme. Purified Streptomyces antibioticus tyrosinase and human tyrosinase will be used for crystallization and x-ray analysis to determine 3-dimensional structure and functional domains of the enzyme. These studies will provide fundamental information on the role of tyrosinase in the regulation of melanin synthesis and the function of this critical pigment enzyme. Knowledge gained will be important for future development of effective therapy for the protection of the skin from the oncogenic effects of ultraviolet radiation, and for promoting normal ocular development.