Biocatalytic production of precursors to lutein and zeaxanthin to address age-related macular degeneration

项目摘要 萎缩性（“干性”）年龄相关性黄斑变性（AMD）是导致黄斑变性的主要原因。 50岁以上的人视力严重丧失。含有叶黄素和 玉米黄质被NEI推荐用于那些有晚期AMD风险的人。出现 对这两种叶黄素的需求也相应增长。 叶黄素和玉米黄质目前主要来自海外种植的金盏花。 这些来源的纯度和可靠性差异很大。叶黄素的合成来源 将确保质量，并为预计将不断增加的 对这种眼睛健康产品的需求。然而，没有商业上可行的合成 叶黄素的天然对映体正确形式（3R，3 'R，6' R）。这道屏障阻止了 开发安全、可靠和可扩展的叶黄素来源。而且 纯合成异构体的不可用性阻碍了对其进行确定性的实验研究。 相对有效性。 目前的建议试图通过展示一个可靠的 对映体校正叶黄素和玉米黄质的合成。前提是 高度对映体富集的（4S）-（+）-伊普斯二烯醇或（4 R）-（-）-伊普斯二烯醇可用于 分别合成天然相同叶黄素或玉米黄质。我们已经开发了一个 创新的酶促工艺，消除了目前过高的成本， 产生对映体富集的异稻瘟二烯醇。此外，我们将优化生产， 重组酶在我们的工艺中使用，进一步降低成本。 一期工程的完成将展示新产品的实用性 叶黄素和玉米黄质的测定方法。这将导致价格大幅下降， 这些化学品的高纯度形式，从而使进一步研究其保护性 特性.第二阶段的工作将证实我们产品的生物活性，并证实， 天然制剂中可能存在的污染物不会产生保护作用 分配给叶黄素和玉米黄质。我们亦会致力拓展 这些化学物质作为食物补充剂。

Project Summary Atrophic (“dry”) age related macular degeneration (AMD) is the leading cause of severe loss of vision for those over age 50. Dietary supplements containing lutein and zeaxanthin are recommended by the NEI for those at risk of late AMD. There has been a corresponding growth in demand for these two xanthophylls. Lutein and zeaxanthin are currently sourced from marigolds grown mostly overseas. The purity and reliability of these sources is highly variable. A synthetic source for lutein would ensure quality and secure adequate supplies for the predicted ever increasing demand for this eye health product. However, there is no commercially viable synthesis of the natural, enantiomerically correct form (3R,3'R,6'R) of lutein. This barrier prevents the development of a secure, reliable, and scalable source for lutein. Furthermore, the unavailability of pure synthetic isomers prevents definitive experimental studies on their relative effectiveness. The current proposal seeks to remove this barrier by demonstrating a reliable synthesis of enantiomerically correct lutein and zeaxanthin. The hypothesis is that highly enantiomerically-enriched (4S)-(+)-ipsdienol or (4R)-(–)-ipsdienol can be used to synthesize nature identical lutein or zeaxanthin, respectively. We have developed an innovative enzymatic process that eliminates the current prohibitively high cost to produce enantiomerically-enriched ipsdienol. Furthermore, we will optimize production of recombinant enzymes used in our process, further reducing costs. Completion of this Phase I project will show the practicality of new production methods for lutein and zeaxanthin. This should lead to significant price reductions for highly pure forms of these chemicals, thus enabling further research into their protective properties. Phase II efforts will confirm the bioactivity of our products and confirm that possible contaminants in natural preparations do not confer the protective effects assigned to lutein and zeaxanthin. We will also seek to expand the potential market for these chemicals as food supplements.