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

项目摘要 萎缩性年龄相关性黄斑变性(AMD)是 50岁以上的人严重失明。含有叶黄素和维生素E的膳食补充剂 玉米黄质是NEI推荐给那些有晚期AMD风险的人的。已经有了 对这两种叶黄素的需求相应增长。 叶黄素和玉米黄质目前主要来自海外种植的万寿菊。 这些来源的纯度和可靠性是高度可变的。一种合成叶黄素的来源 将确保质量并确保充足的供应，以满足预测的日益增长的需求 对这款眼保健品的需求。然而，目前还没有商业上可行的合成方法。 天然的、对映体正确的叶黄素形式(3R、3‘R、6’R)。这道屏障防止了 开发安全、可靠、可扩展的叶黄素来源。此外， 纯合成异构体的不可获得性阻碍了对其进行明确的实验研究 相对有效性。 目前的提案试图通过展示一个可靠的 对映体正确的叶黄素和玉米黄质的合成。假设是这样的 高度富含对映体的(4S)-(+)-ipsdienol或(4R)-(-)-ipsdienol可用于 分别合成天然相同的叶黄素或玉米黄质。我们已经开发出一种 创新的酶法工艺，消除了目前令人望而却步的高昂成本 生产富含对映体的ipsdienol。此外，我们还将优化生产 在我们的工艺中使用了重组酶，进一步降低了成本。 该一期工程的竣工将显示新生产的实用性 叶黄素和玉米黄质的测定方法。这应该会导致以下产品的大幅降价 这些化学物质的高纯度形式，从而使进一步研究它们的保护作用 属性。第二阶段的工作将确认我们产品的生物活性，并确认 天然制剂中可能存在的污染物不具有保护作用 归属于叶黄素和玉米黄质。我们还将寻求扩大潜在的市场 这些化学物质可作为食品补充剂。

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.