Connecting genes to molecules: Natural product biosynthesis in lichen

我的研究计划的总体目标是通过挖掘地衣真菌的基因组来发现具有广泛应用的新天然产物。我们通过将我们在地衣基因组中发现的基因与生物活性小分子的生物合成联系起来来实现这一点。松萝酸是地衣真菌产生的最普遍的天然产物之一，具有从抗生素到抗癌以及破坏生物膜形成的生物活性。然而，地衣真菌产生的其他天然产物的探索程度要小得多。这个项目可能会导致下一个革命性的自然产品的发现，比如青霉素。 最新进展：我们是世界上第一个对地衣真菌生物合成基因簇进行系统研究的团队。我的研究小组已经对地衣真菌Cladonia uncialis的基因组进行了测序，并注释了编码天然产物生物合成的基因簇。我们是第一个确定松萝酸生物合成的基因簇以及卤代异香豆素天然产物。最重要的是，我们已经确定了另外30个基因簇（约240个单独的基因），它们也编码其他新天然产物的生物合成。 目前的提案：目前的发现补助金申请描述了一个研究计划，发现地衣真菌中的新天然产物。 由非地衣真菌产生的天然产物已经被研究了超过世纪，并且已经产生了一些对人类疾病最重要的治疗。β-内酰胺类抗生素（青霉素）和他汀类（洛伐他汀）降胆固醇药物都是在真菌中发现的。 然而，地衣真菌中新分子的发现受到其生长缓慢和培养困难的限制。近年来，基因测序技术的最新进展使发现的步伐加快。地衣真菌产生的天然产物的生物合成是一个未经探索的、欠发达的领域，直到现在才变得可及。我的研究小组在地衣天然产物生物合成的理解上取得了重大突破。这个建议将概述我们如何将我们在C. uncialis基因组的新分子的生物活性。这些新型分子将作为先导化合物用于具有广泛商业利益的新型应用。 我们的研究结果将对更大的天然产物社区产生重大影响，因为它将代表地衣真菌中基因与分子的首次系统性联系。该研究项目将继续使我的研究小组成为天然产物生物合成领域的国际领导者。我的研究小组的培训环境将鼓励新的合作者来寻找我们，并吸引与当地和国家工业的新伙伴关系。

The overarching goal of my research program is to discover new natural products with broad applications by mining the genome of lichen fungi. We achieve this by linking the genes we discover in the lichen genome to the biosynthesis of small biologically active molecules. Usnic acid, one of the most prevalent natural products produced by lichen fungi, has displayed biological activity ranging from antibiotic to anticancer as well as disrupting biofilm formation. However the other natural products produced by lichen fungi have been explored to a much lesser extent. This program may lead to the discovery of the next transformative natural product, like penicillin. Recent Progress: We are the first group in the world to carry out a systematic examination of the biosynthetic gene clusters in lichen fungi. My research group has sequenced the genome of the lichen fungi Cladonia uncialis and annotated the gene clusters that code for natural product biosynthesis. We are the first to identify the gene cluster for usnic acid biosynthesis as well as a halogenated isocoumarin natural product. Most significantly, we have identified an additional 30 gene clusters (~240 individual genes) that also code for the biosynthesis of other novel natural products. Current Proposal: The current Discovery grant application describes a program of research that discover new natural products in lichen fungi. The natural products produced by non-lichen fungi have been investigated for over a century and have produced some of the most significant treatments for human disease. The beta-lactam antibiotics (penicillin) and the statin (lovastatin) cholesterol lowering drugs were both discovered in fungi. However, the discovery on new molecules in lichen fungi is limited by their slow growth and the difficulty in growing cultures. Recent advances in gene sequencing technology have enabled the pace of discovery to increase in recent years. The biosynthesis of the natural products produced by lichen fungi is an unexplored, underdeveloped area that is only now become accessible. My research group is uniquely positioned make significant breakthroughs in our understanding of lichen natural product biosynthesis. This proposal will outline how we will link the genes we have annotated in the C. uncialis genome to new molecules with biological activity. These novel molecules will serve as lead compounds for novel applications that will be of broad commercial interest. Our results will be of significant interest to the larger natural products community, as it will represent the first systematic linking of genes to molecules in lichen fungi. This research program will continue to position my research group as an international leader in the area of natural product biosynthesis. The training environment in my research group will encourage new collaborators to seek us out, and attract new partnerships with both local and national industry.