Redox Enzymes Required for Construction of the Ergot Alkaloid Framework

真菌会产生复杂的小分子，被称为“天然产物”。考虑到生物体产生这些复杂分子所消耗的能量，天然产品可能会为真菌提供一些进化优势。因此，大多数天然产品都表现出某种生物活性。就我们的目的而言，这意味着这些代谢物是一种丰富的资源，可用于广泛的应用，包括开发药物、杀虫剂、除草剂、生物材料和生物能源。我们对一类被称为麦角生物碱的天然产品特别感兴趣，它是由丝状真菌产生的。这些生物碱也在许多植物中发现，尽管人们认为在大多数情况下，与植物相关的真菌产生这些分子。这些分子中有许多具有药用活性；一些用于分娩(甲基麦角新碱)，另一些用于治疗偏头痛(甲基丝氨酸乙酯)。麦角生物碱对神经系统的影响也是众所周知的。Hydergine是一种认知增强剂，半合成麦角生物碱LSD具有深刻的致幻作用。但是，为了有效地利用这些化合物达到我们自己的目的，我们必须开发出强大的方法来大规模生产它们。这需要我们了解真菌用来构建这些分子的生化过程-生物合成。如果我们识别和了解这些生物合成途径进行的复杂化学，那么我们就有可能更有效地生产化合物。此外，我们还可以利用我们对生物合成途径的了解来改变分子的化学结构，产生具有潜在改进生物活性的新化合物。在这项建议中，我们描述了麦角生物碱生物合成的阐明。具体地说，我们将确定负责构建在所有麦角生物碱中发现的结构骨架的基因。

Fungi produce complex small molecules, called "natural products". Given the energy that the organism expends to produce these complex molecules, natural products likely confer some evolutionary advantage to the fungus. Therefore, most natural products exhibit some type of biological activity. For our purposes, this means that these metabolites are a rich resource for a wide range of applications, including the development of pharmaceuticals, insecticides, herbicides, biomaterials and bioenergy sources. We are particularly interested in a class of natural products known as the ergot alkaloids, which are produced by filamentous fungi. These alkaloids are also found in many plants, though it is believed that in most cases fungi associated with the plants produce these molecules. Many of these molecules have medicinal activity; some are used in childbirth (methylergonovine) and others are used to treat migraine headaches (methysergide). The neurological effects of the ergot alkaloids are also well-known. Hydergine is marketed as a "cognitive enhancer", and the semisynthetic ergot alkaloid LSD has profound hallucinogenic effects.However, to effectively utilize these compounds for our own purposes, we must develop robust methods for large-scale production of them. This entails that we understand the biochemical processes- the biosynthesis- that the fungus uses to construct these molecules. If we identify and understand the complex chemistry that these biosynthetic pathways carry out, then we can potentially produce the compounds more effectively. Additionally, we can use our knowledge of the biosynthetic pathway to modify the chemical structure of the molecules, generating new-to-nature compounds with potentially improved biological activities. In this proposal, we describe elucidation of ergot alkaloid biosynthesis. Specifically, we will identify the genes that are responsible for construction of the structural backbone found in all ergot alkaloids.