Redox Enzymes Required for Construction of the Ergot Alkaloid Framework

真菌产生复杂的小分子，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，天然产物可能会赋予真菌一些进化优势。因此，大多数天然产物表现出某种类型的生物活性。就我们的目的而言，这意味着这些代谢物是广泛应用的丰富资源，包括药物，杀虫剂，除草剂，生物材料和生物能源的开发。我们特别感兴趣的一类天然产物被称为麦角生物碱，这是由丝状真菌产生的。这些生物碱也存在于许多植物中，但据信在大多数情况下，与植物相关的真菌会产生这些分子。这些分子中的许多具有药用活性;一些用于分娩（甲基麦角新碱），另一些用于治疗偏头痛（麦角新碱）。麦角生物碱的神经作用也是众所周知的。喜得镇是作为一种“认知增强剂”销售的，半合成麦角生物碱LSD具有深刻的致幻作用。然而，为了有效地利用这些化合物为我们自己的目的，我们必须开发出大规模生产它们的可靠方法。这需要我们了解真菌用来构建这些分子的生物化学过程-生物合成。如果我们确定并理解这些生物合成途径所进行的复杂化学过程，那么我们就有可能更有效地生产这些化合物。此外，我们可以利用我们对生物合成途径的了解来修改分子的化学结构，产生具有潜在改善生物活性的新天然化合物。在这个建议中，我们描述麦角生物碱生物合成的阐明。具体来说，我们将确定基因，负责建设的结构骨架中发现的所有麦角生物碱。

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.