The role of intermediate binding in Type I and Type II acyl carrier proteins

天然产物在人类和兽医学中发挥着巨大的作用，提供了抗生素、抗真菌剂和抗癌剂的宝贵来源。特别是广谱抗生素的广泛使用，其剂量旨在预防疾病而不是治疗感染，这意味着许多生物体对这些药物产生了抗药性。其中包括细菌，尽管政府试图清理病房和改善卫生，但仍会导致住院患者严重感染;导致肺炎和肺结核等呼吸道疾病的细菌;食源性病原体和性传播微生物。一个重要的研究优先事项是在这场不断的来回战斗中开发新的药物，可以处理这些耐药生物。为了解决这个问题，我们正在研究提供这些有价值的天然产品来源的细菌和真菌。在过去的30年里，密集的研究极大地增加了我们对这些生物体如何制造这些分子的理解。事实证明，这并不简单。现在我们知道，有非常复杂的酶阵列（复杂的生物分子），它们执行一系列程序化的构建步骤来产生最终的分子。这可以比作一条生产线，其中每个元素都有一个特定的工作要做，并且必须按照正确的顺序和非常高的精度来完成。有时，这些阵列被安排为一个大的组件，在其他情况下，它们作为单独的组件存在，以某种方式根据需要找到彼此。尽管有这些不同的架构，但这些装配线中的每一个都具有共同的组件，即所谓的酰基载体蛋白或ACP。这种蛋白质是一种智能芯片，必须携带被加工的分子到每种酶，在某些情况下可能会将其与周围环境隔离开来。我们想了解这种蛋白质是如何工作的，它如何识别它的伴侣，以及它如何保护它携带的分子。为此，我们使用一种称为核磁共振光谱（NMR）的技术，该技术与蛋白质的水溶液一起工作，并告诉我们它们的形状。我们将联合收割机与我们的能力结合起来，用类似于它携带的天然分子的分子修饰ACP。我们希望了解它是否积极地使用它携带的分子来改变它的形状，以便它正确地适应合成序列中正确的下一个酶。我们将研究一些不同的ACP，它们携带不同类型的分子，并且对分子识别和产物稳定性有不同的需求。我们还发现，一些组件在关键连接处使用一个以上的ACP，这些可能有助于缓解生物合成序列中的瓶颈。我们对这些ACP的理解非常有限，因此我们希望开始了解2或3个ACP如何组合在一起并相互合作。

Natural products play an enormous role in human and veterinary medicine providing a valuable source of antibiotics, antifungals and anticancer agents. The widespread use of, particularly, broad-spectrum antibiotics at doses aimed at disease prevention rather than the treatment of infections has meant that many organisms have developed resistance to these drugs. These include bacteria, which cause serious infections in hospitalised patients despite government attempts to clean up wards and improve hygiene; bacteria that cause respiratory diseases such as pneumonia and tuberculosis; food-borne pathogens and sexually transmitted organisms. A significant research priority is to develop new drugs in this constant to and fro battle, which can deal with these resistant organisms. To combat this we are studying the bacteria and fungi that provide these valuable sources of natural products. Intense research over the last 30 years has greatly increased our understanding of how these organisms make these molecules. It turns out not to be simple. It is now known that there are vastly complex arrays of enzymes (complex biological molecules) that perform a series of programmed building steps to produce the final molecule. This can be likened to a production line where each element has a particular job to do and must do it in the correct order and with very high precision. Sometimes these arrays are arranged as one large assembly, in others they are present as separate components that somehow find each other as required. Despite these different architectures, each of these assembly lines features a common component, a so called Acyl Carrier Protein or ACP. This protein is an intelligent chip that must carry the molecule being processed to each enzyme and in some cases may shield it from the surrounding environment. We want to understand how this protein works, how it recognises its partners and how it may protect the molecule it is carrying. To do this, we use a technique called Nuclear Magnetic Resonance spectroscopy (NMR) that works with aqueous solutions of the proteins and tells us their shape. We combine this technique with our ability to modify the ACP with molecules that resemble the natural molecules it carries. We wish to understand if it actively uses the molecule it carries to change its shape so it then fits correctly into the correct next enzyme in the synthetic sequence. We will look at a number of different ACPs that carry different types of molecules and which have a varying need for molecular recognition and product stabilisation. We have also discovered that some assemblies use more than one ACP at critical junctions and these may help relieve bottlenecks in the biosynthetic sequence. Our understanding of these ACPs is very limited so we wish to begin to understand how 2 or 3 ACPs might fit together and cooperate with one another.