Rediscovering Natural Chemical Diversity

描述 摘要： 使用具有精致和多样化催化能力的酶，在不同的王国中合成了大量复杂的天然产物（NP）。大量的化学多样性，特别是来自植物和微生物的纳米颗粒，有助于纳米颗粒显示出广泛的有用的生物活性。总的来说，NP和NP衍生药物对于治疗不同疾病和预防性维持健康生活方式是不可或缺的。由于疾病对现有药物的耐药性越来越强，新药的开发渠道越来越少，我们对化学多样性的需求变得越来越重要。挖掘化学多样性的最佳来源仍然是纳米颗粒。虽然传统的，基于表型的筛选NP从生物体中发现在世界上的深奥的部分仍然是一个新的化学实体的来源，它已经变得很清楚，新的方法，使用大量的基因组信息，以及强大的工具，在化学生物学可以应用于重新发现天然化学多样性，从丰富的NP生物合成信息积累至今。从本质上讲，我们相信许多已经鉴定和培养的微生物含有比迄今为止开发的更多的生物合成潜力，并且已知生物合成酶的操纵将导致比目前可获得的更多的多样性。在这个建议中，我们将使用两种方法来重新发现自然界的化学多样性。首先，我们将使用基因组学驱动的方法来发现大多数在正常培养条件下由微生物编码但不合成的NP。将开发天然和异源宿主中的合成生物学策略，以充分实现 已知生物体的生物合成潜力。其次，我们将开发蛋白质工程策略，以进化已知的生物合成酶，从而产生新的化学多样性。的三组分

DESCRIPTION Abstract: Using enzymes that possess exquisite and diverse catalytic power, an enormous array of complex natural products (NPs) is synthesized across the different kingdoms. The vast chemical diversity, especially of NPs from plants and microorganisms, contributes to the wide range of useful biological activities displayed by NPs. Collectively, NP and NP-derived drugs have been indispensible towards the treatment of different diseases and the prophylactic maintenance of healthy lifestyle. Due to increasing disease resistance to existing drugs and a dwindling pipeline of new drug leads, our need to generate chemical diversity is becoming ever more important. The best source to mine chemical diversity remains to be from NPs. While traditional, phenotype-based screening of NP from organisms found in esoteric parts of the world continues to be a source of new chemical entities, it has become clear that new approaches using the vast genomic information, as well as powerful tools in chemical biology can be applied towards the rediscovery of natural chemical diversity, starting from the wealth of NP biosynthetic information accumulated to date. Essentially, we believe that many of the microorganisms already identified and cultured contain far more biosynthetic potential than what has been tapped so far, and the manipulation of the known biosynthetic enzymes will lead to even more diversity than currently accessible. In this proposal, we will use two approaches to rediscover the chemical diversity from Nature. First, we will use genomics driven methods to discover the majority of NPs that are encoded, but not synthesized by microorganisms during normal cultivating conditions. Synthetic biology strategies in both the native and heterologous hosts will be developed to fully realize the biosynthetic potential of known organisms. Second, we will develop protein engineering strategy to evolve known biosynthetic enzymes towards generation of new chemical diversity. A three component