Genomics-directed activation of cryptic natural product pathways deciphers codes for biosynthesis and molecular function
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REVIEW
Genomics‑directed activation of cryptic natural product pathways deciphers codes for biosynthesis and molecular function Yuta Tsunematsu1 Received: 15 October 2020 / Accepted: 6 November 2020 © The Author(s) 2020
Abstract Natural products, which can be isolated from living organisms worldwide, have played a pivotal role in drug discovery since ancient times. However, it has become more challenging to identify a structurally novel molecule with promising biological activity for pharmaceutical development, mainly due to the limited methodologies for their acquisition. In this review, we summarize our recent studies that activate the biosynthetic potential of filamentous fungi by genetic engineering to harness the metabolic flow for the efficient production of unprecedented natural products. The recent revolution in genome sequencing technology enables the accumulation of vast amounts of information on biosynthetic genes, the blueprint of the molecular construction. Utilizing the established heterologous expression system, activation of the pathway-specific transcription factor coupled with a knockout strategy, and manipulating the global regulatory gene, the biosynthetic genes were exploited to activate biosynthetic pathways and decipher the encoded enzyme functions. We show that this methodology was beneficial for acquiring fungal treasures for drug discovery. These studies also enabled the investigation of the molecular function of natural products in fungal development. Keywords Biosynthesis · Natural products · Spiro compounds
Introduction Humans utilize natural products, defined as small organic molecules, originating from natural resources such as plants, animals, and microbes [1]. The prescription of willow tree extract for the treatment of pain, fever, and childbirth by Hippocrates of Kos, the father of all doctors, more than 2000 years ago is an example of nature-driven drug discovery [2]. Although these medications were administered as crude materials since ancient times, the active substance salicin was identified and isolated for the first time in the nineteenth century. Purification of the substance enabled the development of acetylsalicylic acid, aspirin, a painkiller used to reduce pain, fever, and inflammation. Historically, once a compound was isolated as a pure material from natural resources, analysis of its effects on living organisms was greatly accelerated, making it possible to develop novel medicines. Therefore, human beings have been searching * Yuta Tsunematsu tsunematsu@u‑shizuoka‑ken.ac.jp 1
Department of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422‑8526, Japan
for compounds exhibiting useful biological activities from natural resources worldwide since the nineteenth century. At present, no small number of natural products or artificially designed molecules, inspired by the structure of natural products are being used as drugs [3]. Additionally, they are essential as medicines and research tools for unveiling many biological phenomena. For instance, leptom
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