Kim Eunji, Moore Bradley S, Yoon Yeo Joon
Department of Chemistry and Nano Science, Ewha Womans University, Seoul, Republic of Korea.
1] Scripps Institution of Oceanography, University of California at San Diego, La Jolla, California, USA. [2] Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, La Jolla, California, USA.
Nat Chem Biol. 2015 Sep;11(9):649-59. doi: 10.1038/nchembio.1893.
Natural products continue to play a pivotal role in drug-discovery efforts and in the understanding if human health. The ability to extend nature's chemistry through combinatorial biosynthesis--altering functional groups, regiochemistry and scaffold backbones through the manipulation of biosynthetic enzymes--offers unique opportunities to create natural product analogs. Incorporating emerging synthetic biology techniques has the potential to further accelerate the refinement of combinatorial biosynthesis as a robust platform for the diversification of natural chemical drug leads. Two decades after the field originated, we discuss the current limitations, the realities and the state of the art of combinatorial biosynthesis, including the engineering of substrate specificity of biosynthetic enzymes and the development of heterologous expression systems for biosynthetic pathways. We also propose a new perspective for the combinatorial biosynthesis of natural products that could reinvigorate drug discovery by using synthetic biology in combination with synthetic chemistry.
天然产物在药物研发以及对人类健康的认知方面持续发挥着关键作用。通过组合生物合成扩展自然化学的能力——通过操纵生物合成酶来改变官能团、区域化学和骨架结构——为创造天然产物类似物提供了独特的机会。纳入新兴的合成生物学技术有可能进一步加速组合生物合成的优化，使其成为天然化学药物先导物多样化的强大平台。在该领域诞生二十年后，我们讨论了组合生物合成当前的局限性、现状和技术水平，包括生物合成酶底物特异性的工程改造以及生物合成途径异源表达系统的开发。我们还提出了一种天然产物组合生物合成的新视角，即通过将合成生物学与合成化学相结合来重振药物研发。
