Lim Yan Ping, Go Maybelle K, Raida Manfred, Inoue Takao, Wenk Markus R, Keasling Jay D, Chang Matthew W, Yew Wen Shan
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, 117597, Singapore.
NUS Synthetic Biology for Clinical and Technological Innovation, Centre for Life Sciences, and Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, 28 Medical Drive, 117456, Singapore.
ACS Omega. 2018 Sep 30;3(9):11050-11061. doi: 10.1021/acsomega.8b01620. Epub 2018 Sep 12.
Caloric restriction (CR) is an intervention that can increase maximal lifespan in organisms, but its application to humans remains challenging. A more feasible approach to achieve lifespan extension is to develop CR mimetics that target biochemical pathways affected by CR. Recent studies in the engineering and structural characterization of polyketide synthases (PKSs) have facilitated their use as biocatalysts to produce novel polyketides. Here, we show that by establishing a combinatorial biosynthetic route in and exploring the substrate promiscuity of a mutant PKS from alfalfa, 413 potential anti-ageing polyketides were biosynthesized. In this approach, novel acyl-coenzyme A (CoA) precursors generated by promiscuous acid-CoA ligases were utilized by PKS to generate polyketides which were then fed to to study their potential efficacy in lifespan extension. It was found that CR mimetics like resveratrol can counter the age-associated decline in mitochondrial function and increase the lifespan of . Using the mitochondrial respiration profile of supplemented for 8 days with 50 μM resveratrol as a blueprint, we can screen our novel polyketides for potential CR mimetics with improved potency. This study highlights the utility of synthetic enzymology in the development of novel anti-ageing therapeutics.
热量限制（CR）是一种能够延长生物体最大寿命的干预措施，但其应用于人类仍具有挑战性。一种更可行的实现寿命延长的方法是开发针对受CR影响的生化途径的CR模拟物。最近关于聚酮合酶（PKSs）的工程和结构表征的研究促进了它们作为生物催化剂用于生产新型聚酮化合物。在此，我们表明，通过在中建立组合生物合成途径并探索来自苜蓿的突变型PKS的底物选择性，生物合成了413种潜在的抗衰老聚酮化合物。在这种方法中，由混杂的酸 - 辅酶A连接酶产生的新型酰基辅酶A（CoA）前体被PKS用于生成聚酮化合物，然后将其用于研究它们在寿命延长方面的潜在功效。研究发现，白藜芦醇等CR模拟物可以对抗与年龄相关的线粒体功能衰退并延长的寿命。以用50μM白藜芦醇补充8天的的线粒体呼吸谱为蓝本，我们可以筛选我们的新型聚酮化合物以寻找具有更高效力的潜在CR模拟物。这项研究突出了合成酶学在新型抗衰老疗法开发中的效用。
