Opportunities in metabolic engineering to facilitate scalable alkaloid production Citation

Citation Leonard, Effendi et al. " Opportunities in metabolic engineering to facilitate scalable alkaloid production. The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Abstract 1 2 Numerous drugs and drug precursors in the current pharmacopoeia 3 originate from plant sources. The limited yield of bioactive compounds in 4 plant tissues, however, presents a significant challenge for large-scale 5 drug development reliant on whole plant extracts. Because of their 6 sophisticated molecular architecture, efficient chemical syntheses for 7 many plant-derived drugs are also seldom available. Metabolic engineering 8 has facilitated the development of plant cell and tissue systems for the 9 overproduction of high-value plant pharmaceuticals that can be 10 conveniently scaled-up in a controlled environment. Nevertheless, effective 11 metabolic engineering approaches, and the predictability of genetic 12 transformations are often obscured due to the myriad complexity of 13 cellular biology. Progress in systems biology has aided the understanding 14 of the genome-wide interconnectivity in plant-based systems. In parallel, 15 the bottom-up assembly of plant biosynthetic pathways in microorganisms 16 demonstrated the possibilities of a new production means. In this 17 Perspective, we discuss the advances and challenges of metabolic 18 engineering implementation in various scalable production platforms for 19 the bio-based synthesis of natural and unnatural plant alkaloids. 20 21 3 Bioactive compounds with " privileged structures " are highly sought 22 paradigms in drug development. Functionally, a privileged structure is a 23 molecular scaffold that can accommodate various pharmacophores arranged to 24 While many have been synthetically 26 designed, nature remains the largest source of highly sophisticated biologically 27 active privileged compounds because presumably they play a key role in 28 In fact, about one-third of the ~980 new 30 pharmaceuticals in the past two and a half decades originated from or were 31 inspired by natural products{Newman, 2007 #5}. 32 With over 10,000 structurally characterized members, plant alkaloids are 33 important privileged compounds from which many key clinical medicines are 34 The endogeneous role of alkaloids in plants has not been 36 fully elucidated. However, current evidence suggests that alkaloids are generally 37 involved in plant defense against pathogens, insects, and herbivores due to their 38 potent toxicity{Hartmann, 2004 #12}. For example, the indolizidine, indolizine, 39 and -carbolines paradigmatic alkaloid backbone structures can exert over 25 40 biological activities, such as dopamine reuptake inhibitor, glucosidase inhibitor, 41 …