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Retrosynthetic Design of Metabolic Pathways to Chemicals Not Found in Nature

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Retrosynthetic Design of Metabolic Pathways to Chemicals Not Found in Nature Retrosynthetic design of metabolic pathways to chemicals not found in nature The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Lin, Geng-Min et al. "Retrosynthetic design of metabolic pathways to chemicals not found in nature." Biology 14 (April 2019): 82-107 © 2019 The Authors As Published http://dx.doi.org/10.1016/J.COISB.2019.04.004 Publisher Elsevier BV Version Final published version Citable link https://hdl.handle.net/1721.1/125854 Terms of Use Creative Commons Attribution-NonCommercial-NoDerivs License Detailed Terms http://creativecommons.org/licenses/by-nc-nd/4.0/ Available online at www.sciencedirect.com Current Opinion in ScienceDirect Systems Biology Retrosynthetic design of metabolic pathways to chemicals not found in nature Geng-Min Lin1, Robert Warden-Rothman1 and Christopher A. Voigt Abstract simpler chemical building blocks derived from pe- Biology produces a universe of chemicals whose precision and troleum or other sources [1]. Chemicals that are large complexity is the envy of chemists. Over the last 30 years, the and complex with many functional groups and ster- expansive field of metabolic engineering has many successes eocenters have required Herculean efforts to build; in optimizing the overproduction of metabolites of industrial in- for example, halichondrin B has 32 stereocenters (4 terest, including moving natural product pathways to production billion isomers) and requires a sprawling total syn- hosts (e.g., plants to yeast). However, there are stunningly few thesis whose longest linear path is 47 reactions [2]. examples where enzymes are artificially combined to make a Solutions have been found to incredibly challenging chemical that is not found somewhere in nature. Here, we review retrosynthesis problems, many of which are recorded these efforts and discuss the challenges limiting the construc- in the tomes Classics in Total Synthesis I, II, and III tion of such pathways. An analogy is made to the retrosynthesis [3e5]. Human creativity has been the power behind problem solved in chemistry using algorithmic approaches, these solutions, but as the literature size has grown to recently harnessing artificial intelligence, noting key differences an unmanageable size, computer algorithms have in the needs of the optimization problem. When these issues are been developed to guide the identification of reaction addressed, we see a future where chemistry and biology are paths [**6]. intertwined in reaction networks that draw on the power of both to build currently unobtainable molecules across consumer, Cells are the envy of chemists as they are able to build industrial, and defense applications. complex chemicals at high yields under ambient con- ditions. They excel in dictating patterns of stereo- Addresses chemistry, and their products are impossibly Synthetic Biology Center, Department of Biological Engineering, functionalized. In fact, many of the most lauded retro- Massachusetts Institute of Technology, Cambridge, MA, USA synthesis efforts are to rebuild the chemicals made by Corresponding author: Voigt, Christopher A ([email protected]) biology, for example, hard-to-source pharmaceuticals, 1 Equally contributing authors. which can be built with fewer steps biosynthetically (Figure 1). With a view of the complex chemicals built by the natural world, it is clear that it would be revo- Current Opinion in Systems Biology 2019, 14:82–107 lutionary to be able to harness these processes to build This reviews comes from a themed issue on Synthetic biology unnatural molecules of such complexity by design. Edited by Jeff Tabor and Julius Lucks For a complete overview see the Issue and the Editorial Reaching this vision has been inhibited by several Available online 18 April 2019 challenges. Only a fraction of the enzymes sequenced have been characterized. Their high specificity makes it https://doi.org/10.1016/j.coisb.2019.04.004 more difficult to mix and match them between path- 2452-3100/© 2019 The Authors. Published by Elsevier Ltd. This is an ways as part of retrosynthetic effort. Before the emer- open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). gence of DNA synthesis, it was difficult to come by the genetic material for enzymes described in the literature [7]. Physically combining enzyme-encoding genes to Keywords Synthetic biology, Systems biology, Artificial intelligence, Machine build a pathway has only recently been made possible learning. with genetic part libraries to control expression, DNA assembly to put the enzymes together, ‘Foundries’ to build and debug designs, and methods to work with Introduction nonmodel organisms [8e16]. Directed evolution has When posed with a new molecule to build, organic been able to expand enzyme specificity to more sub- chemists have to work backwards. Known as ‘retro- strates and catalyze new reactions, including those not synthesis,’ they identify the series of chemical known to occur in nature [17,18]. Artificial intelligence transformations that can construct the target from is increasingly being applied to the design process. Current Opinion in Systems Biology 2019, 14:82–107 www.sciencedirect.com Retrosynthetic design of metabolic pathways to chemicals not found in nature Lin et al. 83 Figure 1 O OPP GAS GAO CYP71BL2 O CYP71CA1 O HO O OH O OH O O Farnesyl pyrophosphate (+)-Costunolide Parthenolide 4 steps, 30.6% Ac2O SeO2, tBuOOH 1. TBDPSCl, imidazole MnO2 Essential oil HO TBDPSO TBDPSO OH py OAc CH2Cl2 OAc 2. K2CO3, MeOH OH CH2Cl2 O 98% 73% 50% 88% TiCl4, iPr2NEt AUX = N o S CH2Cl2, -78 C O O O O 47% HO P O EtO OH o O TBSCl, imidazole OEt O 1. (COCl)2, toluene, DMF, rt 1. nBuLi, HMDS, THF, -78 C HO TBSO OH HO TBSO TBSO TBSO O N O o OH AUX Glycerol DMF NaHMDS, THF, 0 C-rt 2. NaH, L-(+)-camphorsultam S 2. NH4Cl(aq) 83% 80% 59% O O 89% O O OH O O 1. HCl, H2O, EtOH, 0 oC O 1. LAH, THF, 0 oC O H2O2, (NH4)6Mo7O24 O TBAF TBDPSO AUX TBDPSO TBDPSO TBDPSO TBSO 2. 2-methoxypropene, 2. PhSSPh, nBu3P tBuOH, py THF, rt PPTS, DMF, rt toluene, rt O AUX SPh 86% SO2Ph 95% 74% 92% SO2Ph O O 1. Ti(O-iPr)4, D-(-)-DIPT O CBr4, PPh3 O KHMDS Mg, MeOH PPTS, MeOH TBHP, CH2Cl2, -20 oC HO Br O O o o O O 2,6-lutidine, 0 C THF, 0 C rt (CH2OH)2, rt HO 2. TEMPO, PhI(OAc)2, O O O SO Ph Ph HO CH2Cl2, RT 2 94% SO2 84% 74% 78% Parthenolide 62% 18 steps, 2.3% yield Current Opinion in Systems Biology Comparison of metabolic and chemical routes to parthenolide [339,340]. The pathway has been identified and transferred from its native organism (Tanacetum parthenium) to yeast, and the theoretical yield of the biosynthetic route is shown (0.306 g/g glucose). The rise of the bioeconomy will see biochemistry merge intracellular conditions. This is solved by replacing with organic chemistry as the means by which novel portions of the pathway sourced from different organ- chemicals are discovered and produced. This manu- isms. Figure 2a shows published pathways that are not script reviews the first steps of this process towards the entirely sourced from a single organism and require automation of retrosynthetic design in biochemistry. more than two enzymatic steps from the nearest cellular Like its counterpart in chemistry, the goal of metabolic metabolite [**23e56]. retrosynthetic design is to start with a desired chemical and then determine the enzymatic transformations The route to noscapine, an anticancer alkaloid derived required to build it from metabolites made by the cell. from the opium poppy, is the most complex example to First, we review the metabolic retrosynthesis projects date [**23]. A pathway was constructed in yeast to completed to date. As in chemistry, they have relied on make noscapine from tyrosine, requiring 18 enzymatic human expertise and creativity, and the largest projects steps, of which only 13 involve enzymes from the opium have been to rebuild natural products in a production poppy (Papever somniferum). Of the remaining five, one is strain (e.g., move a plant pathway to yeast). Second, we from the brown rat (Rattus novegicus), one from bacteria will describe efforts to mine enzymes and evolve their (Pseudomonas putida), and three from other plants (Coptis specificity and ability to perform reactions not found in japonica and Eschscholzia californica) [**23,*57e59]. nature. Finally, we will review recent efforts to develop Another example is the reconstruction of the tetrahy- algorithms where a user can specify a chemical structure drocannabinol (THC) pathway from Cannabis sativa in and the software identifies the combination of enzymes yeast [39,60e64]. Only 5 enzymes were from the native required to build it in a cell. plant, with the remaining 6 sourced from four diverse bacterial species. Both the noscapine and THC projects Classics in total retrobiosynthesis required protein engineering to alter the enzymes to Moving natural product pathways from plants to pro- eliminate feedback inhibition and alter localization tags. duction hosts, such as yeast, makes up the most complex Broad enzyme substrate specificity was recognized as metabolic engineering projects to date. All the biosyn- being critical in combining enzymes from diverse sour- thetic enzymes are present in the plant, and in some ces to form a new pathway. cases, they can all be moved into the new host together [19e22]. This is not always possible as an enzyme may Xenobiotic molecules are those not known to occur in be unknown or it is nonfunctional in the new host due to nature. Retrobiosynthetic design has been applied to misfolding, localization, missing cofactors, precursor build these compounds by combining a series of en- supply, feedback inhibition, or differences in the zymes that synthesize it from a cellular metabolite www.sciencedirect.com Current Opinion in Systems Biology 2019, 14:82–107 84 Synthetic biology [**24,26,**28,41e47,65e71].
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