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Biosynthesis and Molecular Engineering of Templated Natural Products National Science Review REVIEW 4: 553–575, 2017 doi: 10.1093/nsr/nww045 Advance access publication 11 August 2016 CHEMISTRY Biosynthesis and molecular engineering of templated natural products Ming Chen1, Jingyu Liu1, Panpan Duan1, Mulin Li1 and Wen Liu1,2,3,∗ Downloaded from https://academic.oup.com/nsr/article/4/4/553/2615234 by guest on 27 September 2021 ABSTRACT Bioactive small molecules that are produced by living organisms, often referred to as natural products (NPs), historically play a critical role in the context of both medicinal chemistry and chemical biology. How nature creates these chemical entities with stunning structural complexity and diversity using a limited range of simple substrates has not been fully understood. Focusing on two types of NPs that share a highly evolvable ‘template’-biosynthetic logic, we here provide specific examples to highlight the conceptual and technological leaps in NP biosynthesis and witness the area of progress since the beginning of the twenty-first century. The biosynthesis of polyketides, non-ribosomal peptides and their hybrids thatshare an assembly-line enzymology of modular multifunctional proteins exemplifies an extended ‘central dogma’ that correlates the genotype of catalysts with the chemotype of products; in parallel, post-translational modifications of ribosomally synthesized peptides involve a number of unusual biochemical mechanisms for molecular maturation. Understanding the biosynthetic processes of these templated NPs would largely 1 State Key Laboratory facilitate the design, development and utilization of compatible biosynthetic machineries to address the of Bioorganic and challenge that often arises from structural complexity to the accessibility and efficiency of current chemical Natural Products Chemistry, Shanghai synthesis. Institute of Organic Keywords: natural products, biosynthesis, template enzymology Chemistry, Chinese Academy of Sciences, Shanghai 200032, INTRODUCTION bio-macromolecules in cellular networks, includ- 2 China; State Key Nature utilizes simple substrates, such as short car- ing proteins and nucleic acids, thereby enabling Laboratory of boxylic acids, amino acids and sugars, to prepare var- strategies using chemical probes to exquisitely con- Microbial ious building blocks; enzymatic polymerization and trol and examine life phenomena in biological sys- Metabolism, School of Life Science & combination/permutation of these monomers, in tems [6]. The generation of NP-like libraries isa Biotechnology, many cases followed by various post-modifications, major area of current interest in diversity-oriented Shanghai Jiao Tong eventually lead to the generation of diverse natural synthesis, which has emerged in aid of searching bi- University, Shanghai products (NPs) such as polyketides, peptides, ter- ologically active small molecules based on the ex- 200240, China and penoids, alkaloids and their hybrids in living organ- pansion of both their chemical and functional spaces 3Huzhou Center of isms (Fig. 1)[1]. These chemical entities exhibit an [7–9]. However, advances in chemical synthesis Bio-Synthetic extremely wide range of biological activities, which may not always keep pace with the high-throughput Innovation, Huzhou underlie the critical roles of NPs in both the history screening (HTS) technique [10], primarily due to 313000, China and context of medicinal chemistry and chemical bi- the tremendous challenge posed by the structural ology as various drugs, biological tools and synthetic complexity of NPs. ∗ Corresponding targets [2–4]. Of the chemotherapeutical agents We should always keep in mind that NPs do not author: E-mail: that have been clinically approved, particularly those initially exist for the purposeful use of human beings. [email protected] with anti-infection, antitumor and immunosuppres- In fact, the living organisms produce them, usually sive activities, approximately 50% are NPs and their as secondary metabolites, to modulate or participate Received 31 March semi-synthetic derivatives or are chemically synthe- in numerous internal biochemical processes and to 2016; Revised 13 sized but inspired by the pharmaceutically impor- fight against external environmental concerns, such May 2016; Accepted tant moieties arising from NPs [5]. Many of these as signal transduction, competition and adaptation 13 May 2016 small molecules are capable of specifically targeting [11–13]. These processes/situations are often C The Author(s) 2016. Published by Oxford University Press on behalf of China Science Publishing & Media Ltd. All rights reserved. For permissions,please e-mail: [email protected] 554 Natl Sci Rev, 2017, Vol. 4, No. 4 REVIEW O O O O O N N N O N O O R OH N OH N N O O O indole.C2N R O NH O NH O N O N H N H H N O 2 COOH OH OH C C N O HO O O 6 2 OH O NH O O NH O O Taxol C5 isoprene unit O HO N NH (Antitumor) O O OH 2 SCoA HOOC OH ... ... O O O O O N N Substrates Dactinomycin O OH SCoA (Antitumor) OH O O OH OH NH2 HOOC NH Building Blocks Downloaded from https://academic.oup.com/nsr/article/4/4/553/2615234 by guest on 27 September 2021 OH O C6C2 ... ... HO N OH H2N NH2 O HO O C6C1 O O O COOH NH2 O O HO O X CH3 O O C1 (X=O, N, C) Gentamicin C1a O N NH O O OCH OH Rifamycin B 3 (Antiinfection) (Antiinfection) H O HO H2N O OH O Erythromycin A O O HN O O (Antibacteria) O H H OH O OH H2N OH O Mitomycin ... ... Artemisinin (Antitumor) HO O OH OH OH OH O OH (Antimalaria) H O H2N Amphotericin B O O HO (Antifungi) Natural Products CH3 O O OH O O HO OH OH NH2 O S HO HO N OH O O Doxorubicin COOH NH2 (Antitumor) Thienamycin (Antiinfection) Figure 1. Selected substrates, building blocks and representative natural products (NPs) with a variety of biological activities. dynamic, and could feed back into the related bio- are produced by non-templated pathways, the tar- synthetic machineries for the diversification, opti- get products described here typically include polyke- mization and, ultimately, selection of suitable active tides and peptides (either ribosomally synthesized small molecules to combat the associated biochem- or non-ribosomally synthesized), both of which ical or environmental changes. Consequently, the share a ‘template’-biosynthetic logic that proceeds interaction between the metabolites of living organ- through the entire process for molecular assembly isms and the macromolecular targets that mediate and modification [14]. It should be noted that we do theirbiologicalfunctionsisconsideredasanintrinsic not intend to provide a comprehensive review of the engine that drives the co-evolution of these metabo- biosynthesis of these NPs over the past 15 years; the lites and their targets in nature [3]. It now seems that incredible and rapidly increasing volume of research NP evolution occurs over a continuous spectrum that has been completed during this time frame pre- spanning millennia, and the imaginable permuta- cludes such an effort. Instead, we report on the exam- tions or mutations of prototypes (e.g. biosynthetic ples in which we are involved or with which we are pathways, biochemical reactions, catalytic enzymes most familiar, to highlight the practices of what we and encoding genes) are manifested to some extent have learned from nature, how we recognize the gen- to create NPs that possess a multitude of biological erality and specificity in NP biosynthesis and, follow- functions and display an unimaginable diversity ing the natural theme in the development of biolog- of molecular architectures. This evolution has a ically active small molecules, whether we are able to constant theme, with the generality that typically ac- accelerate the NP-diversification process to advance counts for the relevance of NPs in biosynthesis and the expansion of their molecular utility. structure and with the specificity for unique mem- bers that can be individually recognized in nature. With a focus on templated bacterial NPs, this TEMPLATED ASSEMBLY-LINE review examines the progress of biosynthesis by ENZYMOLOGY exemplifying the conceptual and technological Polyketides, non-ribosomal peptides and their leaps in the twenty-first century. In contrast to hybrids, many of which have been successfully oligosaccharides, isoprenoids and other NPs that exploited as clinically used pharmaceuticals, REVIEW Chen et al. 555 (a) Downloaded from https://academic.oup.com/nsr/article/4/4/553/2615234 by guest on 27 September 2021 (b) Figure 2. Assembly-line enzymology. (a) Conversion of the thiolation (T) domain/protein from an inactive apo-form into an active holo-form through phosphopantetheinyl transfer. (b) Modular PKSs and NRPSs for the formation of the C–C and C–N bonds in the biosynthesis of polyketides, non-ribosomal peptides and their hybrids. veterinary agents and agrochemicals, consti- NRPSs are often giant enzymes organized into tute a large family of NPs whose biosynthetic modules (Fig. 2), which each contains a com- pathways share a templated multifunctional mon thiolation (T) domain that tethers an enzymology for skeleton assembly [15]. Polyke- activated monomer or growing intermediate via a tide synthases (PKSs) usually catalyse C–C 20-A-long˚ phosphopantetheinyl group derived from bond formation using short carboxylic acids as coenzyme A (CoA) (Fig. 2a) [18]. A prototype monomers (in activated (alkyl)malonyl thioester of a PKS module consists of an acyltransferase forms) [16], whereas non-ribosomal peptide (AT) domain that is responsible for selection and synthetases (NRPSs) incorporate amino acids transfer of an (alkyl)malonyl
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