Introduction: Unusual Enzymology in Natural Product Synthesis

Apr 26, 2017 - Biography. Wilfred A. van der Donk obtained his B.S. and M.S. at Leiden University in The Netherlands under the direction of Jan Reedij...
0 downloads 6 Views 712KB Size
Editorial pubs.acs.org/CR

Introduction: Unusual Enzymology in Natural Product Synthesis or many decades, the field of enzymology has been fueled by a desire to understand the principles that govern the impressive rate accelerations afforded by enzymes. Although questions still remain regarding the mechanisms by which these catalysts control and promote chemical reactivity, the combination of structural and molecular biology with biochemical, bioinformatic, and computational approaches has greatly advanced our knowledge.1,2 Not surprisingly, the enzymes initially studied typically catalyzed reactions in primary metabolism and macromolecule synthesis and degradation. Over time, practitioners of the field have focused increasingly on enzymes involved in disease processes, with the aim of not only understanding the mechanism of catalysis but also using that knowledge for developing enzyme-specific inhibitors. In recent years, with the advent of synthetic biology and largescale genome sequencing, a third major reason for the study of enzymes has opened up. A significant component of the excitement regarding synthetic biology is the potential to rewire or build from scratch pathways toward valuable compounds.3−7 The area of natural product biosynthesis is particularly attractive for synthetic biology applications for a number of reasons. First, pathways to these compounds are already present in Nature, but endogenous systems are typically not optimized for high level production. Second, the genome sequencing efforts of the past decade have illustrated that the biosynthetic potential of microorganisms is much larger than the number of compounds they produce when grown under various laboratory conditions. Thus, synthetic biology offers a route to uncover the hidden diversity of this large class of small molecules with proven therapeutic value. Finally, synthetic biology approaches may overcome economical hurdles of doing medicinal chemistry on structures of high complexity. For all three applications of synthetic biology to natural products, understanding the enzymes involved will improve making informed decisions regarding pathway design and enzyme engineering.8 The spectrum of enzyme-catalyzed chemical transformations involved in the biosynthesis of specialized small molecules (“secondary metabolites”) is much more diverse than that of primary metabolism. Whereas the latter processes tend to be conserved among closely related species, the production of natural products is typically strain-specific, and both the structures and biological activities of the final compounds are highly varied. The enormous diversity of biosynthetic space is starting to come into focus with the genome sequencing efforts and the associated analyses of natural product pathways.9−12 This thematic issue highlights some of the remarkable enzymology of these biosynthetic pathways.

F

cyclization strategies in this issue.13 The former typically involve radical chemistry initiated by members from a variety of enzyme classes such as cytochrome P450s, radical-SAM proteins, and α-ketoglutarate-dependent oxygenases. Alternative strategies involve oxidative installation of temporary reactive handles that are traceless in the final products, and a wide variety of unusual chemistries, including Favorskii rearrangements, ring expansions and contractions, and Pictet−Spengler condensations. Macrocyclization, including redox cyclization, is very common in the products of assembly line enzymology. Because of the exciting developments in the structural biology of these systems, this area of natural product biosynthesis has recently been reviewed extensively.14−22 In this issue, Keatinge-Clay focuses on the current understanding of polyketide cisacyltransferase assembly lines, with special attention to unusual enzymology, such as uncommon domain architectures and offloading strategies.23 One particularly intriguing form of macrocyclization involves the enzymatic [4 + 2] cycloaddition reaction. Ruszczycky and Liu and co-workers discuss examples from assembly line biosynthesis and also pathways leading to various other classes of natural products.24 They cover the current understanding of the mechanisms of these reactions, including investigations into whether such enzyme-catalyzed processes can be considered Diels−Alder reactions. Macrocyclization is also commonly involved in ribosomally synthesized and posttranslationally modified peptide natural products (RiPPs).25,26 Mitchell and Naismith and co-workers examine the various chemistries involving YcaO proteins in RiPP biosynthesis.27 These enzymes often use ATP to activate amide carbonyl groups via phosphorylation, followed by a variety of displacement reactions including cyclization to generate azole or amidine structures. The YcaO review covers the major classes of RiPPs that involve these proteins, including thiazole/oxazole modified microcins (TOMMs), thiopeptides, cyanobactins, and bottromycins. An alternative strategy for macrocyclization in RiPPs involves thioether chemistry. Nair and van der Donk review the different strategies that result in such cross-links via conjugate addition reactions of Cys thiols to dehydro amino acids in the four different classes of lanthipeptides.28 Both reviews on RiPP biosynthesis also discuss the recent exciting developments in understanding leader peptide recognition.29−31 A more global view of carbon− sulfur bond formation is provided in the review by Hertweck and co-workers. This comprehensive treatise nicely illustrates the ingenuity by which Nature has utilized the rich chemistry offered by sulfur.32 Peptide natural products from both ribosomal and nonribosomal pathways require the generation of an amide backbone. The canonical peptide bond formation chemistries for these two pathways are activation of the carboxylates of

Topics Covered

Many natural products have macrocyclic structures. Macrocyclization rigidifies compounds to improve target recognition and, in some cases increase metabolic stability and facilitate membrane permeability. Not surprisingly then, a plethora of macrocyclization strategies have evolved. Walsh and Tang and co-workers comprehensively cover oxidative and reductive © 2017 American Chemical Society

Special Issue: Unusual Enzymology in Natural Products Synthesis Received: March 2, 2017 Published: April 26, 2017 5223

DOI: 10.1021/acs.chemrev.7b00124 Chem. Rev. 2017, 117, 5223−5225

Chemical Reviews

Editorial

proteins alone during natural product biosynthesis is only slowly starting to be revealed,38−43 and the aforementioned genome analyses for natural product pathways suggest that many tailoring reactions remain to be characterized. If the past decade has been a preview of what is to come, natural product biosynthesis will continue to deliver extraordinary chemical transformations. In addition to their chemical novelty, these pathways and the resulting products offer so much promise with respect to bioengineering and synthetic biology applications that continuing investigations are warranted.

amino acids in the form of tRNA-bound oxyesters and phosphopantetheine-bound thioesters, respectively. However, in recent years, it has become increasingly clear that aminoacylated tRNAs are not only used for ribosomal peptide synthesis. Gondry and co-workers cover the many natural product pathways in which the use of aminoacylated tRNAs has emerged.33 In some cases, the amino acid attached to the tRNA ends up in the final product, whereas, in other examples, the amino acid is only fleetingly attached to a biosynthetic intermediate. Just as medicinal chemists tinker with a lead structure, Nature decorates active scaffolds with a plethora of functionalities to improve the activity or stability of the final products. These modifications can either occur early, such as in the generation of different starter units for polyketide or nonribosomal peptide biosynthesis, or occur late in the pathway via tailoring reactions after macrocyclization. Because of the limitations on ribosomal peptide synthesis, the latter is the only route possible for RiPPs, as discussed in the review on lanthipeptides.28 One particularly interesting type of functionalization is halogenation. Moore and co-workers discuss the various types of halogenation enzymes involved in natural product biosynthesis: flavin, non-heme iron, vanadium, and SAM-dependent halogenases.34 In addition, the authors cover various enzymatic dehalogenation strategies. Isoprenoids are a very large class of natural products. The elucidation of their biosynthetic pathway via the mevalonate pathway was one of the early successes of combining enzymology with precursor labeling studies. However, as discussed in the contribution by Frank and Groll,35 the labeling patterns of some isoprenoids presented inconsistencies and hinted at possible alternative routes. Indeed, through the combined efforts of many laboratories, the methylerythritol pathway to isoprenoids has been unraveled, and this pathway contains some amazing and unprecedented transformations. The authors provide an in depth review of the mechanism and structures of the enzymes involved. Zechel and Horsman comprehensively cover the biosynthesis and breakdown of naturally occurring phosphonates and phosphinates.36 Although some compounds suggest that exceptions exist, a very large majority of these compounds are biosynthesized using the same initial step in which the C−P bond is fashioned from phosphoenol pyruvate. The pathways diverge after this initial reaction, but a recurring theme is the utilization of mechanistically unusual transformations. Unique chemical reactions are also encountered in the various means by which organisms succeed in liberating the phosphorus from phosphonates in the form of phosphate. Whereas the reviews discussed thus far all involve carbon− carbon or carbon−heteroatom bond formation or breakage, natural selection does not limit pathways to such bonds, and indeed, many compounds have evolved that contain heteroatom−heteroatom bonds. Of course, that raises the question how such bonds are formed. Balskus and co-workers cover the remarkable breadth of strategies that are utilized to fashion heteroatom−heteroatom bonds, an area where many exciting discoveries undoubtedly still await.37 The sampling of enzymatic processes described in this issue illustrates the rich chemistry in natural product biosynthesis, but by no means can one issue possibly cover all of the marvelous chemical processes that have been uncovered during studies of the assembly of this massive class of compounds. For instance, the breadth of chemistry catalyzed by radical-SAM

Wilfred A. van der Donk University of Illinois at UrbanaChampaign

AUTHOR INFORMATION ORCID

Wilfred A. van der Donk: 0000-0002-5467-7071 Notes

Views expressed in this editorial are those of the author and not necessarily the views of the ACS. The author declares no competing financial interest. Biography

Wilfred A. van der Donk obtained his B.S. and M.S. at Leiden University in The Netherlands under the direction of Jan Reedijk and Willem Driessen, studying bioinorganic chemistry. In 1989 he moved to Rice University, where he completed his Ph.D. in organic chemistry with Kevin Burgess. After postdoctoral studies in the enzymology of ribonucleotide reductase with JoAnne Stubbe at MIT, he started his independent career in 1997 at the University of Illinois, where he currently holds the Richard E. Heckert chair in the Department of Chemistry. Since 2008, he has been an Investigator of the Howard Hughes Medical Institute. His research interests involve the use of organic chemistry and molecular biology to gain a better understanding of the molecular mechanisms of enzyme catalysis, and to explore the utility of enzymes for synthetic purposes. Of particular interest has been the biosynthesis of natural products and radical chemistry in proteins such as cyclooxygenase and lipoxygenase.

REFERENCES (1) Klinman, J. P. Dynamically achieved active site precision in enzyme catalysis. Acc. Chem. Res. 2015, 48 (2), 449−456. (2) Herschlag, D.; Natarajan, A. Fundamental challenges in mechanistic enzymology: progress toward understanding the rate enhancements of enzymes. Biochemistry 2013, 52 (12), 2050−2067. (3) Wurtzel, E. T.; Kutchan, T. M. Plant metabolism, the diverse chemistry set of the future. Science 2016, 353 (6305), 1232−1236. (4) Keasling, J. D. Synthetic biology for synthetic chemistry. ACS Chem. Biol. 2008, 3 (1), 64−76. 5224

DOI: 10.1021/acs.chemrev.7b00124 Chem. Rev. 2017, 117, 5223−5225

Chemical Reviews

Editorial

(5) Nielsen, J.; Keasling, J. D. Engineering cellular metabolism. Cell 2016, 164 (6), 1185−1197. (6) Smanski, M. J.; Zhou, H.; Claesen, J.; Shen, B.; Fischbach, M. A.; Voigt, C. A. Synthetic biology to access and expand nature’s chemical diversity. Nat. Rev. Microbiol. 2016, 14 (3), 135−149. (7) Erb, T. J.; Jones, P. R.; Bar-Even, A. Synthetic metabolism: metabolic engineering meets enzyme design. Curr. Opin. Chem. Biol. 2017, 37, 56−62. (8) Khosla, C. Quo vadis, enzymology? Nat. Chem. Biol. 2015, 11 (7), 438−441. (9) Doroghazi, J. R.; Albright, J. C.; Goering, A. W.; Ju, K. S.; Haines, R. R.; Tchalukov, K. A.; Labeda, D. P.; Kelleher, N. L.; Metcalf, W. W. A roadmap for natural product discovery based on large-scale genomics and metabolomics. Nat. Chem. Biol. 2014, 10 (11), 963− 968. (10) Cimermancic, P.; Medema, M. H.; Claesen, J.; Kurita, K.; Wieland Brown, L. C.; Mavrommatis, K.; Pati, A.; Godfrey, P. A.; Koehrsen, M.; Clardy, J.; et al. Insights into secondary metabolism from a global analysis of prokaryotic biosynthetic gene clusters. Cell 2014, 158 (2), 412−421. (11) Skinnider, M. A.; Dejong, C. A.; Rees, P. N.; Johnston, C. W.; Li, H.; Webster, A. L.; Wyatt, M. A.; Magarvey, N. A. Genomes to natural products PRediction Informatics for Secondary Metabolomes (PRISM). Nucleic Acids Res. 2015, 43 (20), 9645−9662. (12) Wang, H.; Fewer, D. P.; Holm, L.; Rouhiainen, L.; Sivonen, K. Atlas of nonribosomal peptide and polyketide biosynthetic pathways reveals common occurrence of nonmodular enzymes. Proc. Natl. Acad. Sci. U. S. A. 2014, 111 (25), 9259−9264. (13) Tang, M. C.; Zou, Y.; Watanabe, K.; Walsh, C. T.; Tang, Y. Oxidative cyclization in natural product biosynthesis. Chem. Rev. 2017, DOI: 10.1021/acs.chemrev.6b00478. (14) Smith, J. L.; Skiniotis, G.; Sherman, D. H. Architecture of the polyketide synthase module: surprises from electron cryo-microscopy. Curr. Opin. Struct. Biol. 2015, 31, 9−19. (15) Weissman, K. J. The structural biology of biosynthetic megaenzymes. Nat. Chem. Biol. 2015, 11 (9), 660−670. (16) Keatinge-Clay, A. T. Stereocontrol within polyketide assembly lines. Nat. Prod. Rep. 2016, 33 (2), 141−149. (17) Marahiel, M. A. A structural model for multimodular NRPS assembly lines. Nat. Prod. Rep. 2016, 33 (2), 136−140. (18) Pang, B.; Wang, M.; Liu, W. Cyclization of polyketides and nonribosomal peptides on and off their assembly lines. Nat. Prod. Rep. 2016, 33 (2), 162−173. (19) Robbins, T.; Liu, Y. C.; Cane, D. E.; Khosla, C. Structure and mechanism of assembly line polyketide synthases. Curr. Opin. Struct. Biol. 2016, 41, 10−18. (20) Sundaram, S.; Hertweck, C. On-line enzymatic tailoring of polyketides and peptides in thiotemplate systems. Curr. Opin. Chem. Biol. 2016, 31, 82−94. (21) Walsh, C. T. Insights into the chemical logic and enzymatic machinery of NRPS assembly lines. Nat. Prod. Rep. 2016, 33 (2), 127− 135. (22) Gulick, A. M. Structural insight into the necessary conformational changes of modular nonribosomal peptide synthetases. Curr. Opin. Chem. Biol. 2016, 35, 89−96. (23) Keatinge-Clay, A. T. The uncommon enzymology of cisacyltransferase assembly lines Chem. Rev. 2017, DOI: 10.1021/ acs.chemrev.6b00683. (24) Jeon, B.-s.; Wang, S. A.; Ruszczycky, M. W.; Liu, H.-w. Natural [4 + 2]-Cyclases. Chem. Rev. 2017, DOI: 10.1021/acs.chemrev.6b00578. (25) Arnison, P. G.; Bibb, M. J.; Bierbaum, G.; Bowers, A. A.; Bugni, T. S.; Bulaj, G.; Camarero, J. A.; Campopiano, D. J.; Challis, G. L.; Clardy, J.; et al. Ribosomally synthesized and post-translationally modified peptide natural products: overview and recommendations for a universal nomenclature. Nat. Prod. Rep. 2013, 30 (1), 108−160. (26) Truman, A. W. Cyclisation mechanisms in the biosynthesis of ribosomally synthesised and post-translationally modified peptides. Beilstein J. Org. Chem. 2016, 12, 1250−1268.

(27) Burkhart, B. J.; Schwalen, C.; Mann, G.; Naismith, J. H.; Mitchell, D. A. YcaO-dependent posttranslational amide activation: biosynthesis, structure, and function. Chem. Rev. 2017, DOI: 10.1021/ acs.chemrev.6b00623. (28) Repka, L. M.; Chekan, J. R.; Nair, S. K.; van der Donk, W. A. Mechanistic understanding of lanthipeptide biosynthetic enzymes. Chem. Rev. 2017, DOI: 10.1021/acs.chemrev.6b00591. (29) Ortega, M. A.; Hao, Y.; Zhang, Q.; Walker, M. C.; van der Donk, W. A.; Nair, S. K. Structure and mechanism of the tRNAdependent lantibiotic dehydratase NisB. Nature 2015, 517 (7535), 509−512. (30) Koehnke, J.; Mann, G.; Bent, A. F.; Ludewig, H.; Shirran, S.; Botting, C.; Lebl, T.; Houssen, W. E.; Jaspars, M.; Naismith, J. H. Structural analysis of leader peptide binding enables leader-free cyanobactin processing. Nat. Chem. Biol. 2015, 11 (8), 558−563. (31) Burkhart, B. J.; Hudson, G. A.; Dunbar, K. L.; Mitchell, D. A. A prevalent peptide-binding domain guides ribosomal natural product biosynthesis. Nat. Chem. Biol. 2015, 11 (8), 564−570. (32) Hertweck, C.; Dunbar, K. L.; Scharf, D. H.; Litomska, A. Enzymatic Carbon-Sulfur Bond Formation in Natural Product Biosynthesis. Chem. Rev. 2017, DOI: 10.1021/acs.chemrev.6b00697. (33) Moutiez, M.; Belin, P.; Gondry, M. Aminoacyl-tRNA-utilizing enzymes in natural product biosynthesis. Chem. Rev. 2017, DOI: 10.1021/acs.chemrev.6b00523. (34) Agarwal, V.; Miles, Z. D.; Winter, J. M.; Eustaquio, A. S.; El Gamal, A. A.; Moore, B. S. Enzymatic halogenation and dehalogenation reactions: pervasive and mechanistically diverse. Chem. Rev. 2017, DOI:10.1021/acs.chemrev.6b00571. (35) Frank, A.; Groll, M. The methylerythritol phosphate pathway to isoprenoids. Chem. Rev. 2017, DOI: 10.1021/acs.chemrev.6b00537. (36) Horsman, G. P.; Zechel, D. L. Phosphonate biochemistry. Chem. Rev. 2017, DOI:10.1021/acs.chemrev.6b00536. (37) Waldman, A. J.; Ng, T. L.; Wang, P.; Balskus, E. P. Heteroatom−heteroatom bond formation in natural product biosynthesis. Chem. Rev. 2017, DOI: 10.1021/acs.chemrev.6b00621. (38) Bandarian, V. Radical SAM enzymes involved in the biosynthesis of purine-based natural products. Biochim. Biophys. Acta, Proteins Proteomics 2012, 1824 (11), 1245−1253. (39) Banerjee, R. Introduction to the thematic minireview series on radical S-adenosylmethionine (SAM) enzymes. J. Biol. Chem. 2015, 290 (7), 3962−3963. (40) Bauerle, M. R.; Schwalm, E. L.; Booker, S. J. Mechanistic diversity of radical S-adenosylmethionine (SAM)-dependent methylation. J. Biol. Chem. 2015, 290 (7), 3995−4002. (41) Jarrett, J. T. The biosynthesis of thiol- and thioether-containing cofactors and secondary metabolites catalyzed by radical Sadenosylmethionine enzymes. J. Biol. Chem. 2015, 290 (7), 3972− 3979. (42) Ruszczycky, M. W.; Ogasawara, Y.; Liu, H. W. Radical SAM enzymes in the biosynthesis of sugar-containing natural products. Biochim. Biophys. Acta, Proteins Proteomics 2012, 1824 (11), 1231− 1244. (43) Mehta, A. P.; Abdelwahed, S. H.; Mahanta, N.; Fedoseyenko, D.; Philmus, B.; Cooper, L. E.; Liu, Y.; Jhulki, I.; Ealick, S. E.; Begley, T. P. Radical S-adenosylmethionine (SAM) enzymes in cofactor biosynthesis: a treasure trove of complex organic radical rearrangement reactions. J. Biol. Chem. 2015, 290 (7), 3980−3986.

5225

DOI: 10.1021/acs.chemrev.7b00124 Chem. Rev. 2017, 117, 5223−5225