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Explorations of fungal biosynthesis of reduced polyketides – a personal viewpoint John C. Vederas* This viewpoint on biosynthesis of reduced polyketides in fungi traces evolution of the research area over more than 4 decades. It is a companion to the related articles by two personal and scientific friends with whom there has been free exchange of ideas for over 30 years. Beginning with very rudimentary

Received 27th June 2014

knowledge about assembly of such natural products, developments using stable isotope labelling and subsequently identification of biosynthetic genes, led to understanding of the processive nature of

DOI: 10.1039/c4np00091a

polyketide formation. Recent expression and isolation of fungal iterative polyketide synthase enzymes

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has enabled more detailed exploration of the mechanisms of these fascinating molecular machines.

Introduction As the author of this semi-historical viewpoint on fungal polyketide biosynthesis, I have considerable common ground with Thomas J. Simpson and Craig A. Townsend. All three of us were born in 1947, and completed our Ph.D. studies in the early 1970's on different aspects of natural products chemistry, namely, bioactive metabolite isolation & structure elucidation (TJS), corrin labeling & biosynthesis (CAT), and chemical synthesis & methodology (JCV). We then embarked on postdoctoral studies that enticed us fully into the emerging eld of biosynthesis of secondary metabolites, including fungal products. Though widely separated geographically, we met early in our independent academic careers and established personal and scientic friendships that have lasted more than 3 decades. My Ph.D. studies with the late Professor George B¨ uchi at MIT had little to do with biosynthesis or fungi, but focused instead on chemical synthesis of carotenoid degradation products that were of interest as perfumes1 and on biomimetic synthesis of thiazole containing antibiotics. However, I soon realized that George B¨ uchi had amazing and prescient insight into how molecules might be assembled in nature, something that appeared totally magical and mysterious to me. Eventually I asked him whether I might join the group of Professor Christoph Tamm at the University of Basel as a postdoctoral fellow in order to study the biosynthesis of cytochalasins, fungal metabolites whose structures had just been elucidated by his group and reported with proposals for their biogenesis.2,3 The three years I spent in the Tamm laboratory (1973–76) proved to be timely and highly educational. Christoph Tamm's predictions on the biosynthesis of cytochalasins via construction of a linear polyunsaturated polyketide chain terminating in an amino acid that then

Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada. E-mail: [email protected]; Fax: +780-492-8231; Tel: +780-492-5475

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underwent intramolecular Diels–Alder reaction is being conrmed by recent work.4–6 It also provided a template for their total chemical syntheses.4,7,8 His prediction of biological Baeyer Villiger reactions9 to convert initially formed macrocyclic ketones to macrolide lactones and carbonates has also been recently conrmed using an isolated enzyme.10 A subsequent postdoctoral year with Professor Heinz Floss at Purdue University not only provided further insights into biosynthesis, but also afforded valuable experience working with puried enzymes11,12 (Fig. 1).

Stable isotope labelling, gene identification and the processive nature of polyketide biosynthesis Prior to 1973 many published proposals about biosynthesis of partially reduced polyketides showed long chains covered with b-keto groups that were then proposed to be selectively reduced at certain sites, oxidized at others and cyclized by various mechanisms.2 The order of steps, the actual intermediates and the mechanisms were completely speculative. The main methodology used for experimental probing of these suggestions was still incorporation of radioactive 14C and 3H labelled precursors followed by extensive degradation of the metabolite to crystalline derivatives in order to locate the labelled site(s) and the extent of precursor utilization. However, the development of 13C labeling with simple precursors (e.g. acetate, propionate) in conjunction with 13C NMR analysis by Masato Tanabe and the late Haruo Seto in 197013 prompted others to use this method as it did not require degradation of the nal metabolite. Their subsequent development in 1973 of “bond labelling” using precursors having adjacent 13C labels was a signicant breakthrough in assessing distribution of simple precursor units such as acetate in complex metabolites.14 In studies on cytochalasin biosynthesis in the Tamm laboratory, the results of a year's worth of 14C labelling experiments with extensive degradations were conrmed in a

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Proposed biosynthesis of cytochalasin E based on identification and engineering of the gene cluster from Aspergillus clavatus NRRL 1.5,10 The structure in the dashed box is proposed to be the first product produced by the iterative HR PKS-NRPS CcsA and its partner enoyl reductase CcsF. Formation of the enzyme bound octaketide, and condensation with L-phenylalanine may be followed by reduction to the aldehyde, aldol cyclization and then Diels–Alder reaction. Disruption of the flavin-dependent monooxygenase CcsB results in formation of the diketone precursor in the solid box. This is transformed by CcsB into the carbonate shown. Fig. 1

single week by using 13C precursors and NMR analysis.15 Subsequent development of other “bond labelling” experiments with 2H and 13C by the group of James Staunton,16 using 18O and 13C in our group17 and utilising 15N and 13C by Ian Spenser and others18 restricted the possibilities for intermediate oxidation states and mechanisms. These labelling experiments elucidated modes of ring formation or group migration in a host of biosynthetic studies in the 1980s.19 Interestingly, the use of biosynthetic 13C labelling of secondary metabolites such as lovastatin (mevinolin) to enable multidimensional NMR assignment of resonances20 preceded its use for labelling of proteins for analogous NMR studies.21 In addition to collaborative studies described in the accompanying viewpoint by Tom Simpson, we also looked at

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possible intermediate oxidation states and cyclization modes in averun,17 sterigmatocystin,22 griseofulvin,23 ravenelin,24 lasalocid A,25 lovastatin (mevinolin),26 fungichromin (pentamycin),27 cladosporin,28 A26771B and dehydrocurvularin.29 Toward the end of that decade, the groups of Cane and Hutchinson demonstrated that partly assembled di- and triketides derived from propionate could be incorporated intact into macrolides (erythromycin and tylactone) as their N-acetylcysteamine (SNAC) thioesters by bacterial cultures.30,31 In favourable cases, such as dehydrocurvularin, it was possible to incorporate di- and tetraketide SNAC esters into using fungi.32 However, this approach frequently failed with fungal cultures because of degradation of the precursors (Fig. 2).

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6-deoxyerythronolide synthase (DEBS)33,34 in Saccharopolyspora erythraea. This work depended on extensive earlier studies of Streptomyces genetics by David Hopwood.35 The DEBS assembly

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A great breakthrough in 1990–91 was publication of the independent reports by the groups of Peter Leadlay and Leonard Katz of the polyketide synthase (PKS) genes for

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Fig. 2 Selected metabolites with origins of carbon–carbon and carbon–oxygen bonds shown below each one as determined by isotopic labelling experiments completed in the 1980s. Two patterns occur for griseofulvin and ravenelin due to symmetrical biosynthetic intermediates.

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line arrangement of modules for chain extension and specic reduction conrmed the emerging view of processive chain growth with modications akin to fatty acid formation occurring aer each chain extension. This opened the door to numerous studies on mechanisms and module structures of non-iterative bacterial PKS systems that are still continuing at present.36–39 In fungi, the iterative partially-reducing (PR) PKS gene for 6-methylsalicylic acid produced by Penicillium patulum was reported in 1990,40 and the corresponding protein was fully puried by Spencer and Jordan in 1992.41 However, it was only in 1999 that a part of a highly reducing (HR) fungal PKS gene for lovastatin biosynthesis was identied by the group of

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Christopher Reeves42 with the full gene cluster described by the late Richard (Dick) Hutchinson working together with our group.43 In contrast to the bacterial non-iterative DEBS PKS, which consists of 3 large proteins, the lovastatin (mevinolin) iterative PKS (LovB) is a single protein with a separate enoyl reductase (LovC) that uses the same domains repeatedly to assemble dihydromonacolin L in ca. 35 chemical steps. In addition, we were able to assign functions to the genes for production of the side chain (lovF) and its attachment (lovD).43–45 Interestingly, the decalin system is formed by LovB and LovC in what is formally an enzyme-catalysed intramolecular Diels–Alder reaction.46 Enzymatic Diels–Alder

Fig. 3 Proposed biosynthesis of lovastatin (mevinolin).43–45,56 Assembly of a hexaketide triene thioester by the iterative HR PKS LovB and enoyl reductase LovC58 results in intramolecular Diels–Alder reaction to form the decalin thioester bound to the acyl carrier protein (ACP) domain.46 This is then further elaborated by the these enzymes to the nonaketide. This is cleaved by the thioesterase LovG to produce the initial PKS product dihydromonacolin L (DML) (unlactonised form shown).58 The multifunctional P450 enzyme LovA sequentially oxidizes DML to form monacolin L and monacolin J.59 The iterative HR PKS LovF assembles the methylated diketide that is directly transferred from the enzyme to monacolin J by LovD.

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reactions now appear likely in a large number of biosyntheses of fungal polyketide metabolites, for example, cytochalasins4,10 and the HIV-1 integrase inhibitor equisetin, which was studied by Eric Schmidt and coworkers.47

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Expression and isolation of fungal iterative PKS enzymes As described in the accompanying viewpoint by Tom Simpson, the Bristol group including Russell Cox and Colin Lazarus developed methods to rapidly identify and classify numerous fungal iterative type I PKS clusters in the early-mid 2000s.48,49 Yi Tang and collaborators expressed two intact non-reducing (NR) PKS enzymes for detailed biochemical analysis from Gibberella fujikuroi and G. zeae in 2007–2008.50,51 The group of Craig Townsend working together with Shiou-Chuan (Sheryl) Tsai made great advances in heterologous expression, purication, reconstitution and structural analyses of non-reducing (NR) PKS systems such as norsolorinic acid synthase in the aatoxin pathway (see accompanying viewpoint).52–54 Analysis of the detailed mechanisms of the expanding number of fungal HR PKS enzymes was initially very difficult because the amounts of enzyme produced are oen quite low as are the turnover rates.46,55 This problem has now been solved in many cases by improved heterologous expression of the PKS proteins. In the case of lovastatin, our collaborator Yi Tang has used an engineered yeast strain developed by Nancy DaSilva to enable production of larger amounts of pure LovB and LovC proteins for mechanistic studies.56 This allowed in vitro reconstitution of the pathway for formation of the initial PKS product, dihydromonacolin L. It also prompted the eventual identication of LovG as an essential thioesterase for product release.57 Ultimately it permitted the crystallographic analysis of the enoyl reductase partner LovC.58 Expression of lovA, a P450 enzyme, in collaboration with the group of Dae-Kyun Ro has demonstrated that it transforms dihydromonacolin L to monacolin J by two specic but quite different oxidations.59 It rst generates a double bond by allylic hydroxylation followed by elimination of water to give monacolin L, and then hydroxylates at C-8 aer reloading with oxygen. This theme of highly specic but multiple sequential oxidations by a single enzyme is now emerging in a number of other biosyntheses60 (Fig. 3).

Some future directions for study of fungal HR PKS enzyme A host of questions and possibilities confront investigators of fungal PKS systems,61 including those posed in the accompanying viewpoints. The iterative highly reducing (HR) PKS enzymes are fascinating molecular machines that oen require a partner protein for correct function. The HR PKS enzymes that make aromatics with partially reduced rings generally require protein–protein interactions with a non-reducing (NR) PKS (e.g. zearalenone,62,63 radicicol,64 hypothemycin,65 dehydrocurvularin66). A second group of HR PKS bear complete or partial nonribosomal peptide synthase domains on their

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termini and require interaction with an external enoyl reductase (ER) to make the correct product (e.g. lovastatin,43–45 equisetin,47 cytochalasins,4 tennelin67). Structural understanding of the protein–protein interactions could allow synthesis of rationally modied products through mix and match combinations with appropriate mutation to modify the interface between the two partners. In a very simple example, replacement of the enoyl reductase LovC by a homologous protein MlcG allows the HR PKS LovB to construct an unmethylated analog of dihydromonacolin L.56 Interestingly, although a compatible enoyl reductase is absolutely essential to achieve correct chain length and functionality at the tetraketide stage using LovB, it may not be required at the heptaketide stage.68 Stereochemistry of ketoreductions has been shown to depend on length of the growing chain for hypothemycin biosynthesis,69 but the control of actual nal carbon chain length is not understood. It appears that the growing chain length and/or its substitution patterns will control the rates of the next reaction by each domain in the HR PKS. The fastest reaction at each stage would in turn control the nal outcome in terms of functionality and overall chain length. A series of X-ray crystallographic analyses of full length HR PKS enzymes bearing a growing polyketide chain of specic length and functionality will be essential to understand the mechanisms of these highly mobile enzymes. For a fungal iterative NR PKS enzyme this has been partly achieved,52 but the challenge for HR PKS remains to be solved.

Acknowledgements I thank my group members and collaborators, past and present, for their enthusiastic efforts and stimulating discussions. I am also grateful to my senior mentors, George B¨ uchi, Christoph Tamm and Heinz Floss, for their example, guidance and support. Finally, more than three decades of friendship and scientic interaction with Craig Townsend and Tom Simpson are much appreciated.

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9 M. Binder and Ch. Tamm, Helv. Chim. Acta, 1973, 56, 966– 976. 10 Y. Hu, D. Dietrich, W. Xu, A. Patel, J. A. J. Thuss, J. Wang, W.-B. Yin, K. Qiao, K. N. Houk, J. C. Vederas and Y. Tang, Nat. Chem. Biol., 2014, 10, 552–554. 11 H. G. Floss, E. Schleicher, J. C. Vederas, C. M. Tatum and S. J. Benkovic, J. Chem. Soc., Chem. Commun., 1977, 218–220. 12 J. C. Vederas, E. Schleicher, M. D. Tsai and H. G. Floss, J. Biol. Chem., 1978, 253, 5350–5354. 13 M. Tanabe and H. Seto, J. Org. Chem., 1970, 36, 2087– 2088. 14 H. Seto, L. W. Cary and M. Tanabe, J. Chem. Soc., Chem. Commun., 1973, 867–868. 15 W. Graf, J. L. Robert, J. C. Vederas, Ch. Tamm, P. H. Solomon, I. Miura and K. Nakanishi, Helv. Chim. Acta, 1974, 57, 1801–1815. 16 M. J. Garson and J. Staunton, Chem. Soc. Rev., 1979, 539–569. 17 J. C. Vederas and T. T. Nakashima, J. Chem. Soc., Chem. Commun., 1980, 183–185. 18 G. Grue-Sørensen and I. D. Spenser, Can. J. Chem., 1982, 60, 643–662. 19 J. C. Vederas, Nat. Prod. Rep., 1987, 4, 277–337. 20 J. K. Chan, R. N. Moore, T. T. Nakashima and J. C. Vederas, J. Am. Chem. Soc., 1983, 105, 3334–3336. 21 W. M. Westler, M. Kainosho, H. Nagao, M. Tomonaga and J. L. Markley, J. Am. Chem. Soc., 1988, 112, 4093–4095. 22 T. T. Nakashima and J. C. Vederas, J. Chem. Soc., Chem. Commun., 1982, 206–208. 23 M. P. Lane, T. T. Nakashima and J. C. Vederas, J. Am. Chem. Soc., 1982, 104, 913–915. 24 J. G. Hill, T. T. Nakashima and J. C. Vederas, J. Am. Chem. Soc., 1982, 104, 1745–1748. 25 C. R. Hutchinson, M. M. Sherman, J. C. Vederas and T. T. Nakashima, J. Am. Chem. Soc., 1981, 103, 5953–5956. 26 K. Wagschal, Y. Yoshizawa, D. J. Witter, Y. Liu and J. C. Vederas, J. Chem. Soc., Perkin Trans. 1, 1996, 2357–2363. 27 H. Noguchi, P. H. Harrison, K. Arai, T. T. Nakashima, L. A. Trimble and J. C. Vederas, J. Am. Chem. Soc., 1988, 110, 2938–2945. 28 B. J. Rawlings, P. B. Reese, S. E. Ramer and J. C. Vederas, J. Am. Chem. Soc., 1989, 111, 3382–3390. 29 K. Arai, B. J. Rawlings, Y. Yoshizawa and J. C. Vederas, J. Am. Chem. Soc., 1989, 111, 3391–3399. 30 S. Yue, J. S. Duncan, Y. Yamamoto and C. R. Hutchinson, J. Am. Chem. Soc., 1987, 109, 1253–1255. 31 D. E. Cane and C.-C. Yang, J. Am. Chem. Soc., 1987, 109, 1255–1257. 32 Y. Yoshizawa, Z. Li, P. B. Reese and J. C. Vederas, J. Am. Chem. Soc., 1990, 112, 3212–3213. 33 J. Cortes, S. F. Haydock, G. A. Roberts, D. J. Bevitt and P. F. Leadlay, Nature, 1990, 348, 176–178. 34 S. Donadio, M. J. Staver, J. B. McAlpine, S. J. Swanson and L. Katz, Science, 1991, 252, 675–679. 35 H. Malpartida and D. A. Hopwood, Nature, 1984, 309, 462– 464. 36 J. Staunton and K. J. Weissman, Nat. Prod. Rep., 2001, 18, 380–416.

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37 T. Bretschneider, J. B. Heim, D. Heine, R. Winkler, B. Busch, B. Kusebauch, T. Stehle, G. Zocher and C. Hertweck, Nature, 2013, 502, 124–130. 38 B. Lowry, T. Robbins, C.-H. Weng, R. V. O'Brien, D. E. Cane and C. Khosla, J. Am. Chem. Soc., 2014, 35, 16809–16812. 39 C. Khosla, D. Herschlag, D. E. Cane and C. T. Walsh, Biochemistry, 2014, 53, 2875–2883. 40 J. Beck, S. Ripka, A. Siegner, E. Schiltz and E. Schweizer, Eur. J. Biochem., 1990, 192, 487–498. 41 J. B. Spencer and P. M. Jordan, Biochem. J., 1992, 288, 839– 846. 42 L. Hendrickson, C. R. Davis, C. Roach, D. K. Nguyen, T. Aldrich, P. C. McAda and C. D. Reeves, Chem. Biol., 1999, 6, 429–439. 43 J. Kennedy, K. Auclair, S. G. Kendrew, C. Park, J. C. Vederas and C. R. Hutchinson, Science, 1999, 284, 1368–1372. 44 C. R. Hutchinson, J. Kennedy, C. Park, S. Kendrew, K. Auclair and J. C. Vederas, Antonie van Leeuwenhoek, 2000, 78, 287– 295. 45 C. R. Hutchinson, J. Kennedy, C. Park, K. Auclair and J. C. Vederas, Handbook of Industrial Mycology, ed. Z. An, Marcel Dekker Inc., New York, 2000, ch. 17, pp. 479–492. 46 K. Auclair, A. Sutherland, J. Kennedy, D. J. Witter, J. P. Van den Heever, C. R. Hutchinson and J. C. Vederas, J. Am. Chem. Soc., 2000, 122, 11519–11520. 47 J. W. Sims and E. W. Schmidt, J. Am. Chem. Soc., 2008, 130, 11149–11155. 48 T. P. Nicholson, C. M. Lazarus, B. A. M. Rudd, M. J. Dawson, T. J. Simpson and R. J. Cox, Chem. Biol., 2001, 8, 151–178. 49 R. J. Cox, Org. Biomol. Chem., 2007, 5, 2010–2016. 50 S. M. Ma, J. Zhan, K. Watanabe, X. Xie, W. Zhang, C. C. Wang and Y. Tang, J. Am. Chem. Soc., 2007, 129, 10642–10643. 51 H. Zhou, J. Zhan, K. Watanabe, X. Xie and Y. Tang, Proc. Natl. Acad. Sci. U. S. A., 2008, 105, 6249–6254. 52 J. M. Crawford, T. P. Korman, J. W. Labonte, A. L. Vagstad, E. A. Hill, O. Kamari-Bidkorpeh, S.-C. Tsai and C. A. Townsend, Nature, 2009, 461, 1139–1143. 53 J. M. Crawford and C. A. Townsend, Nat. Rev. Microbiol., 2010, 8, 879–889. 54 A. L. Vagstad, A. G. Newman, P. A. Storm, K. Belecki, J. M. Crawford and C. A. Townsend, Angew. Chem., Int. Ed., 2013, 52, 1718–1721. 55 D. A. Burr, X. B. Chen and J. C. Vederas, Org. Lett., 2007, 9, 161–164. 56 S. M. Ma, J. W.-H. Li, J. W. Choi, H. Zhou, M. K. K. Lee, V. A. Moorthie, X. Xie, J. T. Kealey, N. A. Da Silva, J. C. Vederas and Y. Tang, Science, 2009, 326, 589–592. 57 W. Xu, Y.-H. Chooi, J. W. Choi, S. Li, J. C. Vederas, N. A. Da Silva and Y. Tang, Angew. Chem., Int. Ed., 2013, 52, 6472– 6475. 58 B. Ames, C. Nguyen, J. Bruegger, P. Smith, W. Xu, S. Ma, E. Wong, S. Wong, X. Xie, J. W.-H. Li, J. C. Vederas, Y. Tang and S.-C. Tsai, Proc. Natl. Acad. Sci. U. S. A., 2012, 109, 11144–11149. 59 J. Barriuso, D. T. Nguyen, J. W.-H. Li, J. N. Roberts, G. MacNevin, J. L. Chaytor, S. L. Marcus, J. C. Vederas and D. K. Ro, J. Am. Chem. Soc., 2011, 133, 8078–8081.

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60 R. V. K. Cochrane and J. C. Vederas, Acc. Chem. Res., invited review submitted. 61 Y.-H. Chooi and Y. Tang, J. Org. Chem., 2012, 77, 9933–9953. 62 Y. T. Kim, Y. R. Lee, J. Jin, K. H. Han, H. Kim, J. C. Kim, T. Lee, S. H. Yun and Y. W. Lee, Mol. Microbiol., 2005, 58, 1102–1113. 63 I. Gaffoor, D. W. Brown, R. Plattner, R. H. Proctor, W. Qi and F. Trail, Eukaryotic Cell, 2005, 4, 1926–1933. 64 H. Zhou, K. Qiao, Z. Gao, J. C. Vederas and Y. Tang, J. Biol. Chem., 2010, 285, 41412–41421. 65 Z. Gao, J. Wang, A. K. Norquay, K. Qiao, Y. Tang and J. C. Vederas, J. Am. Chem. Soc., 2013, 135, 1735–1738.

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66 Y. Xu, T. Zhou, Z. Zhou, S. Su, S. A. Roberts, W. R. Montfort, J. Zeng, M. Chen, W. Zhang, M. Lin, J. Zhan and I. Moln´ ar, Proc. Natl. Acad. Sci. U. S. A., 2013, 110, 5398–5403. 67 L. M. Halo, J. W. Marshall, A. A. Yakasai, Z. Song, C. P. Butts, M. P. Crump, M. Heneghan, A. M. Bailey, T. J. Simpson, C. M. Lazarus and R. J. Cox, ChemBioChem, 2008, 9, 585–594. 68 J. L. Sorensen and J. C. Vederas, Chem. Commun., 2003, 1492–1493. 69 M. H. Zhou, Z. Gao, K. Qiao, J. Wang, J. C. Vederas and Y. Tang, Nat. Chem. Biol., 2012, 8, 331–333.

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Explorations of fungal biosynthesis of reduced polyketides - a personal viewpoint.

This viewpoint on biosynthesis of reduced polyketides in fungi traces evolution of the research area over more than 4 decades. It is a companion to th...
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