Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Chemoenzymatic approaches for exploring structure–activity relationship studies of bioactive natural products

Nature Synthesis volume 2, pages 708–718 (2023)Cite this article

Subjects

An Author Correction to this article was published on 25 September 2023

This article has been updated

Abstract

Spurred by advancements in microbial genetics and enzyme engineering, chemoenzymatic strategies, which combine enzymatic and synthetic transformations, have increasingly made an impact in the synthesis of bioactive natural products, pharmaceutical components and other valuable molecules. Beyond target-oriented synthesis, researchers have also leveraged chemoenzymatic approaches in structure–activity relationship (SAR) studies of bioactive natural products by using enzymatic reactions in either the early-stage construction of key building blocks or the late-stage modification of key intermediates. This Review summarizes the applications of chemoenzymatic approaches for SAR exploration of natural products, categorizing the case studies according to the stage in which the enzymatic reactions are performed. Current challenges in the field are also discussed, along with emerging technologies that may provide solutions to these challenges in the future.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Strategic considerations for performing SAR studies with chemoenzymatic synthesis.
Fig. 2: Chemoenzymatic synthesis and SAR analysis of cepafungin I.
Fig. 3: Chemoenzymatic synthesis and SAR analysis of GE81112 B1.
Fig. 4: Chemoenzymatic synthesis and SAR study of the bis-THIQ alkaloids.
Fig. 5: Chemoenzymatic synthesis and SAR study of the juvenimicins.
Fig. 6: Chemoenzymatic synthesis and SAR study of cryptophycin analogues.
Fig. 7: Chemoenzymatic synthesis and SAR study of derivatives of daptomycin and A54145.
Fig. 8: Late-stage diversification of daptomycin via enzymatic alkylation and SAR study of the resulting derivatives.
Fig. 9: Chemoenzymatic synthesis and SAR study of aromatic C-glycosides.

Similar content being viewed by others

Change history

References

  1. Crum-Brown, A. & Fraser, T. The connection of chemical constitution and physiological action. Trans. R. Soc. Edinburgh 25, 257 (1865).

  2. Okano, A., Isley, N. A. & Boger, D. L. Total syntheses of vancomycin-related glycopeptide antibiotics and key analogues. Chem. Rev. 117, 11952–11993 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Wright, P. M., Seiple, I. B. & Myers, A. G. The evolving role of chemical synthesis in antibacterial drug discovery. Angew. Chem. Int. Ed. 53, 8840–8869 (2014).

    CAS  Google Scholar 

  4. Li, Q. et al. Synthetic group A streptogramin antibiotics that overcome Vat resistance. Nature 586, 145–150 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Sears, J. E. & Boger, D. L. Total synthesis of vinblastine, related natural products, and key analogues and development of inspired methodology suitable for the systematic study of their structure–function properties. Acc. Chem. Res. 48, 653–662 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Nestl, B. M., Hammer, S. C., Nebel, B. A. & Hauer, B. New generation of biocatalysts for organic synthesis. Angew. Chem. Int. Ed. 53, 3070–3095 (2014).

    CAS  Google Scholar 

  7. Ramsden, J. I., Cosgrove, S. C. & Turner, N. J. Is it time for biocatalysis in fragment-based drug discovery? Chem. Sci. 11, 11104–11112 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Wu, S., Snajdrova, R., Moore, J. C., Baldenius, K. & Bornscheuer, U. T. Biocatalysis: enzymatic synthesis for industrial applications. Angew. Chem. Int. Ed. 60, 88–119 (2021).

    CAS  Google Scholar 

  9. Amatuni, A., Shuster, A., Adibekian, A. & Renata, H. Concise chemoenzymatic total synthesis and identification of cellular targets of cepafungin I. Cell Chem. Biol. 27, 1318–1326 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Zwick, C. R., Sosa, M. B. & Renata, H. Modular chemoenzymatic synthesis of GE81112 B1 and related analogues enables elucidation of its key pharmacophores. J. Am. Chem. Soc. 143, 1673–1679 (2021).

    PubMed  PubMed Central  Google Scholar 

  11. Tanifuji, R. et al. Chemo-enzymatic total syntheses of jorunnamycin A, saframycin A, and N-Fmoc saframycin Y3. J. Am. Chem. Soc. 140, 10705–10709 (2018).

    CAS  PubMed  Google Scholar 

  12. Lowell, A. N. et al. Chemoenzymatic total synthesis and structural diversification of tylactone-based macrolide antibiotics through late-stage polyketide assembly, tailoring, and C–H functionalization. J. Am. Chem. Soc. 139, 7913–7920 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Schmidt, J. J. et al. A versatile chemoenzymatic synthesis for the discovery of potent cryptophycin analogs. ACS Chem. Biol. 15, 524–532 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Kopp, F., Grünewald, J., Mahlert, C. & Marahiel, M. A. Chemoenzymatic design of acidic lipopeptide hybrids: new insights into the structure–activity relationship of daptomycin and A54145. Biochemistry 45, 10474–10481 (2006).

    CAS  PubMed  Google Scholar 

  15. Scull, E. M. et al. Chemoenzymatic synthesis of daptomycin analogs active against daptomycin-resistant strains. Appl. Microbiol. 104, 7853–7865 (2020).

    CAS  Google Scholar 

  16. Xie, K., Zhang, X., Sui, S., Ye, F. & Dai, J. Exploring and applying the substrate promiscuity of a C-glycosyltransferase in the chemo-enzymatic synthesis of bioactive C-glycosides. Nat. Commun. 11, 5162 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Li, F., Zhang, X. & Renata, H. Enzymatic CH functionalizations for natural product synthesis. Curr. Opin. Chem. Biol. 49, 25–32 (2019).

    CAS  PubMed  Google Scholar 

  18. Shoji, J. et al. Isolation of cepafungins I, II and III from Pseudomonas species. J. Antibiot. 43, 783–787 (1990).

    CAS  Google Scholar 

  19. Stein, M. L. et al. One-shot NMR analysis of microbial secretions identifies highly potent proteasome inhibitor. Proc. Natl Acad. Sci. USA 109, 18367–18371 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Schmidt, U., Kleefeldt, A. & Mangold, R. The synthesis of glidobactin A. J. Chem. Soc. Chem. Commun. 1992, 1687–1689 (1992).

    Google Scholar 

  21. Krahn, D., Ottmann, C. & Kaiser, M. The chemistry and biology of syringolins, glidobactins and cepafungins (syrbactins). Nat. Prod. Rep. 28, 1854–1867 (2011).

    CAS  PubMed  Google Scholar 

  22. Amatuni, A. & Renata, H. Identification of a lysine 4-hydroxylase from the glidobactin biosynthesis and evaluation of its biocatalytic potential. Org. Biomol. Chem. 17, 1736–1739 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Amatuni, A., Shuster, A., Abegg, D., Adibekian, A. & Renata, H. Comprehensive structure–activity relationship studies of cepafungin enabled by biocatalytic C–H oxidations. ACS Cent. Sci. 9, 239–251 (2023).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Brandi, L. et al. Novel tetrapeptide inhibitors of bacterial protein synthesis produced by a Streptomyces sp. Biochemistry 45, 3692–3702 (2006).

    CAS  PubMed  Google Scholar 

  25. Jürjens, G. et al. Total synthesis and structural revision of the antibiotic tetrapeptide GE81112A. Angew. Chem. Int. Ed. 57, 12157–12161 (2018).

    Google Scholar 

  26. Zwick, C. R. III, Sosa, M. B. & Renata, H. Characterization of a citrulline 4-hydroxylase from nonribosomal peptide GE81112 biosynthesis and engineering of its substrate specificity for the chemoenzymatic synthesis of enduracididine. Angew. Chem. Int. Ed. 58, 18854–18858 (2019).

    CAS  Google Scholar 

  27. Le, V. H., Inai, M., Williams, R. M. & Kan, T. Ecteinascidins. A review of the chemistry, biology and clinical utility of potent tetrahydroisoquinoline antitumor antibiotics. Nat. Prod. Rep. 32, 328–347 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Leal, J. et al. PM01183, a new DNA minor groove covalent binder with potent in vitro and in vivo anti-tumour activity. Br. J. Pharmacol. 161, 1099–1110 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Scott, J. D. & Williams, R. M. Chemistry and biology of the tetrahydroisoquinoline antitumor antibiotics. Chem. Rev. 102, 1669–1730 (2002).

    CAS  PubMed  Google Scholar 

  30. Koketsu, K., Watanabe, K., Suda, H., Oguri, H. & Oikawa, H. Reconstruction of the saframycin core scaffold defines dual Pictet–Spengler mechanisms. Nat. Chem. Biol. 6, 408–410 (2010).

    CAS  PubMed  Google Scholar 

  31. Tanifuji, R., Haraguchi, N. & Oguri, H. Chemo-enzymatic total syntheses of bis-tetrahydroisoquinoline alkaloids and systematic exploration of the substrate scope of SfmC. Tetrahedron Chem 1, 100010 (2022).

    Google Scholar 

  32. Tanifuji, R., Tsukakoshi, K., Ikebukuro, K., Oikawa, H. & Oguri, H. Generation of C5-desoxy analogs of tetrahydroisoquinoline alkaloids exhibiting potent DNA alkylating ability. Bioorg. Med. Chem. Lett. 29, 1807–1811 (2019).

    CAS  PubMed  Google Scholar 

  33. Kishi, T., Harada, S., Yamana, H. & Miyake, A. Studies on juvenimicin, a new antibiotic. II. Isolation, chemical characterization and structures. J. Antibiot. 29, 1171–1181 (1976).

    CAS  Google Scholar 

  34. Kinumaki, A., Harada, K. I., Suzuki, T., Suzuki, M. & Okuda, T. Macrolide antibiotics M-4365 produced by Micromonospora. II. Chemical structures. J. Antibiot. 30, 450–454 (1977).

    CAS  Google Scholar 

  35. DeMars, M. D. et al. Biochemical and structural characterization of MycCI, a versatile P450 biocatalyst from the mycinamicin biosynthetic pathway. ACS Chem. Biol. 11, 2642–2654 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Oh, H.-S. & Kang, H.-Y. Total synthesis of pikromycin. J. Org. Chem. 77, 1125–1130 (2012).

    CAS  PubMed  Google Scholar 

  37. Matsumoto, T., Maeta, H., Suzuki, K. & Tsuchihashi, L. G. First total synthesis of mycinamicin IV and VII.: successful application of new glycosidation reaction. Tetrahedron Lett. 29, 3575–3578 (1988).

    CAS  Google Scholar 

  38. Magarvey, N. A. et al. Biosynthetic characterization and chemoenzymatic assembly of the cryptophycins. Potent anticancer agents from nostoc cyanobionts. ACS Chem. Biol. 1, 766–779 (2006).

    CAS  PubMed  Google Scholar 

  39. Ding, Y., Rath, C. M., Bolduc, K. L., Håkansson, K. & Sherman, D. H. Chemoenzymatic synthesis of cryptophycin anticancer agents by an ester bond-forming non-ribosomal peptide synthetase module. J. Am. Chem. Soc. 133, 14492–14495 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Schwartz, R. E. et al. Pharmaceuticals from cultured algae. J. Ind. Microbiol. 5, 113–123 (1990).

    CAS  Google Scholar 

  41. D’Agostino, G. et al. A multicenter phase II study of the cryptophycin analog LY355703 in patients with platinum-resistant ovarian cancer. Int. J. Gynecol. Cancer 16, 71–76 (2006).

    PubMed  Google Scholar 

  42. Su, D. et al. Modulating antibody–drug conjugate payload metabolism by conjugation site and linker modification. Bioconjug. Chem. 29, 1155–1167 (2018).

    CAS  PubMed  Google Scholar 

  43. Verma, V. A. et al. The cryptophycins as potent payloads for antibody drug conjugates. Bioorg. Med. Chem. Lett. 25, 864–868 (2015).

    CAS  PubMed  Google Scholar 

  44. Weiss, C., Sammet, B. & Sewald, N. Recent approaches for the synthesis of modified cryptophycins. Nat. Prod. Rep. 30, 924–940 (2013).

    CAS  PubMed  Google Scholar 

  45. Beck, Z. Q., Aldrich, C. C., Magarvey, N. A., Georg, G. I. & Sherman, D. H. Chemoenzymatic synthesis of cryptophycin/arenastatin natural products. Biochemistry 44, 13457–13466 (2005).

    CAS  PubMed  Google Scholar 

  46. Bolduc, K. L., Larsen, S. D. & Sherman, D. H. Efficient, divergent synthesis of cryptophycin unit A analogues. Chem. Commun. 48, 6414–6416 (2012).

    CAS  Google Scholar 

  47. Baltz, R. H., Miao, V. & Wrigley, S. K. Natural products to drugs: daptomycin and related lipopeptide antibiotics. Nat. Prod. Rep. 22, 717–741 (2005).

    CAS  PubMed  Google Scholar 

  48. Raja, A., LaBonte, J., Lebbos, J. & Kirkpatrick, P. Daptomycin. Nat. Rev. Drug Discov. 2, 943–944 (2003).

    CAS  PubMed  Google Scholar 

  49. Cottagnoud, P. et al. Daptomycin is highly efficacious against penicillin-resistant and penicillin- and quinolone-resistant pneumococci in experimental meningitis. Antimicrob. Agents Chemother. 48, 3928–3933 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Robbel, L. & Marahiel, M. A. Daptomycin, a bacterial lipopeptide synthesized by a nonribosomal machinery. J. Biol. Chem. 285, 27501–27508 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Grünewald, J., Sieber, S. A., Mahlert, C., Linne, U. & Marahiel, M. A. Synthesis and derivatization of daptomycin: a chemoenzymatic route to acidic lipopeptide antibiotics. J. Am. Chem. Soc. 126, 17025–17031 (2004).

    PubMed  Google Scholar 

  52. Lam, H. Y. et al. Total synthesis of daptomycin by cyclization via a chemoselective serine ligation. J. Am. Chem. Soc. 135, 6272–6279 (2013).

    CAS  PubMed  Google Scholar 

  53. Barnawi, G. et al. An entirely fmoc solid phase approach to the synthesis of daptomycin analogs. Peptide Sci. 111, e23094 (2019).

    Google Scholar 

  54. He, Y. et al. Reduced pulmonary surfactant interaction of daptomycin analogs via tryptophan replacement with alternative amino acids. Bioorg. Med. Chem. Lett. 22, 6248–6251 (2012).

    CAS  PubMed  Google Scholar 

  55. Elshahawi, S. I. et al. Structure and specificity of a permissive bacterial C-prenyltransferase. Nat. Chem. Biol. 13, 366–368 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Hoffmeister, D., Dräger, G., Ichinose, K., Rohr, J. & Bechthold, A. The C-glycosyltransferase UrdGT2 is unselective toward d- and l-configured nucleotide-bound rhodinoses. J. Am. Chem. Soc. 125, 4678–4679 (2003).

    CAS  PubMed  Google Scholar 

  57. Chen, D. et al. Probing the catalytic promiscuity of a regio- and stereospecific C-glycosyltransferase from Mangifera indica. Angew. Chem. Int. Ed. 54, 12678–12682 (2015).

    CAS  Google Scholar 

  58. Simić, S. et al. Shortening synthetic routes to small molecule active pharmaceutical ingredients employing biocatalytic methods. Chem. Rev. 122, 1052–1126 (2022).

    PubMed  Google Scholar 

  59. Hong, B., Luo, T. & Lei, X. Late-stage diversification of natural products. ACS Cent. Sci. 6, 622–635 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Marshall, J. R. et al. Screening and characterization of a diverse panel of metagenomic imine reductases for biocatalytic reductive amination. Nat. Chem. 13, 140–148 (2021).

    CAS  PubMed  Google Scholar 

  61. Zhang, C. et al. Exploiting the reversibility of natural product glycosyltransferase-catalyzed reactions. Science 313, 1291–1294 (2006).

    CAS  PubMed  Google Scholar 

  62. Gao, L. et al. Enzymatic control of endo- and exo-stereoselective Diels–Alder reactions with broad substrate scope. Nat. Catal. 4, 1059–1069 (2021).

    CAS  Google Scholar 

  63. Baek, M. et al. Accurate prediction of protein structures and interactions using a three-track neural network. Science 373, 871–876 (2021).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Mazurenko, S., Prokop, Z. & Damborsky, J. Machine learning in enzyme engineering. ACS Catal. 10, 1210–1223 (2020).

    CAS  Google Scholar 

  65. Jacques, P. et al. High-throughput strategies for the discovery and engineering of enzymes for biocatalysis. Bioprocess. Biosyst. Eng. 40, 161–180 (2017).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the National Institute of General Medical Sciences (grant R35 GM128895) for support with the writing of this manuscript and with our laboratory’s studies in this area. All enzyme structures were prepared using UCSF Chimera (version 1.16). H.R. is a CPRIT scholar in cancer research.

Author information

Authors and Affiliations

  1. Department of Natural Medicine, School of Pharmacy, Fudan University, Shanghai, China

    Fuzhuo Li

  2. Department of Chemistry, BioScience Research Collaborative, Rice University, Houston, TX, USA

    Heping Deng & Hans Renata

Authors
  1. Fuzhuo Li
    View author publications

    Search author on:PubMed Google Scholar

  2. Heping Deng
    View author publications

    Search author on:PubMed Google Scholar

  3. Hans Renata
    View author publications

    Search author on:PubMed Google Scholar

Contributions

H.R. conceived of the scope of this Review. F.L., H.D. and H.R. wrote and edited the manuscript.

Corresponding author

Correspondence to Hans Renata.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Synthesis thanks Xiaoguang Lei and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Thomas West, in collaboration with the Nature Synthesis team.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, F., Deng, H. & Renata, H. Chemoenzymatic approaches for exploring structure–activity relationship studies of bioactive natural products. Nat. Synth 2, 708–718 (2023). https://doi.org/10.1038/s44160-023-00358-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s44160-023-00358-8

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing