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.

Polyketide Biosynthesis

An artificial pathway for polyketide biosynthesis

Nature Catalysis volume 3, pages 536–538 (2020)Cite this article

Subjects

Polyketide synthases are multi-domain enzymes that catalyse the construction of many bioactive natural products. Now, some of the inefficiencies and limitations of these systems have been solved by designing an artificial pathway for carbon–carbon bond formation via iterative rounds of non-decarboxylative thio-Claisen reactions.

Polyketides are a class of natural products with diverse and potent biological activities, owing to their structural complexity and chemical diversity. Notable examples of polyketides include lovastatin (anticholesterol), doxorubicin (anticancer), ivermectin (antiparasitic), and erythromycin A (macrolide antibiotic). All polyketides are assembled via the repeated decarboxylative thio-Claisen condensation between malonyl-coenzyme A (malonyl-CoA) derivatives catalysed by enzyme machinery called polyketide synthases (PKSs). Type I PKSs are multi-modular mega-enzyme complexes, type II PKSs are a collection of cooperative enzymes, and type III PKSs iteratively catalyse chain elongation via ketosynthase domains. Though they differ in complexity and molecular organization, the three PKS types share similar substrate scopes, which largely consist of malonyl- and methylmalonyl-CoA extender units and simple acyl-CoA starter units, such as acetyl-, propionyl-, and isobutyryl-CoA. Site-selective modular control of oxidation levels by PKSs facilitates structural diversity in the polyketide scaffold that contributes to their biological activity1. In spite of the proven ability to leverage PKSs for the production of blockbuster polyketide drugs, polyketide biosynthesis suffers from slow reaction kinetics, low energy efficiency, and poor carbon economy — only two out of three extender unit carbons incorporate into the polyketide backbone with loss of CO2. In addition, the formation of the commonly utilized malonyl-CoA extender unit from acetyl-CoA, ATP and bicarbonate by acetyl-CoA carboxylase (ACC) is highly regulated and a likely rate-limiting step2. While type II and III PKSs can be less complicated than their type I counterparts, they often do not express well in tractable heterologous hosts such as Escherichia coli (E. coli) and access to substrates is susceptible to competition with primary metabolism.

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

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

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

Fig. 1: Natural and artificial pathways to polyketide products.

References

  1. Kalkreuter, E. & Williams, G. J. Curr. Opin. Microbiol. 45, 140–148 (2018).

    Article  CAS  Google Scholar 

  2. Wu, X. & Huang, T. Future Med. Chem. 12, 533–561 (2020).

    Article  CAS  Google Scholar 

  3. Tan, Z., Clomburg, J. M., Cheong, S., Qian, S. & Gonzalez, R. Nat. Catal. https://doi.org/10.1038/s41929-020-0471-8 (2020).

    Article  Google Scholar 

  4. Haapalainen, A. M., Gitte, M. & Rik, K. W. Trends Biochem. Sci. 31, 64–71 (2006).

    Article  CAS  Google Scholar 

  5. Tang, S. et al. J. Am. Chem. Soc. 135, 10099–10103 (2013).

    Article  CAS  Google Scholar 

  6. Kalkreuter, E., CroweTipton, J. M., Lowell, A. N., Sherman, D. H. & Williams, G. J. J. Am. Chem. Soc. 141, 1961–1969 (2019).

    Article  CAS  Google Scholar 

  7. Bonk, B. M., Tarasova, Y., Hicks, M. A., Tidor, B. & Prather, K. L. J. Biotechnol. Bioeng. 115, 2167–2182 (2018).

    Article  CAS  Google Scholar 

  8. Blaisse, M. R., Fu, B. & Chang, M. C. Y. Biochemistry 57, 3155–3166 (2018).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Chemistry, NC State University, Raleigh, NC, USA

    Anuran K. Gayen, Lindsay Nichols & Gavin J. Williams

Authors
  1. Anuran K. Gayen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lindsay Nichols
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gavin J. Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gavin J. Williams.

Ethics declarations

Competing Interests

The authors declare no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gayen, A.K., Nichols, L. & Williams, G.J. An artificial pathway for polyketide biosynthesis. Nat Catal 3, 536–538 (2020). https://doi.org/10.1038/s41929-020-0483-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41929-020-0483-4

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