An enzyme for high-yield, ATP-driven C-terminal thioester generation

an-enzyme-for-high-yield,-atp-driven-c-terminal-thioester-generation
An enzyme for high-yield, ATP-driven C-terminal thioester generation
  • Research Briefing
  • Published:

Nature Chemistry (2025)Cite this article

Subjects

Current tools for protein bioconjugation at the C-terminal have limited yields. Now, an enzymatic strategy for ATP-dependent activation of protein and peptide C termini has been developed. This versatile tool can be deployed for synthesis of C-terminal thioesters that enhance the yield and accessibility of diverse protein bioconjugation methods.

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

Access options

Access Nature and 54 other Nature Portfolio journals

Get Nature+, our best-value online-access subscription

$32.99 / 30 days

cancel any time

Subscribe to this journal

Receive 12 print issues and online access

$259.00 per year

only $21.58 per issue

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF

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

Fig. 1: MccB-catalysed C-terminal activation.

References

  1. Stephanopoulos, N. & Francis, M. B. Choosing an effective protein bioconjugation strategy. Nat. Chem. Biol. 7, 876–884 (2011). A review article that presents considerations and strategies for protein bioconjugation.

    CAS  PubMed  Google Scholar 

  2. Walsh, C. T., Tu, B. P. & Tang, Y. Eight kinetically stable but thermodynamically activated molecules that power cell metabolism. Chem. Rev. 118, 1460–1494 (2018). This review article describes the chemical logic by which cellular metabolism is coupled to energetic driving forces.

    CAS  PubMed  Google Scholar 

  3. Thompson, R. E. & Muir, T. W. Chemoenzymatic semisynthesis of proteins. Chem. Rev. 120, 3051–3126 (2020). This review article surveys chemical and enzymatic strategies that can be used for protein semisynthesis.

    CAS  PubMed  Google Scholar 

  4. Burroughs, A. M., Iyer, L. M. & Aravind, L. Natural history of the E1‐like superfamily: Implication for adenylation, sulfur transfer, and ubiquitin conjugation. Proteins Struct. Funct. Bioinform. 75, 895–910 (2009). This paper describes the functional diversity and evolutionary history of the ThiF enzyme superfamily.

    CAS  Google Scholar 

  5. Roush, R. F., Nolan, E. M., Löhr, F. & Walsh, C. T. Maturation of an Escherichia coli ribosomal peptide antibiotic by ATP-consuming N−P bond formation in microcin C7. J. Am. Chem. Soc. 130, 6055–6055 (2008). This paper describes the enzymatic strategy used by MccB for ATP-dependent N–P bond formation via a C-terminal adenylate intermediate.

    CAS  Google Scholar 

Download references

Additional information

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

This is a summary of: Frazier, C. L. et al. Engineered reactivity of a bacterial E1-like enzyme enables ATP-driven modification of protein and peptide C termini. Nat. Chem. https://doi.org/10.1038/s41557-025-01871-3 (2025).

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

An enzyme for high-yield, ATP-driven C-terminal thioester generation. Nat. Chem. (2025). https://doi.org/10.1038/s41557-025-01872-2

Download citation

  • Published:

  • DOI: https://doi.org/10.1038/s41557-025-01872-2