Butelase‐Mediated Macrocyclization of <scp>d</scp>‐Amino‐Acid‐Containing Peptides

Nguyen, Giang Kien Truc; Hemu, Xinya; Quek, Jun-Ping; Tam, James P.

doi:10.1002/ange.201607188

Cited by 33 publications

(26 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It was found that kB1 and SFIT‐1 can be cyclized by butelase 1 with excellent efficiency (>95% yeild) 183 . Butelase 1 has a broad application as it could also recognize and cyclize peptide with nonnatural amino acids such as (N14)‐D‐SFTI‐1 184 . Similarly, OaAEP1b was shown to generate bioactive kB1 effectively 25,180 .…”

Section: Transforming Plant Cyclic Peptide Production and Drug Development With Insights Gained From Their Biosynthesismentioning

confidence: 99%

Exploring and exploiting plant cyclic peptides for drug discovery and development

Zhang

Yuan

et al. 2021

Medicinal Research Reviews

View full text Add to dashboard Cite

Ever since the discovery of insulin, natural peptides have become an important resource for therapeutic development. Decades of research has led to the discovery of a long list of peptide drugs with broad applications in clinics, from antibiotics to hypertension treatment to pain management. Many of these US FDA‐approved peptide drugs are derived from microorganisms and animals. By contrast, the great potential of plant cyclic peptides as therapeutics remains largely unexplored. These macrocyclic peptides typically have rigid structures, good bioavailability and membrane permeability, making them appealing candidates for drug development and engineering. In this review, we introduce the three major classes of plant cyclic peptides and summarize their potential medical applications. We discuss how we can leverage the genome information of many different plants to quickly search for new cyclic peptides and how we can take advantage of the insights gained from their biosynthetic pathways to transform the process of production and drug development. These recent developments have provided a new angle for exploring and exploiting plant cyclic peptides, and we believe that many more peptide drugs derived from plants are about to come.

show abstract

Section: Transforming Plant Cyclic Peptide Production and Drug Development With Insights Gained From Their Biosynthesismentioning

confidence: 99%

Exploring and exploiting plant cyclic peptides for drug discovery and development

Zhang

Yuan

et al. 2021

Medicinal Research Reviews

View full text Add to dashboard Cite

show abstract

“…Given the considerable interest in developing efficient macrocyclizing enzymes as tools for producing highly stable bioactive molecules, butelase 1, the most efficient native cyclizing AEP known to date, has attracted a great deal of attention (Nguyen et al ., , ,b; Bi et al ., ). However, the practicality of butelase 1 as a tool for synthetic production of cyclic peptides has been limited by an inability to produce it as a recombinant protein (Nguyen et al ., ).…”

Section: Introductionmentioning

confidence: 99%

The macrocyclizing protease butelase 1 remains autocatalytic and reveals the structural basis for ligase activity

et al. 2019

View full text Add to dashboard Cite

Plant asparaginyl endopeptidases (AEPs) are expressed as inactive zymogens that perform maturation of seed storage protein upon cleavage-dependent autoactivation in the low-pH environment of storage vacuoles. The AEPs have attracted attention for their macrocyclization reactions, and have been classified as cleavage or ligation specialists. However, we have recently shown that the ability of AEPs to produce either cyclic or acyclic products can be altered by mutations to the active site region, and that several AEPs are capable of macrocyclization given favorable pH conditions. One AEP extracted from Clitoria ternatea seeds (butelase 1) is classified as a ligase rather than a protease, presenting an opportunity to test for loss of cleavage activity. Here, making recombinant butelase 1 and rescuing an Arabidopsis thaliana mutant lacking AEP, we show that butelase 1 retains cleavage functions in vitro and in vivo. The in vivo rescue was incomplete, consistent with some trade-off for butelase 1 specialization toward macrocyclization. Its crystal structure showed an active site with only subtle differences from cleaving AEPs, suggesting the many differences in its peptide-binding region are the source of its efficient macrocyclization. All considered, it seems that either butelase 1 has not fully specialized or a requirement for autocatalytic cleavage is an evolutionary constraint upon macrocyclizing AEPs.

show abstract

“…Homology‐based modelling of Butelase 1 suggested that a putative extended C‐terminal domain could contribute to its ligase activity by binding the cleaved substrate at the active site and protecting the acyl intermediate from hydrolysis in a similar manner to PatG, a cyanobacterial serine protease capable of cyclization (Koehnke et al ., ; Nguyen et al ., ). The C. ternatea‐ extracted AEP was highly efficient and has been subsequently used to cyclize or ligate an impressive host of non‐native targets (Nguyen et al ., , ,b; Hemu et al ., ); however, attempts by Nguyen et al . () to generate recombinant protein failed, limiting its potential for commercial use.…”

Section: Plant Aeps With Macrocyclizing Abilitymentioning

confidence: 99%

Macrocyclization by asparaginyl endopeptidases

2017

View full text Add to dashboard Cite

Contents Summary923I.Introduction923II.Plant AEPs with macrocyclizing ability924III.Mechanism of macrocyclization by AEPs925IV.Conclusions927Acknowledgements927References927 Summary Plant asparaginyl endopeptidases (AEPs) are important for the post‐translational processing of seed storage proteins via cleavage of precursor proteins. Some AEPs also function as peptide bond‐makers during the biosynthesis of several unrelated classes of cyclic peptides, namely the kalata‐type cyclic peptides, PawS‐Derived Peptides and cyclic knottins. These three families of gene‐encoded peptides have different evolutionary origins, but all have recruited AEPs for their maturation. In the last few years, the field has advanced rapidly, with the biochemical characterization of three plant AEPs capable of peptide macrocyclization, and insights have been gained from the first AEP crystal structures, albeit mammalian ones. Although the biochemical studies have improved our understanding of the mechanism of action, the focus now is to understand what changes in AEP sequence and structure enable some plant AEPs to perform macrocyclization reactions.

show abstract

Butelase‐Mediated Macrocyclization of d‐Amino‐Acid‐Containing Peptides

Cited by 33 publications

References 41 publications

Exploring and exploiting plant cyclic peptides for drug discovery and development

Exploring and exploiting plant cyclic peptides for drug discovery and development

The macrocyclizing protease butelase 1 remains autocatalytic and reveals the structural basis for ligase activity

Macrocyclization by asparaginyl endopeptidases

Contact Info

Product

Resources

About