skip to main content
US FlagAn official website of the United States government
dot gov icon
Official websites use .gov
A .gov website belongs to an official government organization in the United States.
https lock icon
Secure .gov websites use HTTPS
A lock ( lock ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Explore Research Products in the PAR
It may take a few hours for recently added research products to appear in PAR search results.


Title: Organometallic Oxidative Addition Complexes for S -Arylation of Free Cysteines
Development of bioconjugation strategies to efficiently modify biomolecules is of key importance for fundamental and translational scientific studies. Cysteine S-arylation is an approach which is becoming more popular due to generally rapid kinetics and high chemoselectivity, as well as the strong covalently bonded S-aryl linkage created in these processes. Organometallic approaches to cysteine S-arylation have been explored that feature many advantages compared to their more traditional organic counterparts. In this Viewpoint, progress in the use of Au(III) and Pd(II) oxidative addition (OA) complexes for stoichiometric cysteine S-arylation is presented and discussed. A focus is placed on understanding the rapid kinetics of these reactions under mild conditions, as well as the ability to generate biomolecular heterostructures. Potential avenues for further exploration are addressed and usefulness of these methods to the practitioner are emphasized in the discussion.  more » « less
Award ID(s):
2003946
PAR ID:
10542801
Author(s) / Creator(s):
; ;
Publisher / Repository:
ACS Publications
Date Published:
Journal Name:
Bioconjugate Chemistry
Volume:
35
Issue:
7
ISSN:
1043-1802
Page Range / eLocation ID:
883 to 889
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. ; ; ; ; (, Chemistry – A European Journal)
    Abstract This study presents a Ni‐photoredox method for indoleN‐arylation, broadening the range of substrates to include indoles with unprotected C3‐positions and base‐sensitive groups. Through detailed mechanistic inquiries, a Ni(I/III) mechanism was uncovered, distinct from those commonly proposed for Ni‐catalyzed amine, thiol, and alcohol arylation, as well as from the Ni(0/II/III) cycle identified for amide arylation under almost identical conditions. The key finding is the formation of a Ni(I) intermediate bearing the indole nucleophile as a ligand prior to oxidative addition, which is rare for Ni‐photoredox carbon‐heteroatom coupling and has a profound impact on the reaction kinetics and scope. The pre‐coordination of indole renders a more electron‐rich Ni(I) intermediate, which broadens the scope by enabling fast reactivity even with challenging electron‐rich aryl bromide substrates. Thus, this work highlights the often‐overlooked influence of X‐type ligands on Ni oxidative addition rates and illustrates yet another mechanistic divergence in Ni‐photoredox C‐heteroatom couplings. 
    more » « less
  2. ; ; ; ; ; ; (, Chemical Science)
    In silicoexamination of 13P,N-ligated Au(iii) OACs determined the key mechanistic factors governing Au(iii)-mediatedS-arylation. Three complexes were synthesized which exhibited bimolecular coordination rate constants as high as 20 200 M−1s−1. 
    more » « less
  3. ; ; (, Journal of Bacteriology)
    Shank, Elizabeth Anne (Ed.)
    ABSTRACT Posttranscriptional modifications to tRNA are critical elements for the folding and functionality of these adaptor molecules. Sulfur modifications in tRNA are installed by specialized enzymes that act on cognate tRNA substrates at specific locations. Most studied organisms contain a general cysteine desulfurase to mobilize sulfur for the synthesis of S-tRNA and other thio-cofactors. Bacillus subtilis and other Gram-positive bacteria encode multiple cysteine desulfurases that partner with specific sulfur acceptors in the biosynthesis of thio-cofactors. This metabolic layout suggests an alternate mode of regulation in these biosynthetic pathways. In this study, tRNA modifications were exploited as a readout for the functionality of pathways involving cysteine desulfurases. These analyses showed that the relative abundance of 2-thiouridine-modified tRNA (s 2 U) responds to sulfur availability in the growth medium in a dose-dependent manner. This study found that low sulfur concentrations lead to decreased levels of the s 2 U cysteine desulfurase YrvO and thiouridylase MnmA, without altering the levels of other cysteine desulfurases, SufS, NifS, and NifZ. Analysis of pathway metabolites that depend on the activity of cysteine desulfurases indicates that sulfur nutrient availability specifically impacts s 2 U accumulation while having no effect on the levels of other S-modified tRNA or activity levels of Fe-S enzymes. Collectively, these results support a model in which s 2 U tRNA serves as a marker for sulfur availability in B. subtilis . IMPORTANCE The 2-thiouridine (s 2 U) tRNA modification is found ubiquitously across all domains of life. YrvO and MnmA, the enzymes involved in this modification, are essential in B. subtilis , confirming the well-established role of s 2 U in maintaining translational efficiency and, consequently, cellular viability. Herein, we show that in the model Gram-positive organism Bacillus subtilis , the levels of s 2 U are responsive to sulfur availability. Downregulation of the s 2 U biosynthetic components leads to lower s 2 U levels, which may serve as a signal for the slowing of the translational apparatus during cellular nutrient insufficiency. Our findings provide the basis for the identification of a potential bacterial mode of regulation during S-metabolite depletion that may use s 2 U as a marker of suboptimal metabolic status. 
    more » « less
  4. ; ; ; ; ; ; ; (, Protein Science)
    Abstract We report the recombinant preparation fromEscherichia colicells of samples of two closely related, small, secreted cysteine‐rich plant peptides: rapid alkalinization factor 1 (RALF1) and rapid alkalinization factor 8 (RALF8). Purified samples of the native sequence of RALF8 exhibited well‐resolved nuclear magnetic resonance (NMR) spectra and also biological activity through interaction with a plant receptor kinase, cytoplasmic calcium mobilization, andin vivoroot growth suppression. By contrast, RALF1 could only be isolated from inclusion bodies as a construct containing an N‐terminal His‐tag; its poorly resolved NMR spectrum was indicative of aggregation. We prepared samples of the RALF8 peptide labeled with15N and13C for NMR analysis and obtained near complete1H,13C, and15N NMR assignments; determined the disulfide pairing of its four cysteine residues; and examined its solution structure. RALF8 is mostly disordered except for the two loops spanned by each of its two disulfide bridges. 
    more » « less
  5. ; ; ; (, Chemistry – A European Journal)
    Abstract This work reports a novel chlorooxime mediated modification of native peptides and proteins under physiologic conditions. This method features fast reaction kinetics (apparentk2=306±4 M−1s−1for GSH) and exquisite selectivity for cysteine residues. This cysteine conjugation reaction can be carried out with just single‐digit micromolar concentrations of the labeling reagent. The conjugates show high stability towards acid, base, and external thiol nucleophiles. A nitrile oxide species generated in situ is likely involved as the key intermediate. Furthermore, a bis‐chlorooxime reagent is synthesized to enable facile Cys‐Cys stapling in native peptides and proteins. This highly efficient cysteine conjugation and stapling was further implemented on bacteriophage to construct chemically modified phage libraries. 
    more » « less
  • Citation Formats
  • MLA
  • APA
  • Chicago
  • BibTeX
  • Save / Share this Record
  • Send to Email