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.


  • NSF Public Access
  • Search Results
  • Single-Step Replacement of an Unreactive C–H Bond by a C–S Bond Using Polysulfide as the Direct Sulfur Source in the Anaerobic Ergothioneine Biosynthesis
Title: Single-Step Replacement of an Unreactive C–H Bond by a C–S Bond Using Polysulfide as the Direct Sulfur Source in the Anaerobic Ergothioneine Biosynthesis
Ergothioneine, a natural longevity vitamin and antioxidant, is a thiol-histidine derivative. Recently, two types of biosynthetic pathways were reported. In the aerobic ergothioneine biosyntheses, non-heme iron enzymes incorporate a sulfoxide into an sp2 C–H bond from trimethyl-histidine (hercynine) through oxidation reactions. In contrast, in the anaerobic ergothioneine biosynthetic pathway in a green-sulfur bacterium, Chlorobium limicola, a rhodanese domain containing protein (EanB), directly replaces this unreactive hercynine C–H bond with a C–S bond. Herein, we demonstrate that polysulfide (HSSnSR) is the direct sulfur source in EanB catalysis. After identifying EanB’s substrates, X-ray crystallography of several intermediate states along with mass spectrometry results provide additional mechanistic details for this reaction. Further, quantum mechanics/molecular mechanics (QM/MM) calculations reveal that the protonation of Nπ of hercynine by Tyr353 with the assistance of Thr414 is a key activation step for the hercynine sp2 C–H bond in this trans-sulfuration reaction.  more » « less
Award ID(s):
2004109
PAR ID:
10250068
Author(s) / Creator(s):
Date Published:
Journal Name:
ACS catalysis
Volume:
10
Issue:
16
ISSN:
2155-5435
Page Range / eLocation ID:
8981
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. (, ACS catalysis)
    null (Ed.)
    In the anaerobic ergothioneine biosynthetic pathway, a rhodanese domain-containing enzyme (EanB) activates the hercynine’s sp2 ε-C–H bond and replaces it with a C–S bond to produce ergothioneine. The key intermediate for this trans-sulfuration reaction is the Cys412 persulfide. Substitution of the EanB-Cys412 persulfide with a Cys412 perselenide does not yield the selenium analogue of ergothioneine, selenoneine. However, in a deuterated buffer, perselenide-modified EanB catalyzes the deuterium exchange between hercynine’s sp2 ε-C–H bond and D2O. Results from quantum mechanics/molecular mechanics calculations suggest that the reaction involves a carbene intermediate and that Tyr353 plays a key role. We hypothesize that modulating the pKa of Tyr353 will affect the deuterium exchange rate. Indeed, the 3,5-difluoro tyrosine-containing EanB catalyzes the deuterium exchange reaction with a kex ∼10-fold greater than the wild-type EanB (EanBWT). With regard to potential mechanisms, these results support the involvement of a carbene intermediate in the EanB catalysis, rendering EanB as one of the few carbene intermediate-involving enzymatic systems. 
    more » « less
  2. ; ; ; ; ; ; ; ; ; ; et al (, Angewandte Chemie)
    Abstract Ergothioneine (ESH) and ovothiol A (OSHA) are two natural thiol‐histidine derivatives. ESH has been implicated as a longevity vitamin and OSHA inhibits the proliferation of hepatocarcinoma. The key biosynthetic step of ESH and OSHA in the aerobic pathways is the O2‐dependent C−S bond formation catalyzed by non‐heme iron enzymes (e.g., OvoA in ovothiol biosynthesis), but due to the lack of identification of key reactive intermediate the mechanism of this novel reaction is unresolved. In this study, we report the identification and characterization of a kinetically competentS=1 iron(IV) intermediate supported by a four‐histidine ligand environment (three from the protein residues and one from the substrate) in enabling C−S bond formation in OvoA fromMethyloversatilis thermotoleran, which represents the first experimentally observed intermediate spin iron(IV) species in non‐heme iron enzymes. Results reported in this study thus set the stage to further dissect the mechanism of enzymatic oxidative C−S bond formation in the OSHA biosynthesis pathway. They also afford new opportunities to study the structure‐function relationship of high‐valent iron intermediates supported by a histidine rich ligand environment. 
    more » « less
  3. ; ; ; (, Journal of the American Chemical Society)
    Chromoselective bond activation has been achieved in organic helicenium (nPr-DMQA+)-based photoredox catalysis. Consequently, control over chromoselective C(sp2)–X bond activation in multihalogenated aromatics has been demonstrated. nPr-DMQA+ can only initiate the halogen atom transfer (XAT) pathway under red light irradiation to activate low-energy-accessible C(sp2)–I bonds. In contrast, blue light irradiation initiates consecutive photoinduced electron transfer (conPET) to activate more challenging C(sp2)–Br bonds. Comparative reaction outcomes have been demonstrated in the α-arylation of cyclic ketones with red and blue lights. Furthermore, red-light-mediated selective C(sp2)–I bonds have been activated in iodobromoarenes to keep the bromo functional handle untouched. Finally, the strength of the chromoselective catalysis has been highlighted with two-fold functionalization using both photo-to-transition metal and photo-to-photocatalyzed transformations. 
    more » « less
  4. ; ; (, Synthesis)
    Abstract C–H functionalization is a highly appealing strategy for accessing complex molecular structures. Herein, we show that π-tethered pincer ligands can engage in C–H activation when coordinated to iron. These reactions result in C(sp2)–C(sp2) bond formation through oxidative coupling and β-hydride elimination/reductive elimination pathways with alkynes and isocyanides. 
    more » « less
  5. ; ; ; ; (, Nature Communications)
    Abstract The search for more effective and highly selective C–H bond oxidation of accessible hydrocarbons and biomolecules is a greatly attractive research mission. The elucidating of mechanism and controlling factors will, undoubtedly, help to broaden scope of these synthetic protocols, and enable discovery of more efficient, environmentally benign, and highly practical new C–H oxidation reactions. Here, we reveal the stepwise intramolecular SN2 nucleophilic substitution mechanism with the rate-limiting C–O bond formation step for the Pd(II)-catalyzed C(sp3)–H lactonization in aromatic 2,6-dimethylbenzoic acid. We show that for this reaction, the direct C–O reductive elimination from both Pd(II) and Pd(IV) (oxidized by O2oxidant) intermediates is unfavorable. Critical factors controlling the outcome of this reaction are the presence of the η3-(π-benzylic)–Pd and K+–O(carboxylic) interactions. The controlling factors of the benzylic vs ortho site-selectivity of this reaction are the: (a) difference in the strains of the generated lactone rings; (b) difference in the strengths of the η3-(π-benzylic)–Pd and η2-(π-phenyl)–Pd interactions, and (c) more pronounced electrostatic interaction between the nucleophilic oxygen and K+cation in the ortho-C–H activation transition state. The presented data indicate the utmost importance of base, substrate, and ligand in the selective C(sp3)–H bond lactonization in the presence of C(sp2)–H. 
    more » « less
  • Citation Formats
  • MLA
  • APA
  • Chicago
  • BibTeX
  • Save / Share this Record
  • Send to Email