A Chemical Proteomic Probe for the Mitochondrial Pyruvate Carrier Complex

Yu Yamashita, Ekaterina V. Vinogradova, Xiaoyu Zhang, Radu M. Suciu, Benjamin F. Cravatt*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Target engagement assays are crucial for establishing the mechanism-of-action of small molecules in living systems. Integral membrane transporters can present a challenging protein class for assessing cellular engagement by small molecules. The chemical proteomic discovery of alpha-chloroacetamide (αCA) compounds that covalently modify cysteine-54 (C54) of the MPC2 subunit of the mitochondrial pyruvate carrier (MPC) is presented. This finding is used to create an alkyne-modified αCA, YY4-yne, that serves as a cellular engagement probe for MPC2 in click chemistry-enabled western blotting or global mass spectrometry-based proteomic experiments. Studies with YY4-yne revealed that UK-5099, an alpha-cyanocinnamate inhibitor of the MPC complex, engages MPC2 with remarkable selectivity in human cells. These findings support a model where UK-5099 inhibits the MPC complex by binding to C54 of MPC2 in a covalent reversible manner that can be quantified in cells using the YY4-yne probe.

Original languageEnglish (US)
Pages (from-to)3896-3899
Number of pages4
JournalAngewandte Chemie - International Edition
Issue number10
StatePublished - Mar 2 2020
Externally publishedYes


  • chemical proteomics
  • cysteine
  • mitochondrial pyruvate complex
  • target engagement
  • α-chloroacetamide

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)


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