LanCLs add glutathione to dehydroamino acids generated at phosphorylated sites in the proteome

Kuan Yu Lai, Sébastien R.G. Galan, Yibo Zeng, Tianhui Hina Zhou, Chang He, Ritu Raj, Jitka Riedl, Shi Liu, K. Phin Chooi, Neha Garg, Min Zeng, Lyn H. Jones, Graham J. Hutchings, Shabaz Mohammed, Satish K. Nair, Jie Chen, Benjamin G. Davis, Wilfred A. van der Donk

Research output: Contribution to journalArticlepeer-review


Enzyme-mediated damage repair or mitigation, while common for nucleic acids, is rare for proteins. Examples of protein damage are elimination of phosphorylated Ser/Thr to dehydroalanine/dehydrobutyrine (Dha/Dhb) in pathogenesis and aging. Bacterial LanC enzymes use Dha/Dhb to form carbon-sulfur linkages in antimicrobial peptides, but the functions of eukaryotic LanC-like (LanCL) counterparts are unknown. We show that LanCLs catalyze the addition of glutathione to Dha/Dhb in proteins, driving irreversible C-glutathionylation. Chemo-enzymatic methods were developed to site-selectively incorporate Dha/Dhb at phospho-regulated sites in kinases. In human MAPK-MEK1, such “elimination damage” generated aberrantly activated kinases, which were deactivated by LanCL-mediated C-glutathionylation. Surveys of endogenous proteins bearing damage from elimination (the eliminylome) also suggest it is a source of electrophilic reactivity. LanCLs thus remove these reactive electrophiles and their potentially dysregulatory effects from the proteome. As knockout of LanCL in mice can result in premature death, repair of this kind of protein damage appears important physiologically.

Original languageEnglish (US)
Pages (from-to)2680-2695.e26
Issue number10
StatePublished - May 13 2021


  • C-glutathionylation
  • LanCL
  • MEK1
  • dehydroalanine
  • dehydrobutyrine
  • eliminylome
  • lanthionine
  • phosphoThr lyase
  • protein damage

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology


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