Mapping of Ligandable tyrosine and lysine residues in proteins implicated in mitochondrial DNA depletion and therapeutic relevance

AI Summary

Chemoproteomic mapping of ligandable lysine and tyrosine residues expands covalent drug discovery and chemical biology beyond cysteine.
Analysis of 950 ligandable proteins shows significant enrichment of genes linked to mitochondrial DNA depletion syndromes.
Ligandable sites in SUCLG1 (active-site lysine) and AGK (tyrosine) highlight opportunities for covalent inhibition and allosteric modulation of mitochondrial disease targets.

TL;DR (AI Generated)

Several MDDS-associated proteins contained ligandable lysine or tyrosine residues, highlighting opportunities for therapeutic intervention in genetically validated mitochondrial disease targets.

We discuss two representative examples: SUCLG1, which contains a ligandable active-site lysine that may enable covalent inhibition, and AGK, which contains a ligandable tyrosine that may provide an allosteric strategy for modulating mitochondrial and immune signaling.

These findings extend emerging links between chemoproteomic ligandability and human genetics to mitochondrial DNA depletion disorders, suggest new opportunities for chemical probe and drug discovery, and provide a framework for prioritizing disease-relevant targets identified through covalent chemoproteomics.

Basic summary

Bioorg Med Chem Lett. 2026 Nov 13:130815. doi: 10.1016/j.bmcl.2026.130815. Online ahead of print.

ABSTRACT

Chemoproteomic mapping of ligandable lysine and tyrosine residues has expanded covalent drug discovery and chemical biology beyond cysteine. Analysis of 950 ligandable proteins revealed a significant enrichment of genes associated with mitochondrial DNA depletion syndromes (MDDS). Several MDDS-associated proteins contained ligandable lysine or tyrosine residues, highlighting opportunities for therapeutic intervention in genetically validated mitochondrial disease targets. We discuss two representative examples: SUCLG1, which contains a ligandable active-site lysine that may enable covalent inhibition, and AGK, which contains a ligandable tyrosine that may provide an allosteric strategy for modulating mitochondrial and immune signaling. These findings extend emerging links between chemoproteomic ligandability and human genetics to mitochondrial DNA depletion disorders, suggest new opportunities for chemical probe and drug discovery, and provide a framework for prioritizing disease-relevant targets identified through covalent chemoproteomics.

PMID:43025474 | DOI:10.1016/j.bmcl.2026.130815

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