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Cooperative Aldehyde Chemistry Maps an Orthogonal Lysine Reactivity Landscape

ABSTRACT: Reactive metabolites are often associated with nonspecific protein damage, if harnessed cooperatively they could be repurposed into precision tools for targeted labeling, redefining how we probe and manipulate protein function in complex biological systems. Here, we introduce a bioinspired cooperative metabolite strategy that harnesses the synergistic chemistry of malondialdehyde (MDA) and monoaldehydes to generate highly reactive intermediates that selectively modify lysine residues across proteins and proteomes. Dose-dependent chemoproteomic profiling of proteins modified by MDA-monoaldehyde complexes reveals 245 peptides and 167 unique proteins commonly modified in all doses. Among these, nearly 100 proteins feature a single modification at only hyperreactive lysine residue, indicating distinct microenvironmental features that enhance lysine reactivity and selectivity toward cooperative metabolite modification. Captured proteins were found to be linked to disease pathways and environmental exposures, revealing previously unrecognized patterns of metabolic susceptibility.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Riley Hughes

LAB HEAD: Monika Raj

PROVIDER: PXD067614 | Pride | 2026-04-14

REPOSITORIES: Pride

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			Action	DRS
	20250220_AV_1000A.raw	Raw
	20250220_AV_1000B.raw	Raw
	20250220_AV_100A.raw	Raw
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	20250220_AV_2000A.raw	Raw

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