Version 2 2024-03-19, 15:05Version 2 2024-03-19, 15:05
Version 1 2024-03-12, 13:07Version 1 2024-03-12, 13:07
journal contribution
posted on 2024-03-19, 15:05authored bySteven
W. M. Crossley, Logan Tenney, Vanha N. Pham, Xiao Xie, Michelle W. Zhao, Christopher J. Chang
Formate
is a major reactive carbon species in one-carbon metabolism,
where it serves as an endogenous precursor for amino acid and nucleic
acid biosynthesis and a cellular source of NAD(P)H. On the other hand,
aberrant elevations in cellular formate are connected to progression
of serious diseases, including cancer and Alzheimer’s disease.
Traditional methods for formate detection in biological environments
often rely on sample destruction or extensive processing, resulting
in a loss of spatiotemporal information. To help address these limitations,
here we present the design, synthesis, and biological evaluation of
a first-generation activity-based sensing system for live-cell formate
imaging that relies on iridium-mediated transfer hydrogenation chemistry.
Formate facilitates an aldehyde-to-alcohol conversion on various fluorophore
scaffolds to enable fluorescence detection of this one-carbon unit,
including through a two-color ratiometric response with internal calibration.
The resulting two-component probe system can detect changes in formate
levels in living cells with a high selectivity over potentially competing
biological analytes. Moreover, this activity-based sensing system
can visualize changes in endogenous formate fluxes through alterations
of one-carbon pathways in cell-based models of human colon cancer,
presaging the potential utility of this chemical approach to probe
the continuum between one-carbon metabolism and signaling in cancer
and other diseases.