Chemical Probes to Study Formaldehyde Biology

Project Summary/Abstract
Formaldehyde (FA) is a ubiquitous small molecule that plays a diverse array of important
roles in human health and disease. As the simplest aldehyde and reactive carbonyl
species, FA is a major environmental toxin that is classified as a carcinogen, and FA
exposure is also connected to a variety of other serious diseases ranging from chronic
liver disorders to cancer, cardiovascular and neurodegenerative diseases, and diabetes.
At the same time, the body produces this reactive carbonyl species during normal
physiology, primarily through enzymatic demethylation events as well as through the one-
carbon cycle. We seek to develop and apply new chemical reagents for selective imaging
and proteomics of FA in living systems to identify its molecular sources and targets, with
the long-term goal of understanding how and in what context this reactive small molecule
contributes to both physiology and disease. This application will focus on new
technologies to enable selective molecular imaging of FA in biological models to study
sources of FA generation and metabolism, with accompanying chemoproteomics methods
to identify targets of FA in genetic models where FA metabolism is compromised. Specific
aims include developing new fluorescent probes for subcellular imaging of FA and
enzymatic oxidation to formate, applying unbiased activity-based protein profiling (ABPP)
methods to identify cysteine-derived targets of FA in whole proteomes, and performing
biochemical and cellular studies to decipher roles of FA targets in regulating one-carbon
metabolism.

Grant Number: 5R01ES028096-11
NIH Institute/Center: NIH
Principal Investigator: Christopher Chang