A Chemical Toolkit to Define Formaldehyde’s Enigmatic Biology

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Formaldehyde (HCHO), the simplest aldehyde, is a highly reactive human metabolite. Despite its toxicity and carcinogenicity at high concentrations and its disease-inducing effects in Fanconi's anaemia patients, the mechanisms underpinning its biology are remarkably unknown. The recent pioneering discovery of HCHO production by chromatin demethylases, as well as recent work on HCHO-mediated C1 metabolism, suggest functionally relevant roles for HCHO under 'normal' conditions. However, detailed research in this area has been precluded by a lack of methods.From a chemical perspective, HCHO is highly reactive with biomolecules. This reactivity, which is exploited for uses e.g. in embalming and immunoprecipitation assays, is likely responsible for its biological functions. However, chemical insight is lacking.Given the routine production of HCHO in cells and its toxicity at high concentrations, the potential for it to regulate human health is clear and compelling. I therefore hypothesise that endogenous HCHO is a key functional regulator in human biology and potentially one of the most important small molecules in human cells. Dysregulation of cellular HCHO levels is likely to cause disease, making HCHO a potential 'silent killer'. Modulating cellular HCHO with small molecules is also likely to have therapeutic potential, opening up new avenues for drug discovery.HCHO's reactivity, volatility and small size make it very challenging to manipulate and study in biological systems. Consequently, HCHO's biology has been largely overlooked. In this project, I will therefore use my multidisciplinary background in organic synthesis, biochemistry, cell biology and analytical techniques to develop the first 'chemical HCHO toolkit' - this toolkit will enable the first systematic quantitative analysis of HCHO's functions in human biology. Specific objectives are:(1) To synthesise and validate first-in-class HCHO-releasing small molecules (FORMs) that enable controlled quantifiable release of HCHO in cells.(2) To synthesise and validate irreversible HCHO scavengers (FOSCs) that can reduce cellular HCHO concentrations.(3) To develop and validate the first sensitive cellular HCHO quantification methods using irreversible FOSCs coupled to NMR and GC/MS analyses.This pioneering toolkit will make it possible to identify reactions between HCHO and molecules in cells, to determine how HCHO levels vary in health and disease, to correlate these changes with biological phenotypes, and ultimately to validate HCHO modulation as a therapeutic strategy. These abilities are currently not possible but are essential to studying HCHO in cells. Therefore, this ambitious and timely project will provide the state-of-the-art platform technologies essential to establishing and furthering HCHO biological research in the UK and internationally. The work will also position my group at the forefront of this potentially transformative field, and will ultimately lead to new treatments for human diseases.