Richard Hopkinson
Understanding the functional role of formaldehyde in health and disease
Research summary
Formaldehyde (HCHO) is one of simplest organic molecules found in nature but is toxic and carcinogenic to humans above threshold levels. Acute exposure to HCHO either through inhalation or ingestion may result in convulsions and kidney failure, whereas chronic exposure is linked to increased risk of cancers including nasopharyngeal cancer and leukaemia. In addition to its use in many industrial settings (HCHO is an occupational health hazard to workers in industries including plastics manufacturing, leather tanning and hairdressing), recent studies have revealed that HCHO is produced inside human cells. Although it is proposed that cells possess mechanisms to remove HCHO (at least when HCHO levels are not too high), it appears that cells have to maintain HCHO concentrations below critical levels to avoid its toxic and carcinogenic effects. There is some evidence that HCHO levels increase in some disease states (e.g. some neurodegenerative diseases) and with age, suggesting that controlling cellular exposure to HCHO is crucial to maintaining health, and the regulatory pathways are susceptible to changes in environment.
I am interested in determining how HCHO induces toxicity and carcinogenicity in human cells, and also how cells are able to regulate HCHO levels. The high reactivity of HCHO reveals the potential for it to react with biologically relevant molecules such as proteins and DNA inside cells, affecting their functions. Following on from work on the HCHO-producing histone demethylase enzymes (which are often over-expressed in cancer and developmental disorders), my research focuses on identifying cellular reactions involving HCHO, characterising cellular biomolecule-HCHO adducts, defining all pathways of cellular HCHO production and metabolism, and assessing HCHO’s effects on cell functions. These studies aim to fully define HCHO biochemistry at the molecular level and will help to identify novel preventative and therapeutic strategies against HCHO-mediated disease.
Humans are exposed to HCHO from environmental sources (e.g. pollution, cosmetics, industrial waste and cavity wall insulation) and from enzymatic demethylation reactions on DNA and proteins. Cellular HCHO is metabolised by at least two pathways, which both involve initial reactions of HCHO with nucleophiles (glutathione thiol and tetrahydrofolate amine respectively). HCHO also reacts with nucleic acids, proteins, lipids and peptides to form potentially toxic and regulatory cross-linked adducts. Cell-penetrant HCHO-releasing prodrugs and HCHO scavengers can be used to modulate cellular HCHO concentrations.
Key publications
- Pfeffer I, Brewitz L, Krojer T, Jensen SA, Kochan GT, Kershaw NJ, Hewitson KS, McNeill LA, Kramer H, Münzel M, Hopkinson RJ, Oppermann U, Handford PA, McDonough MA, Schofield CJ. (2019) Aspartate/asparagine-β-hydroxylase crystal structures reveal an unexpected epidermal growth factor-like domain substrate disulfide pattern. Nature Communications 10(1):4910.
- Reinbold R, John T, Spingardi P, Kawamura A, Thompson AL, Schofield CJ , Hopkinson RJ (2019) Formaldehyde quantification using ampicillin is not selective Sci Rep 9, 18289 doi:10.1038/s41598-019-54610-3
- Abboud MI, McAllister TE, Leung IKH, Chowdhury R, Jorgensen C, Domene C, Mecinovič _J, Lippl K, Hancock RL, Hopkinson RJ, Kawamura A, Claridge TDW, Schofield CJ (2018) 2-Oxoglutarate regulates binding of hydroxylated hypoxia-inducible factor to prolyl hydroxylase domain 2. ChemComm (Camb). ;54(25):3130-3133.
- Hancock RL, Abboud MI, Smart TJ, Flashman E, Kawamura A, Schofield CJ, Hopkinson RJ. (2018) Lysine-241 Has a Role in Coupling 2OG Turnover with Substrate Oxidation During KDM4-Catalysed Histone Demethylation. Chembiochem 19(9):917-921
- Shishodia S, Zhang D, El-Sagheer A, Brown T, Claridge TDW, Schofiel CJ, Hopkinson RJ. NMR Analyses on N-Hydroxymethylated Nucleobases – Implications for Formaldehyde Toxicity and Nucleic Acid Demethylases. Organic and Biomolecular Chemistry, 16, 4021-4032
- Hopkinson RJ, et al. (2015) 'Studies on the Glutathione-Dependent Formaldehyde-Activating Enzyme from Paracoccus denitrificans.' PloS ONE, vol. 10. P. e0145085
Group members:
Natasha Bulman, Sara Chothia, Vicki Emms