Formaldehyde Stress Responses in Bacterial Pathogens

Abstract

Formaldehyde is the simplest of all aldehydes and is highly cytotoxic. Its use and associated dangers from environmental exposure have been well documented. Detoxification systems for formaldehyde are found throughout the biological world and they are especially important in methylotrophic bacteria, which generate this compound as part of their metabolism of methanol. Formaldehyde metabolizing systems can be divided into those dependent upon pterin cofactors, sugar phosphates and those dependent upon glutathione. The more prevalent thiol-dependent formaldehyde detoxification system is found in many bacterial pathogens, almost all of which do not metabolize methane or methanol. This review describes the endogenous and exogenous sources of formaldehyde, its toxic effects and mechanisms of detoxification. The methods of formaldehyde sensing are also described with a focus on the formaldehyde responsive transcription factors HxlR, FrmR, and NmlR. Finally, the physiological relevance of detoxification systems for formaldehyde in bacterial pathogens is discussed.

The mechanism of a formaldehyde-sensing transcriptional regulator

“…Many of these chemicals have broad reactivity, which presents biological systems with a challenge to specifically sense and then respond to their presence before the cell suffers irreversible damage. Formaldehyde is a toxic electrophilic chemical that is generated endogenously by many organisms12. For example, formaldehyde is generated: (i) as an intermediate in methylotrophic metabolism; (ii) in the degradation of glycine, either by the glycolytic byproduct methylgloxal or by Fenton chemistry; (iii) in the degradation of heme, during iron acquisition by some Gram-positive bacteria; (iv) by lipid peroxidation of sugars; (v) by the demethylation of histones; (vi) as a product of methylated-DNA repair by AlkB; and (vii) by the action of N- methyltryptophan oxidase (SolA)234.…”

“…Formaldehyde-mediated genotoxicity is caused by the formation DNA-DNA and DNA-protein cross-links, as well as covalent DNA monoadducts12567. In addition, formaldehyde is able to covalently modify proteins, inhibiting their functions78.…”

“…In addition, formaldehyde is able to covalently modify proteins, inhibiting their functions78. The life-threatening damage caused by the broad chemical reactivity of formaldehyde has driven the evolution of mechanisms to detoxify formaldehyde and counteract its detrimental effects2. In order to regulate expression of these detoxification systems, it is imperative to maintain specific response-regulators in the cell that can perceive the presence of formaldehyde and induce protective systems before significant damage to vital cell components occurs.…”

ECM-body: A cell-free 3D biomimetic scaffold derived from intact planarian body

“…Although the use of formaldehyde in stabilization solution should kill all the potential contaminating microbes (25), to ensure the suitability of exploitation of ECM-body as a 3D scaffold in cell culture, the ECM-body was further assayed for bacterial and fungal contamination by incubating in mammalian cell culture media. As a result, based on the colour and clarity of the media, no sign of microbial growth was observed after 4 days of incubation ( Fig 3F).…”

Thioproline formation as a driver of formaldehyde toxicity inEscherichia coli

“…Formaldehyde (HCHO) is a highly reactive, toxic, and mutagenic carbonyl compound that all organisms produce in minor amounts during normal metabolism [1][2][3]. It is also a major and mandatory intermediate in natural and engineered ('synthetic') methylotrophic and formatotrophic pathways [1,[4][5][6], and in synthetic pathways to which methanol supplies reducing power but not carbon [7] (Figure 1).…”