Non-enzymatic Covalent Modifications as a New Chapter in the Histone Code

Methylglyoxal Induces Endothelial Dysfunction via Stunning-like Phenotype

“…Although no measurement of MG-derived DNA modifications was made, it would be expected that such modifications would occur at these concentrations leading to the activation of the DNA damage response and ultimately cytotoxicity. It has also been shown that modification of histones by glycation interfere with the epigenetic signature of a cell, thereby changing the regulatory functions in the processing of genetic information, independent of any direct effects that MG might have on the DNA (Rahmanpour and Bathaie, 2011;Zheng et al, 2019;Maksimovic and David, 2021;Talasz et al, 2002;Gugliucci, 1994;Galligan et al, 2018). Modification of the nuclear proteins, rather than the DNA, could therefore be the driving force behind the effects induced by MG. A blockage in transcription and translation, resulting from a change in chromatin dynamics, would be consistent with the observed inhibition in the synthesis of the macromolecules, which occurred at an EC50 that proceeded the cell arrest, the loss in proliferative capacity and cell viability markers.…”

Thiolactone chemistry, a versatile platform for macromolecular engineering

“…This modification of biological proteins, a process called N-homocysteinylation, is detrimental to their function and increases oligomerization through disulfide bridge formation. [29][30][31] For the first time in 1956, Benesch et al mimicked this reaction using N-acetylhomocysteine thiolactone to introduce thiol groups in natural proteins in biochemistry. 26 This atom economical technique enabling the preparation of thiol-containing peptides and similar ones were patented, 32,33 after which N-acetyl homocysteine thiolactone (NHTL) was used for the thiolation of numerous amine-containing natural compounds.…”

Chromatin structure in cancer

“…While metabolic products can alter chromatin structure–function relationships through enzymatic processes, there is evidence that non-enzymatic processes link metabolic outputs and chromatin structure as well. With new insights from non-enzymatic covalent histone modifications (NECMs) [ 51 , 52 ], there are additional opportunities to (1) expand the scope of known chromatin PTMs, and (2) interrogate the recently discovered metabolic drivers of NECMs to ask if they have instructive effects on chromatin structure. Examples include evidence for histone glycation [ 53 ], histone acylation [ 54 ], and histone lipidation [ 55 ].…”