Protein CoAlation and antioxidant function of coenzyme A in prokaryotic cells

Abstract

In all living organisms, coenzyme A (CoA) is an essential cofactor with a unique design allowing it to function as an acyl group carrier and a carbonyl-activating group in diverse biochemical reactions. It is synthesized in a highly conserved process in prokaryotes and eukaryotes that requires pantothenic acid (vitamin B5), cysteine and ATP. CoA and its thioester derivatives are involved in major metabolic pathways, allosteric interactions and the regulation of gene expression. A novel unconventional function of CoA in redox regulation has been recently discovered in mammalian cells and termed protein CoAlation. Here, we report for the first time that protein CoAlation occurs at a background level in exponentially growing bacteria and is strongly induced in response to oxidizing agents and metabolic stress. Over 12% of Staphylococcus aureus gene products were shown to be CoAlated in response to diamide-induced stress. In vitro CoAlation of S. aureus glyceraldehyde-3-phosphate dehydrogenase was found to inhibit its enzymatic activity and to protect the catalytic cysteine 151 from overoxidation by hydrogen peroxide. These findings suggest that in exponentially growing bacteria, CoA functions to generate metabolically active thioesters, while it also has the potential to act as a low-molecular-weight antioxidant in response to oxidative and metabolic stress.

4′‐Phosphopantetheine corrects CoA, iron, and dopamine metabolic defects in mammalian models of PKAN

“…This difference is hypothesized to reflect the portion of CoA synthesis that is specifically attributable to pantothenate kinase 2. We further suggest that regulation of expression of the CoA synthase gene can be controlled by levels of substrate, 4′‐phosphopantetheine, and product, CoA, either directly or possibly via the CoAlation of transcription factors or regulatory proteins (Tsuchiya et al , , ; Gout, ).…”

Mechanistic basis for impaired ferroptosis in cells expressing the African-centric S47 variant of p53

“…The role of CoA in ferroptosis sensitivity remains to be further determined. This thiol can act as a cellular antioxidant (47,48).…”

Covalent Aurora A regulation by the metabolic integrator coenzyme A

“…In addition to an inhibitory effect on Aurora A activity, CoAlation at Cys 290 may serve other regulatory purposes. First, CoA modification might protect Cys 290 from overoxidation, which may lead to an irreversible loss of function and subsequent inactivation and/or degradation of Aurora A. The widespread ability of CoA to act as a low-molecular-weight antioxidant in response to oxidative and metabolic stress in prokaryotic and eukaryotic cells has been recently demonstrated (Tsuchiya et al, 2017, Tsuchiya et al, 2018. In these studies, in vitro CoAlation of the catalytic Cys 151 in glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was shown to protect this essential glycolytic enzyme against irreversible overoxidation and the associated loss of activity.…”

“…This recent discovery was only possible with the development of unique research tools and methodologies, which revealed protein CoAlation as a widespread and reversible PTM involved in cellular redox regulation (Malanchuk et al, 2015). To date, more than one thousand proteins have been found to be CoAlated in a variety of prokaryotic and eukaryotic cells (Tsuchiya et al, 2017, Tsuchiya et al, 2018. Protein CoAlation occurs at a low level in exponentialy growing cells, but is strongly induced in reponse to various oxidising agents, including H2O2, diamide, menadione and t-butyl hydroperoxide.…”