Coenzyme A, protein CoAlation and redox regulation in mammalian cells

Abstract

In a diverse family of cellular cofactors, coenzyme A (CoA) has a unique design to function in various biochemical processes. The presence of a highly reactive thiol group and a nucleotide moiety offers a diversity of chemical reactions and regulatory interactions. CoA employs them to activate carbonyl-containing molecules and to produce various thioester derivatives (e.g. acetyl CoA, malonyl CoA and 3-hydroxy-3-methylglutaryl CoA), which have well-established roles in cellular metabolism, production of neurotransmitters and the regulation of gene expression. A novel unconventional function of CoA in redox regulation, involving covalent attachment of this coenzyme to cellular proteins in response to oxidative and metabolic stress, has been recently discovered and termed protein CoAlation (S-thiolation by CoA or CoAthiolation). A diverse range of proteins was found to be CoAlated in mammalian cells and tissues under various experimental conditions. Protein CoAlation alters the molecular mass, charge and activity of modified proteins, and prevents them from irreversible sulfhydryl overoxidation. This review highlights the role of a key metabolic integrator CoA in redox regulation in mammalian cells and provides a perspective of the current status and future directions of the emerging field of protein CoAlation.

Keywords: coenzyme A; metabolic control analysis; oxidation–reduction; post-translational modification.

Figure 1.. Biosynthesis and degradation of CoA in mammalian cells.

(A) The conventional de novo and alternative pathways of CoA biosynthesis are shown. (B) CoA degradation involves phosphodiesterases, phosphatases and pantetheinases.

Figure 2.. Cellular functions of CoA and its derivatives.

CoA thioester derivatives are implicated in diverse cellular functions, including the Krebs cycle, ketogenesis, biosynthesis of cholesterol and acetylcholine, the degradation of amino acids, the synthesis and oxidation of fatty acids, biosynthesis of neurotransmitters and the regulation of gene expression. Protein CoAlation is a novel, unconventional function of CoA in redox regulation and antioxidant defence.

Figure 3.. Emerging functions of protein CoAlation in mammalian cells.

(A) The effect of CoAlation on the function of modified proteins. (B) Redox regulation of the protein CoAlation/deCoAlation cycle.