The Pathophysiological Role of CoA

Abstract

The importance of coenzyme A (CoA) as a carrier of acyl residues in cell metabolism is well understood. Coenzyme A participates in more than 100 different catabolic and anabolic reactions, including those involved in the metabolism of lipids, carbohydrates, proteins, ethanol, bile acids, and xenobiotics. However, much less is known about the importance of the concentration of this cofactor in various cell compartments and the role of altered CoA concentration in various pathologies. Despite continuous research on these issues, the molecular mechanisms in the regulation of the intracellular level of CoA under pathological conditions are still not well understood. This review summarizes the current knowledge of (a) CoA subcellular concentrations; (b) the roles of CoA synthesis and degradation processes; and (c) protein modification by reversible CoA binding to proteins (CoAlation). Particular attention is paid to (a) the roles of changes in the level of CoA under pathological conditions, such as in neurodegenerative diseases, cancer, myopathies, and infectious diseases; and (b) the beneficial effect of CoA and pantethine (which like CoA is finally converted to Pan and cysteamine), used at pharmacological doses for the treatment of hyperlipidemia.

Keywords: CoA; CoAlation; cancer; coenzyme A; neurodegenerative diseases.

Figure 1

The role of CoA-SH (A) and acetyl-CoA (B) in human metabolism.

Figure 2

Coenzyme A biosynthetic and degradation pathways in humans. Green arrows indicate CoA synthesis and red arrows indicate CoA degradation. PANK—pantothenate kinase, PPanSH—4′-phosphopantetheine, PPCS—phosphopantothenoylcysteine synthetase, PPCDC—phosphopantothenoylcysteine decarboxylase, COASY—CoA synthase, PPAT—4′-phosphopantetheine adenyltransferase, DPCK—dephospho-CoA kinase, ENPP—ectonucleotide pyrophosphatase/phosphodiesterase, AP—alkaline phosphatase, VNN—pantetheinase, NUDT—intracellular degradation, nudix (nucleoside diphosphate linked moiety X)-type motif, and LAP—lysosomal acid phosphatase.

Figure 3

The compartmentalization and interplay of intracellular CoA synthesis and degradation pathways. Pan—pantothenate, PPan—4′-phosphopantothenate, PPanSH—4′-phosphopantetheine, dPCoA—dephospho-CoA, PANK—pantothenate kinase, PPCS—phosphopantothenoylcysteine synthetase, PPCDC—phosphopantothenoylcysteine decarboxylase, COASY—CoA synthase, PanSH—pantetheine, NUDT—intracellular degradation, nudix (nucleoside diphosphate linked moiety X)-type motif, LAP—lysosomal acid phosphatase, SMVT—sodium-dependent multivitamin transporter, and ACOT—acyl-CoA thioesterase. The figure was made based on Naquet et al. [23].

Figure 4

The metabolic effects of pantethine. Red arrows indicate decrease; green arrows indicate increase.