Coenzyme a Biochemistry: From Neurodevelopment to Neurodegeneration

Abstract

Coenzyme A (CoA) is an essential cofactor in all living organisms. It is involved in a large number of biochemical processes functioning either as an activator of molecules with carbonyl groups or as a carrier of acyl moieties. Together with its thioester derivatives, it plays a central role in cell metabolism, post-translational modification, and gene expression. Furthermore, recent studies revealed a role for CoA in the redox regulation by the S-thiolation of cysteine residues in cellular proteins. The intracellular concentration and distribution in different cellular compartments of CoA and its derivatives are controlled by several extracellular stimuli such as nutrients, hormones, metabolites, and cellular stresses. Perturbations of the biosynthesis and homeostasis of CoA and/or acyl-CoA are connected with several pathological conditions, including cancer, myopathies, and cardiomyopathies. In the most recent years, defects in genes involved in CoA production and distribution have been found in patients affected by rare forms of neurodegenerative and neurodevelopmental disorders. In this review, we will summarize the most relevant aspects of CoA cellular metabolism, their role in the pathogenesis of selected neurodevelopmental and neurodegenerative disorders, and recent advancements in the search for therapeutic approaches for such diseases.

GlyNAC (Glycine and N-Acetylcysteine) Supplementation Improves Impaired Mitochondrial Fuel Oxidation and Lowers Insulin Resistance in Patients with Type 2 Diabetes: Results of a Pilot Study

“…Cysteine contains a sulfhydryl (SH) group donor and is an important thiol in antioxidant systems [ 68 ] and for multiple cellular processes, especially in mitochondria [ 69 , 70 , 71 ]. For example, coenzyme A (CoA-SH) is an important intermediate in the mitochondrial β-oxidation of fatty-acids and for pyruvate metabolism in the Krebs’ cycle, and requires cysteine for its synthesis [ 72 ]. Cysteine is also important in maintaining protein structure, iron metabolism and other reactions in the body [ 71 , 73 , 74 ].…”

Pantothenate and L-Carnitine Supplementation Improves Pathological Alterations in Cellular Models of KAT6A Syndrome

“…Vitamin B5, or pantothenate, is the precursor of the CoA biosynthetic pathway [ 60 ]. The molecule is largely widespread in biology [ 61 ] and, in humans, pantothenate deficiency may occur only as a consequence of severe malnutrition.…”

Proton magnetic resonance spectroscopy detects cerebral metabolic derangement in a mouse model of brain coenzyme a deficiency

“…1a). Recent reviews discuss the various molecular consequences of CoA insufficiency in preclinical PKAN models [8,9]. There are no disease-modifying treatments for PKAN, and therapeutics are desperately needed.…”