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Review
. 2023 Mar 21;24(6):5951.
doi: 10.3390/ijms24065951.

Inherited Disorders of Coenzyme A Biosynthesis: Models, Mechanisms, and Treatments

Chiara Cavestro  1 , Daria Diodato  2 , Valeria Tiranti  1 , Ivano Di Meo  1
Affiliations
Review

Inherited Disorders of Coenzyme A Biosynthesis: Models, Mechanisms, and Treatments

Chiara Cavestro et al. Int J Mol Sci. .

Abstract

Coenzyme A (CoA) is a vital and ubiquitous cofactor required in a vast number of enzymatic reactions and cellular processes. To date, four rare human inborn errors of CoA biosynthesis have been described. These disorders have distinct symptoms, although all stem from variants in genes that encode enzymes involved in the same metabolic process. The first and last enzymes catalyzing the CoA biosynthetic pathway are associated with two neurological conditions, namely pantothenate kinase-associated neurodegeneration (PKAN) and COASY protein-associated neurodegeneration (CoPAN), which belong to the heterogeneous group of neurodegenerations with brain iron accumulation (NBIA), while the second and third enzymes are linked to a rapidly fatal dilated cardiomyopathy. There is still limited information about the pathogenesis of these diseases, and the knowledge gaps need to be resolved in order to develop potential therapeutic approaches. This review aims to provide a summary of CoA metabolism and functions, and a comprehensive overview of what is currently known about disorders associated with its biosynthesis, including available preclinical models, proposed pathomechanisms, and potential therapeutic approaches.

Keywords: COASY; NBIA; PANK2; PPCDC; PPCS; cardiomyopathy; coenzyme A; iron accumulation; neurodegeneration.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Coenzyme A homeostasis. (A) Schematic representation of CoA biosynthetic (blue), salvage (green), and degradation pathways. (B) Intracellular localization of CoA biosynthesis. Disease-associated enzymes are in red. Abbreviations: PANK, pantothenate kinase; PPCS, phosphopantothenoylcysteine synthetase; PPCDC, phosphopantothenoylcysteine decarboxylase; PPAT, phosphopantetheine adenyltransferase; DPCK, dephospho-CoA kinase; COASY, CoA synthase; NUDT, nucleoside diphosphate-linked moiety X-type motif; AP, alkaline phosphatase ENPP, ectonucleotide pyrophosphatase/phosphodiesterase.
Figure 2
Figure 2
Coenzyme A cellular functions. CoA is implicated in diverse cellular activities, which can be divided into metabolic (blue) and protein modification (red) functions.
Figure 3
Figure 3
Proposed therapeutic strategies for inherited disorders of CoA biosynthesis and their current stage of development.
See this image and copyright information in PMC

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