Coenzyme A
Overview
Coenzyme A (CoA) is a coenzyme, notable for its role in the synthesis and oxidation of fatty acids, and the oxidation of pyruvate in the citric acid cycle. All genomes sequenced to date encode enzymes that use coenzyme A as a substrate, and around 4% of cellular enzymes use it (or a thioester, such as acetyl-CoA) as a substrate. In humans, CoA biosynthesis requires cysteine, pantothenate, and adenosine triphosphate (ATP).
Structure
Coenzyme A consists of an adenosine 3',5'-bisphosphate, a 4'-phosphopantetheine, and a cysteamine. The molecule carries a high-energy thioester linkage that can power the transfer of acyl groups in metabolism. The acyl group can be transferred to various substrates, thereby playing a crucial role in several metabolic pathways.
Biosynthesis
In bacteria, the biosynthesis of CoA from pantothenic acid (vitamin B5) involves five enzymatic steps. The pathway is regulated through feedback inhibition by CoA and its thioesters. In humans and other mammals, CoA biosynthesis occurs in the cytosol, mitochondria, and peroxisomes, and involves phosphorylation of pantothenic acid by the enzyme pantothenate kinase.
Functions
Coenzyme A is involved in numerous cellular functions, including the citric acid cycle, fatty acid synthesis and oxidation, and the synthesis of sterols, steroids, and other lipids. It also plays a role in the post-translational modification of proteins and the regulation of gene expression.
Clinical Significance
Defects in the biosynthesis of CoA have been linked to a number of human diseases, including neurodegeneration with brain iron accumulation (NBIA), pantothenate kinase-associated neurodegeneration (PKAN), and Coenzyme A synthase protein-associated neurodegeneration (CoPAN). These diseases are characterized by progressive neurodegeneration and the accumulation of iron in the brain.