NUDT7 regulates total hepatic CoA levels and the composition of the intestinal bile acid pool in male mice fed a Western diet.

Nudix hydrolase 7 (NUDT7) is an enzyme that hydrolyzes CoA species, is highly expressed in the liver, and resides in the peroxisomes. Peroxisomes are organelles where the preferential oxidation of dicarboxylic fatty acids occurs and where the hepatic synthesis of the primary bile acids cholic acid and chenodeoxycholic acid is completed. We previously showed that liver-specific overexpression of NUDT7 affects peroxisomal lipid metabolism but does not prevent the increase in total liver CoA levels that occurs during fasting.

Nudt8 is a novel CoA diphosphohydrolase that resides in the mitochondria.

CoA regulates energy metabolism and exists in separate pools in the cytosol, peroxisomes, and mitochondria. At the whole tissue level, the concentration of CoA changes with the nutritional state by balancing synthesis and degradation; however, it is currently unclear how individual subcellular CoA pools are regulated. Liver and kidney peroxisomes contain Nudt7 and Nudt19, respectively, enzymes that catalyze CoA degradation.

Overexpression of Nudt7 decreases bile acid levels and peroxisomal fatty acid oxidation in the liver.

Lipid metabolism requires CoA, an essential cofactor found in multiple subcellular compartments, including the peroxisomes. In the liver, CoA levels are dynamically adjusted between the fed and fasted states. Elevated CoA levels in the fasted state are driven by increased synthesis; however, this also correlates with decreased expression of Nudix hydrolase (Nudt)7, the major CoA-degrading enzyme in the liver.

Nudt19 is a renal CoA diphosphohydrolase with biochemical and regulatory properties that are distinct from the hepatic Nudt7 isoform.

CoA is the major acyl carrier in mammals and a key cofactor in energy metabolism. Dynamic regulation of CoA in different tissues and organs supports metabolic flexibility. Two mammalian Nudix hydrolases, Nudt19 and Nudt7, degrade CoA Nudt19 and Nudt7 possess conserved Nudix and CoA signature sequences and specifically hydrolyze the diphosphate bond of free CoA and acyl-CoAs to form 3',5'-ADP and 4'-(acyl)phosphopantetheine.

Induction of Neuron-Specific Degradation of Coenzyme A Models Pantothenate Kinase-Associated Neurodegeneration by Reducing Motor Coordination in Mice.

Background: Pantothenate kinase-associated neurodegeneration, PKAN, is an inherited disorder characterized by progressive impairment in motor coordination and caused by mutations in PANK2, a human gene that encodes one of four pantothenate kinase (PanK) isoforms. PanK initiates the synthesis of coenzyme A (CoA), an essential cofactor that plays a key role in energy metabolism and lipid synthesis. Most of the mutations in PANK2 reduce or abolish the activity of the enzyme.