Coenzyme A (CoA, CoASH, or HSCoA) is adapted from pantothenic acid and adenosine triphosphate and used in metabolism in areas such as fatty acid oxidization and the citric acid cycle. Its main function is to carry acyl groups such as acetyl as thioesters. A molecule of Coenzyme A carrying an acetyl group is also referred to as acetyl-CoA.
Acetyl-CoA is an important molecule itself. It is the precursor to HMG CoA, which is a vital component in cholesterol and ketone synthesis. Furthermore, it contributes the acetyl group to acetylcholine; the addition of the acetyl group to choline a reaction that is catalysed by choline acetyltransferase. Its main task is conveying the carbon atoms within the acetyl group to the citric acid cycle to be oxidized for energy production.
The conversion of pyruvate into Acetyl- Coenzyme A is referred to as the Pyruvate Dehydrogenase Reaction. It is catalyzed by an enzyme-complex called pyruvate dehydrogenase. The enzyme consists of 60 subunits: 24 pyruvate dehydrogenase, 24 dihydrolipoyl transacetylase , and 12 dihydrolipoyl dehydrogenase (commonly denoted E1, E2, and E3). 24 pyruvate dehydrogenase has the coenzyme TPP incorporated into it, 24 dihydrolipoyl transacetylase has lipoate and Coenzyme A , and 12 dihydrolipoyl dehydrogenase has the coenzymes FAD and NAD+. Through a complex reaction, pyruvate is decarboxylated and turned into acetaldehyde, then attached to Coenzyme A while NAD+ is subsequently reduced to NADH and H+.
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Pank1 plays an important role in coenzyme A homeostasis during fasting
Coenzyme A (CoA) is an essential cofactor synthesized in five steps from pantothenate, and pantothenate kinase (PanK) catalyzes the first and most regulated step. The Pank1 gene encodes two of the four PanK isoforms, PanK1 and 1β. Deletion of exon 3 in the mouse Pank1 gene resulted in loss of expression of both isoforms.
The liver of the Pank1 knockout animals contained 40% less total CoA, and the knockout mice showed a blunted response to a pyruvate challenge, indicating impairment in gluconeogenesis. Fasting increases CoA levels to support β-oxidation and gluconeogenesis.
Following a 48h fast, the CoA levels increased by 70% (from 122 ± 4 to 207 ± 23 nmoles/mg of tissue) in livers from wild type and by 50% (from 71 ± 7 to 107 ± 11 nmole/mg of tissue) in livers from knockout mice. Concomitantly, the knockout livers accumulated five times more triglycerides than controls, and the knockout liver homogenates exhibited a decreased rate of palmitic acid oxidation. These results indicate that the reduction in CoA decreases the efficiency of fatty acid β-oxidation, and that in addition to contributing a large portion of the cofactor pool, Pank1 plays an important role in responding to the increased demand for CoA during fasting.
We also observed that the Pank1 knockout males are hyperphagic and 15% heavier than controls, which correlated with a 50% lower malonyl-CoA in the hypothalamus. Supported by NIH GM062896, CA21765, and ALSAC.
Roberta Leonardi1, Jina Wang1, Karen Miller1, Charles O. Rock1 and Suzanne Jackowski1
1 Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN
The liver of the Pank1 knockout animals contained 40% less total CoA, and the knockout mice showed a blunted response to a pyruvate challenge, indicating impairment in gluconeogenesis. Fasting increases CoA levels to support β-oxidation and gluconeogenesis.
Following a 48h fast, the CoA levels increased by 70% (from 122 ± 4 to 207 ± 23 nmoles/mg of tissue) in livers from wild type and by 50% (from 71 ± 7 to 107 ± 11 nmole/mg of tissue) in livers from knockout mice. Concomitantly, the knockout livers accumulated five times more triglycerides than controls, and the knockout liver homogenates exhibited a decreased rate of palmitic acid oxidation. These results indicate that the reduction in CoA decreases the efficiency of fatty acid β-oxidation, and that in addition to contributing a large portion of the cofactor pool, Pank1 plays an important role in responding to the increased demand for CoA during fasting.
We also observed that the Pank1 knockout males are hyperphagic and 15% heavier than controls, which correlated with a 50% lower malonyl-CoA in the hypothalamus. Supported by NIH GM062896, CA21765, and ALSAC.
Roberta Leonardi1, Jina Wang1, Karen Miller1, Charles O. Rock1 and Suzanne Jackowski1
1 Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN
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