Chemical knockout of pantothenate kinase reveals the metabolic and genetic program responsible for hepatic coenzyme A homeostasis.
Chemical knockout of pantothenate kinase reveals the metabolic and genetic program responsible for hepatic coenzyme A homeostasis.
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DOI：
10.1016/j.chembiol.2007.01.013
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发表时间：
2007-03
影响因子：
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通讯作者：
Yong-mei Zhang;S. Chohnan;Kristopher G. Virga;R. Stevens;O. Ilkayeva;B. Wenner;J. Bain;C. Newgard;Richard E. Lee;C. Rock;S. Jackowski
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文献类型：
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作者：
Yong-mei Zhang;S. Chohnan;Kristopher G. Virga;R. Stevens;O. Ilkayeva;B. Wenner;J. Bain;C. Newgard;Richard E. Lee;C. Rock;S. Jackowski
辅酶A（Coenzyme A，CoA）是代谢中间体中主要的酰基载体。霍潘（HoPan）是一种泛酸激酶的竞争性抑制剂，用于化学拮抗辅酶A的生物合成。HoPan显著降低肝脏CoA，小鼠发生严重低血糖。胰岛素减少，胰高血糖素和皮质酮升高，空腹加速低血糖。代谢分析显示，酰基肉毒碱大幅增加，说明肉毒碱在缓冲酰基以维持非酯化CoASH水平中的作用。HoPan引发了肝脏基因表达的显著变化，大大增加了硫酯酶，从酰基CoA中释放CoASH，并增加了丙酮酸脱氢酶激酶1，阻止CoASH转化为乙酰CoA。这些结果确定了维持CoASH池的代谢重排，CoASH池对线粒体功能至关重要，包括线粒体生成、脂肪酸氧化以及三羧酸和尿素循环。
Coenzyme A (CoA) is the major acyl group carrier in intermediary metabolism. Hopantenate (HoPan), a competitive inhibitor of the pantothenate kinases, was used to chemically antagonize CoA biosynthesis. HoPan dramatically reduced liver CoA and mice developed severe hypoglycemia. Insulin was reduced, glucagon and corticosterone were elevated, and fasting accelerated hypoglycemia. Metabolic profiling revealed a large increase in acylcarnitines, illustrating the role of carnitine in buffering acyl groups to maintain the nonesterified CoASH level. HoPan triggered significant changes in hepatic gene expression that substantially increased the thioesterases, which liberate CoASH from acyl-CoA, and increased pyruvate dehydrogenase kinase 1, which prevents the conversion of CoASH to acetyl-CoA. These results identify the metabolic rearrangements that maintain the CoASH pool which is critical to mitochondrial functions, including gluconeogenesis, fatty acid oxidation, and the tricarboxylic acid and urea cycles.