Discovery of Small Molecule Vanin Inhibitors: New Tools To Study Metabolism and Disease
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- 作者：Patrick A. M. Jansen ; Janna A. van Diepen ; Bas Ritzen ; Patrick L. J. M. Zeeuwen ; Ivana Cacciatore ; Catia Cornacchia ; Ivonne M. J. J. van Vlijmen-Willems ; Erik de Heuvel ; Peter N. M. Botman ; Richard H. Blaauw ; Pedro H. H. Hermkens ; Floris P. J. T. Rutjes ; Joost Schalkwijk
- 刊名：ACS Chemical Biology
- 出版年：2013
- 出版时间：March 15, 2013
- 年：2013
- 卷：8
- 期：3
- 页码：530-534
- 全文大小：266K
- 年卷期：v.8,no.3(March 15, 2013)
- ISSN：1554-8937
文摘
Vanins are enzymes with pantetheinase activity and are presumed to play a role in the recycling of pantothenic acid (vitamin B5) from pantetheine. Pantothenic acid is an essential nutrient required to synthesize coenzyme A, a cofactor involved in many biological processes such as fatty acid synthesis and oxidation of pyruvate to fuel the citric acid cycle. Hydrolysis of pantetheine also liberates cysteamine, a known antioxidant. Vanin-1 is highly expressed in liver and is under transcriptional control of PPAR-伪 and nutritional status, suggesting a role in energy metabolism. The lack of potent and specific inhibitors of vanins has hampered detailed investigation of their function. We hereby report the design, synthesis, and characterization of a novel pantetheine analogue, RR6, that acts as a selective, reversible, and competitive vanin inhibitor at nanomolar concentration. Oral administration of RR6 in rats completely inhibited plasma vanin activity and caused alterations of plasma lipid concentrations upon fasting, thereby illustrating its potential use in chemical biology research.