Discovery of small molecule vanin inhibitors: New tools to study metabolism and disease

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*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

30 Citations (Scopus)

Abstract

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-α 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.

Original languageEnglish
Pages (from-to)530-534
Number of pages5
JournalAcs Chemical Biology
Volume8
Issue number3
DOIs
Publication statusPublished - 15 Mar 2013
Externally publishedYes

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