TY - JOUR
T1 - Discovery of small molecule vanin inhibitors: New tools to study metabolism and disease
AU - Jansen, Patrick A.M.
AU - Van Diepen, Janna A.
AU - Ritzen, Bas
AU - Zeeuwen, Patrick L.J.M.
AU - Cacciatore, Ivana
AU - Cornacchia, Catia
AU - Van Vlijmen-Willems, Ivonne M.J.J.
AU - De Heuvel, Erik
AU - Botman, Peter N.M.
AU - Blaauw, Richard H.
AU - Hermkens, Pedro H.H.
AU - Rutjes, Floris P.J.T.
AU - Schalkwijk, Joost
PY - 2013/3/15
Y1 - 2013/3/15
N2 - 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.
AB - 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.
U2 - 10.1021/cb3006424
DO - 10.1021/cb3006424
M3 - Article
C2 - 23270378
AN - SCOPUS:84875184941
SN - 1554-8929
VL - 8
SP - 530
EP - 534
JO - Acs Chemical Biology
JF - Acs Chemical Biology
IS - 3
ER -