4-Methylumbelliferyl glucuronide contributes to hyaluronan synthesis inhibition [Cell Biology]

We report here that 4-MUG contributes to HA synthesis inhibition. We observed that oral administration of 4-MUG to mice inhibits HA synthesis, promotes FoxP3+ regulatory T-cell expansion, and prevents autoimmune diabetes. Mice fed either 4-MUG or 4-MU had equivalent 4-MU:4-MUG ratios in serum, liver, and pancreas, indicating that 4-MU and 4-MUG reach an equilibrium in these tissues. LC–tandem MS experiments revealed that 4-MUG is hydrolyzed to 4-MU in serum, thereby greatly increasing the effective bioavailability of 4-MU. Moreover, using intravital 2-photon microscopy, we found that 4-MUG (a nonfluorescent molecule) undergoes conversion into 4-MU (a fluorescent molecule) and that 4-MU is extensively tissue bound in the liver, fat, muscle, and pancreas of treated mice. 4-MUG also suppressed HA synthesis independently of its conversion into 4-MU and without depletion of the HA precursor UDP-glucuronic acid (GlcUA). Together, these results indicate that 4-MUG both directly and indirectly inhibits HA synthesis and that the effective bioavailability of 4-MU is higher than previously thought. These findings greatly alter the experimental and therapeutic possibilities for HA synthesis inhibition.

Source: Journal of Biological Chemistry - May 9, 2019 Category: Chemistry Authors: Nadine Nagy, Irina Gurevich, Hedwich F. Kuipers, Shannon M. Ruppert, Payton L. Marshall, Bryan J. Xie, Wenchao Sun, Andrey V. Malkovskiy, Jayakumar Rajadas, Maria Grandoch, Jens W. Fischer, Adam R. Frymoyer, Gernot Kaber, Paul L. Bollyky Tags: Glycobiology and Extracellular Matrices Source Type: research