How does dimethyl fumarate work?
Kornberg MD, Bhargava P, Kim PM, Putluri V, Snowman AM, Putluri N, Calabresi PA, Snyder SH. Dimethyl fumarate targets GAPDH and aerobic glycolysis to modulate immunity. Science. 2018 Mar 29. pii: eaan4665. doi: 10.1126/science.aan4665. [Epub ahead of print]
Activated immune cells undergo a metabolic switch to aerobic (requiring oxygen) glycolysis.
Glycolysis breaks down glucose and forms pyruvate with the production of two molecules of ATP. The pyruvate end product of glycolysis can be used in either anaerobic respiration if no oxygen is available or in aerobic respiration via the TCA cycle which yields much more usable energy for the cell.
Dimethyl fumarate, a derivative of the Krebs cycle (see below) intermediate fumarate, is an immunomodulatory drug used to treat multiple sclerosis and psoriasis.
Although its therapeutic mechanism remains uncertain, it covalently modifies cysteine residues in a process termed “succination.” Here, we show that dimethyl fumarate succinates and inactivates the catalytic cysteine of the glycolytic enzyme GAPDH both in vitro and in vivo. It thereby downregulates aerobic glycolysis in activated myeloid and lymphoid cells, which mediates its anti-inflammatory effects. Our findings provide mechanistic insight into immune modulation by dimethyl fumarate and represent a proof of concept that aerobic glycolysis is a therapeutic target in autoimmunity.