Michael Additions with Fumarate
               Fumarate is an intermediate of the Krebs cycle in intermediary metabolism.   It has been shown that fumarate can serve as a Michael acceptor reacting with cysteine (1), thiol groups in proteins (2), and glutathione (3).  Reaction with glutathione has also been observed (3) forming a product suggested to increase accumulation of reactive oxygen species(ROS).  The formation of S-(2-succinyl)cysteine in glyceraldehyde-3-phosphate has been suggested to be a biomarker of mitochondrial stress (4).  Dimethyl fumarate is an active pharmaceutical ingredient of Fumaderm®‑which is used to treat psoriasis; the formation of a dimethyl fumarate adduct with glutathione has been reported(5,6).  Dimethyl fumarate is rapidly hydrolyzed to monomethyl fumarate which also reacts with glutathione(5).  The reaction of dimethyl fumarate/monomethylhydrogen fumarate with thiols may be important in the action of this drug.  Dimethyl fumarate has also been shown to react with amines (7). Other biochemicals which can serve as Michael Donors include 4-methyleneglutamic acid which is found in peanuts (8) and been shown to react with thiols (9). Dimethyl maleate activates transcription factor Pap1 through modification of cysteine residue(s)(9).
1.  Alderson, N.L., Wang, Y., Blatnik, M., et al., S-(2-succinyl)cysteine: A novel chemical modification of tissue proteins by a Krebs cycle intermediate, Arch.Biochem.Biophys. 450, 1-8, 2006
2.   Blatnik, M., Thorpe, S.R., and Baynes, J.W., Succination of proteins by fumarate. Mechanism of inactivation of glyceraldehyde-3-phosphate dehydrogenase in diabetets, Ann.N.Y.Acad.Sci.1126, 272-275, 2008.
 3. Sullivan, L.B., Martinez-Garcia, E., Nguyen, H., et al., The proto-oncometabolite fumarate binds glutathione to amply ROS-dependent signaling, Molecular Cell 51. 236-248, 2013
4.  Blatnik, M., Frizzell, N., Thorpoe, S.R., and Baynes, J.W., Inactivation of glyceraldehyde-3-phosphate dehydrogenase by fumarate in diabetes. Formation of S-(2-succinyl)cysteine, a novel chemical modification of protein and possible biomarker of mitochondrial stress, Diabetes 57, 41-49, 2008
5.  Schmidt, T.J., Muarrem, A., and Mrowietz, U., Reactivity of dimethyl fumarate and methylhydrogenfumarate towards glutathione and N-acetyl-L-cysteine -Preparation of S-substituted thiosuccinic acid esters, Bioorg.Med.Chem. 15, 333-342, 2007
6.  Dibbert, S., Clement, B., Skak-Nielsen, T., Mrowietz, U., and Rostami-Yazdi, M., Detection of fumarate-glutathione adducts in the portal vein blood of rats: evidence for rapid dimethylfumarate metabolism, Arch.Dermatol. 305, 447-451, 2013
7.  Gurjar, A., Sinha, P., and Bansal, R.K., Tandem Michael addition of amines to maleic anhydride and 1,3-prototropic shift: experimental and theoretical results, Tetrahedron 70, 5052-5056, 2014
8.  Marcus, A., Feeley, J., and Shannon, L.M., Preparation and properties of γ-methyleneglutamic acid, Arch.Biochem.Biophys. 100, 80-85, 1963
9.  Powell, G.K., Winter, H.C., and Dekker, E.E., Michael addition of thiols with 4-methyleneglutamic acid: Preparation of adducts, their properties and presence of peanuts, Biochem.Biophys.Res.Commun. 105, 1361-1367, 1982