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. Author manuscript; available in PMC: 2013 Nov 21.
Published in final edited form as: Nat Rev Cancer. 2012 Jul 19;12(8):10.1038/nrc3278. doi: 10.1038/nrc3278

Figure 3. Beneficial or carcinogenic effects of fumarate depend on its dose and the presence or absence of the enzyme fumarate hydratase.

Figure 3

In normal tissue, the Krebs cycle enzyme fumarate hydratase catalyses the rapid attack of water on the double bond of fumarate, resulting in the formation of malate. Intracellular levels of fumarate are thus kept low in the energy-producing process of the Krebs cycle. However, when fumarate hydratase is mutated and therefore inactive, the concentration of fumarate increases, and it is then susceptible to non-enzymatic attack by cysteine (as the thiolate anion). Reactive cysteine residues (such as Cys151) on the Kelch-like ECH-associated protein 1 (KEAP1) molecule can thus form covalent succinate adducts. This results in a conformational change in KEAP1 and transcriptional activation of NFE2-related factor 2 (NRF2), as shown in FIG. 1. The classic-α,β-unsaturated ketone (eneone) structure of the fumarate molecule is paradigmatic for many other drugs that activate NRF2. Figure courtesy of G. Gribble, Dartmouth College, Hanover, New Hampshire, USA.