Bis-allylic hydrogen in membrane polyunsaturated fatty acids (Bis-allylic C-H bond)

Bis-allylic hydrogens are the hydrogen atoms located on the methylene carbons situated between two double bonds in polyunsaturated fatty acids (PUFAs) such as linoleic and arachidonic acid (Shchepinov, 2007). These specific C-H bonds are the most chemically reactive sites in the lipid bilayer because they have the lowest bond dissociation energy, making them highly susceptible to abstraction by reactive oxygen species (ROS) (Hill et al., 2012). This abstraction initiates a self-propagating chain reaction known as lipid peroxidation, which compromises membrane integrity and generates toxic aldehydes like 4-hydroxynonenal (4-HNE), ultimately leading to ferroptotic cell death (Yang et al., 2016). In therapeutic development, these hydrogens are targeted by isotopic substitution with deuterium (D-PUFAs), which strengthens the bond via the kinetic isotope effect and renders the lipids resistant to peroxidation (Cotsman et al., 2020). This approach is primarily explored for treating neurodegenerative diseases characterized by high oxidative stress, such as Friedreich's ataxia and infantile neuroaxonal dystrophy (Zesiewicz et al., 2018).

Other names

Bis-allylic methylene groupBis-allylic C-H bondsPolyunsaturated fatty acid (PUFA) bis-allylic sitesD-PUFA target site

Stabilization of the bis-allylic C-H bond via deuterium substitution (Kinetic Isotope Effect) to inhibit lipid peroxidation and ferroptosis (Shchepinov, 2007; Hill et al., 2012).