TY - ABST

T1 - Kinetic data for the reactions of alpha,beta-unsaturated aldehydes shed light on their molecular targets and biological effects

AU - Sauerland, Max

AU - Gamon, Luke F.

AU - Davies, Michael J.

PY - 2021

Y1 - 2021

N2 - A wide range of alpha, beta-unsaturated carbonyls (ABuCs) are encountered in everyday life. The toxic molecule acrolein is the smallest ABuC family member, which is present in cigarette smoke, fried foods or automobile exhausts. Peroxidation of polyunsaturated fatty acids also yields acrolein among other ABuCs such as crotonaldehyde, 4-hydroxynonenal and 4-hydroxypentenal. The latter ABuCs have also been proposed to have a signaling action rather than a toxic one. ABuCs have also been utilized as treatments for diseases, with dimethylfumarate used to treat multiple sclerosis and psoriasis, and itaconate showing promise as an anti-inflammatory agent. ABuCs act as soft electrophiles and react with biological nucleophiles via Michael addition. Cysteine residues are major targets since they are relatively abundant and kinetically-favored over other targets (e.g. DNA bases, lysine and histidine residues on proteins). However, the kinetics and selectivity of ABuCs–cysteine reactions are incompletely understood. We therefore aimed to determine kinetic data (rate constants) for these reactions and their downstream effects. The rate constants for addition of GSH to acrolein, crotonaldehyde, dimethylfumarate, cyclohex-1-en-2-one and cyclopent-1-en-2-one are shown to vary by a factor of 350 (rate constants, k, 0.5 – 186 M-1 s-1) indicating that the ABuC structure is a determining factor for reactivity, with acrolein being the most reactive. We also show that the microenvironment of the cysteine residue, and its pKa value, have an impact on the reactivity. Protein incorporated cysteine react up to 30 times faster than free cysteine and GSH. The toxic species acrolein is highly reactive, and reacts in an unspecific manner. Dimethylfumarate on the other hand reacts more slowly and is much more specific. Enzymatic assays show that these Michael addition reactions can inhibit enzyme activity, highlighting the functional consequences of ABuC reactivity. These data can help explain why acrolein is toxic, while dimethylfumarate has beneficial biological effects. Keywords: alpha,beta-unsaturated carbonyls; acrolein; dimethylfumarate; protein modification; michael reaction

AB - A wide range of alpha, beta-unsaturated carbonyls (ABuCs) are encountered in everyday life. The toxic molecule acrolein is the smallest ABuC family member, which is present in cigarette smoke, fried foods or automobile exhausts. Peroxidation of polyunsaturated fatty acids also yields acrolein among other ABuCs such as crotonaldehyde, 4-hydroxynonenal and 4-hydroxypentenal. The latter ABuCs have also been proposed to have a signaling action rather than a toxic one. ABuCs have also been utilized as treatments for diseases, with dimethylfumarate used to treat multiple sclerosis and psoriasis, and itaconate showing promise as an anti-inflammatory agent. ABuCs act as soft electrophiles and react with biological nucleophiles via Michael addition. Cysteine residues are major targets since they are relatively abundant and kinetically-favored over other targets (e.g. DNA bases, lysine and histidine residues on proteins). However, the kinetics and selectivity of ABuCs–cysteine reactions are incompletely understood. We therefore aimed to determine kinetic data (rate constants) for these reactions and their downstream effects. The rate constants for addition of GSH to acrolein, crotonaldehyde, dimethylfumarate, cyclohex-1-en-2-one and cyclopent-1-en-2-one are shown to vary by a factor of 350 (rate constants, k, 0.5 – 186 M-1 s-1) indicating that the ABuC structure is a determining factor for reactivity, with acrolein being the most reactive. We also show that the microenvironment of the cysteine residue, and its pKa value, have an impact on the reactivity. Protein incorporated cysteine react up to 30 times faster than free cysteine and GSH. The toxic species acrolein is highly reactive, and reacts in an unspecific manner. Dimethylfumarate on the other hand reacts more slowly and is much more specific. Enzymatic assays show that these Michael addition reactions can inhibit enzyme activity, highlighting the functional consequences of ABuC reactivity. These data can help explain why acrolein is toxic, while dimethylfumarate has beneficial biological effects. Keywords: alpha,beta-unsaturated carbonyls; acrolein; dimethylfumarate; protein modification; michael reaction

U2 - 10.1016/j.freeradbiomed.2021.08.133

DO - 10.1016/j.freeradbiomed.2021.08.133

M3 - Conference abstract in journal

VL - 177

SP - 596

JO - Free Radical Biology & Medicine

JF - Free Radical Biology & Medicine

SN - 0891-5849

IS - Suppl. 1

ER -