Acrolein, protein reactivity

Several chemical compounds may cause inflammation or constriction of the blood vessel wall (vasoconstriction). Ergot alkaloids at high doses cause constriction and thickening of the vessel wall. Allylamine may also induce constriction of coronary arteries, thickening of their smooth muscle walls, and a disease state that corresponds to coronary heart disease. The culprit is a toxic reactive metabolite of allylamine, acrolein, that binds covalently to nucleophilic groups of proteins and nucleic acids in the cardiac myocytes. 

Numerous other acrolein polymers have been prepared whose structures have not been elucidated. Acrolein polymers are highly reactive and may be converted to various derivatives. Of these, the bisulfite adduct of the polymer prepared by free-radical initiation has been used as an emulsifying agent, as a crosslinking agent for proteins and for cellulose, and to produce water-insoluble adducts, in the form of films or sheets, with poly (vinyl alcohol) (39). 

It is curious to note that fV-CBA-inactivated MAO continues to produce acrolein at pH 7, but at pH 9 incorporates up to 40 equivalents of acrolein into the protein in a time-dependent manner. The increased incorporation at higher pH is consistent with the ionization of nucleophilic groups that partake in Michael addition reactions with the liberated acrolein. The continued production of acrolein after complete inactivation results from reactivation-inactivation cycling of the enzyme by the iV-CBA inhibitor (103). However, with 7Y-(l-methyl)cyclopropyIbenzylamine, the inactivated and reduced enzyme does... 

Cras et al, 1995). Lipid peroxidation is indicated by the high concentrations of the thiobarbituric acid reactive substances malondialdehyde, 4-HNE, acrolein, isopros-tanes, and altered phospholipid composition (Markesbery and Lovell, 1998 Butterfield et al., 2001). Many different proteins involved in AD are oxidatively modified (see Butterfield et al., 2006 for review Sultana et al., 2006). All these modifications are usually linked to a functional loss of proteins leading to their degradation or aggregation, as observed in AD. 

Burcham PC, Fontaine FR, Petersen DR, Pyke SM. Reactivity with Tris(hydroxy-methyl)aminomethane confounds immunodetection of acrolein-adducted proteins. Chem Res Toxicol 2003 16 1196-1201. 

Mechanism of action. Acrolein has two functional groups that can contribute to its biocidal activity. It is an a, jS-unsaturated aldehyde and as such the carbon-carbon double bond is extremely reactive. Nucleophiles, typically sulfur based nucleophiles, can react with the terminal carbon in a Michael type reaction (March, 1992), while the aldehyde group can undergo reactions typical of all aldehydes. From a biocidal point of view, those sulfur-based nucleophiles would include cysteine residues of the cell wall and those proteins associated with the cell wall. The amine containing amino acids (lysine and arginine) may also react with the aldehyde group of acrolein. 

Reaction products of reactive aldehydes derived from oxidised lipids, such as acrolein, ( )-4-hydroxynon-2-enal and malondi-aldehyde, with lysine, arginine and other amino acids are described as examples in Section 4.7.5.6. These products, ALE (advanced lipoxidation end products), formed in vivo are markers of oxidative stress in the organism. Reaction mechanisms are discussed in Section 3.8.1.12.1. As the final reaction products, proteins and oxidised lipids also form dark insoluble macromolecular products that contain variable proportions of lipid and protein fractions. In particular, such products include protein oligomers, proteins with oxidised sulfur amino acids, proteins containing imine bonds (C=N) formed by reaction with aldehydes or hydroperoxides (they mostly arise from the -amino group of bound lysine) and... 

---