Protein adduction 2-alkenal adducts

HNE is a 4-hydroxy-2-alkenal (Fig. 5) that is a product of arachidonic and linoleic acid and better represents the mixture of fatty acids in lipoproteins than do some other oxidation products. HNE is cytotoxic to cells and causes the rapid depletion of glutathione, inhibition of DNA, RNA, and protein synthesis and, at high levels, inhibition of many metabolic processes leading to rapid cell death (E4). HNE is a specific product that has been measured by GC/MS and HPLC (E4). HPLC methods may be more accessible to clinical laboratories than GC/MS and have been used both for measuring levels of HNE and HNE protein adducts (U2), but generally they have been measured only in lipoprotein extracts or tissue and not in whole plasma or serum. 

Reactive aldehydes derived from lipid peroxidation, which are able to bind to several amino acid residues, are also capable of generating novel amino acid oxidation products. By means of specific polyclonal or monoclonal antibodies, the occurrence of malonaldehyde (MDA) and 4-hydroxynonenal (4-HNE) bound to cellular protein has been shown. Lysine modification by lipid peroxidation products (linoleic hydroperoxide) can yield neo-antigenic determinants such as N-c-hexanoyl lysine. Both histidine and lysine are nucleophilic amino acids and therefore vulnerable to modification by lipid peroxidation-derived electrophiles, such as 2-alkenals, 4-hydroxy-2-alkenals, and ketoaldehydes, derived from lipid peroxidation. Histidine shows specific reactivity toward 2-alkenals and 4-hydroxy-2-alkenals, whereas lysine is an ubiquitous target of aldehydes, generating various types of adducts. Covalent binding of reactive aldehydes to histidine and lysine is associated with the appearance of carbonyl reactivity and antigenicity of proteins [125]. 

The representative 2-alkenal adducts are summarized in Figure 6.4. The reactions of lysine with 2-alkenals have been mainly studied with acrolein, crotonaldehyde, and 2-nonenal. Similar to other a,P-unsaturated aldehydes, acrolein selectively reacts with the cysteine, histidine, and lysine residues of proteins. The primary products are their 3-substituted propanals (1) (Figure 6.4a). These p-substituted propanals or Schiff s base crosslinks had been suggested as the predominant acrolein-lysine adducts however, the major product formed upon the reaction of acrolein with a protein was identified to be a novel lysine product, A -(3-formyl-3,4-dehydropiperidino) lysine (FDP-lysine) (2), which requires attachment of two acrolein molecules to one lysine side chain (Uchida et al, 1998b). This and the fact that crotonaldehyde also forms a similar FDP-type adduct, A -(2,5-dimethyl-3-formyl-3,4-dehydropiperidino) lysine (dimethyl-FDP-lysine) (Ichihashi et al., 2001), suggest that this type of condensation reaction is characteristic of the reaction of 2-alkenals with primary amines. Indeed, upon reaction with a lysine derivative, other 2-alkenals, such as... 

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