Proteins lipid peroxidation aldehyde adducts

Aldehydes, which are secondary products of lipid peroxidation, consist of other groups of agents involved in oxidative stress and modification of proteins structures. Protein cross-linking can occur in vitro employing the malondialdehyde (MDA) Schiff-base-type adducts produced by lysine residues. 

The major aldehyde products of lipid peroxidation are malon-dialdehyde and 4-hydroxynonenal (Table 1, Fig. 4). Malondi-aldehyde can react with DNA to generate adducts at the bases A, C, and G. The mutagenic adduct MIG (pyrimido(l,2-a)purin-10(3H)one) has been detected at levels as high as 1 adduct per 10 nucleosides in human tissues. MIG is a reactive electrophile that can undergo further modification, leading to crosslinking of an adducted DNA strand to the opposite strand, or to some protein (22). Exocyclic etheno adducts can also arise from lipid peroxidation, possibly by reaction of an epoxide of 4-hydroxynonenal with A, C, or G in DNA. 

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]. 

IsoK/LGs react nearly instantaneously with primary amines such as the lysyl residues of proteins. Although 4-hydroxynonenal (HNE), an a,p-unsaturated aldehyde that also forms by lipid peroxidation, is often considered to be highly reactive, it reacts at a very pedestrian rate when compared to IsoK/ LG. For instance, when IsoK/LG or HNE is added to human serum albumin, the half-life of unadducted IsoK/LG is less than 20 s, while the half-life of HNE is about 60 min (Brame et al., 1999). In practical terms, the difference in reactivity between IsoK/LG and HNE means that only adducted IsoK/LG can be found in vivo, while unadducted HNE can be readily measured in tissues and plasma. Additionally, the reactivity of IsoK/LG precludes significant diffusion, so that only the proteins nearest the sites of IsoK/LG formation, such as membrane-associated proteins, are likely to be adducted. 

How selective are pyridoxamine and lipophilic pyridoxamine analogs for scavenging y-ketoaldehydes compared to other reactive lipid peroxidation products The reactivity of pyridoxamine with a,p-unsaturated aldehydes is completely trivial, and pyridoxamine does not protect proteins from HNE adduction (Amarnath et ah, 2004 Davies et al., 2006). Pyridoxamine does react with a-ketoaldehydes such as methylglyoxal that form from the oxidative decomposition of carbohydrates and lipids (Voziyan et al., 2002), and these adducts can be detected in the mine of rodents fed pyridoxamine in their drinking water (Metz et... 

This chapter summarizes the state of knowledge abont protein lipoxidation, focusing on the chemistry of lipid peroxidation-derived aldehydes and their adducts with amino acid residnes. In addition, the recent findings on ligand function of lipoxidation products are also reviewed. 

Hydroxynonenal is one of the major aldehyde products of lipid peroxidation and has been reported to be the most toxic aldehyde formed (Bene-detti et al. 1979, 1980, Benedetti and Comporti 1987). Li et al. (1996) found a formation of protein adducts in alveolar macrophages from C3H/HeJ and C57BL/6J mice in a dose-dependent manner. Alveolar macrophages from both strains had extensive apoptosis at 100 [iM 4-hydroxyonenal. 

Figure 29.5 (A) Examples of aldehydes produced either directly (acetaldehyde) or indirectly, e.g. 4-hydroxy-2-nonenal from lipid peroxidation, which can form adducts with (B) sulphydryl groups on amino acids on proteins as well as amino groups on proteins,...

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