Mass spectrometry for detection of 4‐hydroxy‐trans‐2‐nonenal (HNE) adducts with peptides and proteins

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Abstract
I. Introduction 282 A. 4‐Hydroxy‐trans‐2‐Nonenal (HNE): Biological Effects and Mechanism of Formation 282 B. HNE Reactivity and Reaction Mechanisms with Target Proteins 282 C. HNE: Pathological Implications 284 II. Analytical Approaches for Detection of HNE Adducts 285 A. Chemical Methods 285 B. Immunochemical Methods 286 C. Mass Spectrometry 287 III. Interaction of HNE with Peptides 287 A. GSH and Histidine‐Containing Peptides as HNE Detoxifying Agents 287 B. Synthetic and Biological Model Peptides 289 IV. Interaction of HNE with Proteins 291 A. Hemoproteins 291 B. Lipoproteins 293 C. Enzymes 294 1. Glucose‐6‐Phosphate Dehydrogenase (G6PDH) 295 2. Cathepsin B 295 3. Glyceraldehyde‐3‐Phosphate Dehydrogenase (GAPDH) 295 4. Cytochrome‐c Oxidase (CcO) 296 D. Other Proteins 299 1. Rhodopsin 299 2. Insulin 299 3. Epithelial Fatty Acid‐Binding Protein (E‐FABP) 300 V. Conclusions and Future Perspectives 300 Abbreviations 302 References 302 Despite the great technical advancement of mass spectrometry, this technique has contributed in a limited way to the discovery and quantitation of specific/precocious markers linked to free radical‐mediated diseases. Unsaturated aldehydes generated by free radical‐induced lipid peroxidation of polyunsaturated fatty acids, and in particular 4‐hydroxy‐trans‐2 nonenal (HNE), are involved in the onset and progression of many pathologies such as cardiovascular (atherosclerosis, long‐term complications of diabetes) and neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, and cerebral ischemia). Most of the biological effects of HNE are attributed to the capacity of HNE to react with the nucleophilic sites of proteins and peptides (other than nucleic acids), to form covalently modified biomolecules that can disrupt important cellular functions and induce mutations. By considering the emerging role of HNE in several human diseases, an unequivocal analytical approach as mass spectrometry to detect/elucidate the structure of protein‐HNE adducts in biological matrices is strictly needed not only to understand the reaction mechanism of HNE, but also to gain a deeper insight into the pathological role of HNE. This with the aim to provide intermediate diagnostic biomarkers for human diseases. This review sheds focus on the “state‐of‐the‐art” of mass spectrometric applications in the field of HNE‐protein adducts characterization, starting from the fundamental early studies and discussing the different MS‐based approaches that can provide detailed information on the mechanistic aspects of HNE–protein interaction. In the last decade, the increases in the accessible mass ranges of modern instruments and advances in ionization methods have made possible a fundamental improvement in the analysis of protein–HNE adducts by mass spectrometry, and in particular by matrix‐assisted laser desorption/ionization (MALDI) and electrospray ionization (ESI) tandem mass spectrometry. The recent developments and uses of combined analytical approaches to detect and characterize the type/site of interaction have been highlighted, and several other aspects, including sample preparation methodologies, structure elucidation, and data analysis have also been considered. © 2004 Wiley Periodicals, Inc., Mass Spec Rev 23:281–305, 2004

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