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CELLULAR AND MOLECULAR

Protein Cross-Linkage Induced by Formaldehyde Derived from Semicarbazide-Sensitive Amine Oxidase-Mediated Deamination of Methylamine

Neuropsychiatry Research Unit, Departments of Psychiatry (D.G.-H., W.H., M.K., J.S.R., P.H.Y.) and Pharmacology (J.S.R.), University of Saskatchewan, Saskatoon, Saskatchewan, Canada

Semicarbazide-sensitive amine oxidase (SSAO) catalyzes the conversion of methylamine to formaldehyde. This enzyme is located on the surface of the cytoplasmic membrane and in the cytosol of vascular endothelial cells, smooth muscle cells, and adipocytes. Increased SSAO activity has been found in patients with diabetes mellitus, chronic heart failure, and multiple types of cerebral infarcts and is associated with obesity. Increased SSAO-mediated deamination may contribute to protein deposition, the formation of plaques, and inflammation, and thus may be involved in the pathophysiology of chronic vascular and neurological disorders, such as diabetic complications, atherosclerosis, and Alzheimer's disease. In the present study, we demonstrate the induction of cross-linkage of formaldehyde with the lysine moiety of peptides and proteins. Formaldehyde-protein adducts were reduced with sodium cyanoborohydride, hydrolyzed in hydrochloric acid, and the amino acids in the hydrolysates were derivatized with fluorenylmethyl chloroformate and then identified with high-performance liquid chromatography. We further demonstrate that incubation of methylamine in the presence of SSAO-rich tissues, e.g., human brain meninges, results in formaldehyde-protein cross-linkage of particulate bound proteins as well as of soluble proteins. This cross-linkage can be completely blocked by a selective inhibitor of SSAO. Our data support the hypothesis that the SSAO-induced production of formaldehyde may be involved in the alteration of protein structure, which may subsequently cause protein deposition associated with chronic pathological disorders.

Address correspondence to: Dr. Peter H. Yu, Neuropsychiatry Research Unit, University of Saskatchewan, Saskatoon, SK S7N 5E4, Canada. E-mail: yup{at}usask.ca

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