Mechanism of lysine oxidation in human lens crystallins during aging and in diabetes.
Oxidative mechanisms during nuclear sclerosis of the lens are poorly understood, in particular metal-catalyzed oxidation. The lysyl oxidation product adipic semialdehyde (allysine, ALL) and its oxidized end-product 2-aminoadipic acid (2-AAA) were determined as a function of age and presence of diabetes. Surprisingly, whereas both ALL and 2-AAA increased with age and strongly correlated with cataract grade and protein absorbance at 350 nm, only ALL formation but not 2-AAA was increased by diabetes. To clarify the mechanism of oxidation, rabbit lenses were treated with hyperbaric oxygen (HBO) for 48 h, and proteins were analyzed by gas and liquid chromatography mass spectrometry for ALL, 2-AAA, and multiple glycation products. Upon exposure to HBO, rabbit lenses were swollen, and nuclei were yellow. Protein-bound ALL increased 8-fold in the nuclear protein fractions versus controls. A dramatic increase in methyl-glyoxal hydroimidazolone and carboxyethyl-lysine but no increase of 2-AAA occurred, suggesting more drastic conditions are needed to oxidize ALL into 2-AAA. Indeed the latter formed only upon depletion of glutathione and was catalyzed by H(2)O(2). Neither carboxymethyl-lysine nor glyoxal hydroimidazolone, two markers of glyco-/lipoxidation, nor markers of lenticular glycemia (fructose-lysine, glucospane) were elevated by HBO, excluding significant lipid peroxidation and glucose involvement. The findings strongly implicate dicarbonyl/metal catalyzed oxidation of lysine to allysine, whereby low GSH combined with ascorbate-derived H(2)O(2) likely contributes toward 2-AAA formation, since virtually no 2-AAA formed in the presence of methylglyoxal instead of ascorbate. An important translational conclusion is that chelating agents might help delay nuclear sclerosis.
Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106 , USA.
Xingjun
X
Fan
Jianye
J
Zhang
Mathilde
M
Theves
Christopher
C
Strauch
Ina
I
Nemet
Xiaoqin
X
Liu
Juan
J
Qian
Frank J
FJ
Giblin
Vincent M
VM
Monnier
D015074:2-Aminoadipic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000502:physiology*; D000818:Animals; D002417:Cattle; D002648:Child; D003459:Crystallins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D006931:Hyperbaric Oxygenation; D007908:Lens, Crystalline / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D007930:Leucine / Q000737:chemistry; D008239:Lysine / Q000737:chemistry / Q000378:metabolism*; D008670:Metals / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D015394:Molecular Structure; D016877:Oxidants / Q000378:metabolism; D010084:Oxidation-Reduction; D011817:Rabbits; D012044:Regression Analysis; D055815:Young Adult
D003459:Crystallins; D008670:Metals; D016877:Oxidants; D015074:2-Aminoadipic Acid; C000061:allysine; D006861:Hydrogen Peroxide; D007930:Leucine; D008239:Lysine