Methionine regulates copper/hydrogen peroxide oxidation products of Aβ

Abstract

Metal-catalysed oxidation (MCO) may play a causative role in the pathogenesis of Alzheimer's disease (AD). Amyloid beta peptide (Abeta), the major biomarker of AD, in the presence of copper ions reduces Cu(2+) to Cu(+) and catalyses the formation of H(2)O(2) that subsequently induces radicals through Fenton chemistry. Abeta is also subject to attack by free radicals, where the presence of Cu(2+) in conjunction with H(2)O(2) catalyses oxygenation, primarily at the methionine sulfur atom. This work investigates MCO of Abeta, to gain further insight into the role of oxidative stress in AD. By combining a fluorescence assay with gel electrophoresis to monitor MCO reactions of Abeta (1-28) in the presence and absence of methionine it was determined that methionine can both protect some residues against MCO and promote the oxidation of Tyr(10) specifically. Electrospray ionization mass spectrometric analysis of methionine MCO products indicated the formation of methionine sulfoxide, methionine sulfone and related hydroxylated products. Similar products could be formed from the oxidation of Met(35) of Abeta and may relate to changes in properties of the peptide following MCO.

Identification of Physiological and Toxic Conformations in Aβ42 Aggregates

“…[46,47] This reaction might be promoted when Ab42 forms the toxic conformation ( Figure 9). The generated Cu I might also induce the production of hydrogen peroxide and the oligomerization of Ab42 through the formation of a dityrosine crosslink at position 10.…”

Capturing a Reactive State of Amyloid Aggregates

“…5C). This small population of oxidized methionine probably resulted from the initial dissolution of A␤ peptide in a dilute sodium hydroxide solution (10 mM) or during the incubation period (34,80). A control experiment revealed significant oxidation of L-methionine after incubation with Cu 2ϩ and ascorbate (data not shown) (81).…”

“…The NMR data suggest that copper ions are subjected to redox cycling between Cu 2ϩ and Cu ϩ while remaining coordinated to the A␤ fibrils. In addition to biological reductants such as ascorbate, the Met-35 residue of A␤ has been proposed to play a significant role in the redox chemistry of copper ions in this system as well (34). The methyl- 13 ϳ15 ppm (33), but the signal overlapping with methyl-13 C signals of Val-12 and Ala-21 (Fig.…”

“…Cu 2ϩ 7 Cu ϩ ) in the presence of O 2 and biological reductant ascorbate, of which the reported concentration in the brain is in a range of 0.2-10 mM (16). Alternatively, it has been proposed that the oxidizable sulfur group on the side chain of Met-35 of A␤ may participate in the electron transfer redox reaction with Cu 2ϩ to produce ROS such as H 2 O 2 (34,36,38,39). Indeed, it has been shown that A␤ isolated from plaques contains oxidized Met-35 (39,40).…”

Rákellenes és Alzheimer-kórban alkalmazható ligandumok és fémkomplexeinek oldatkémiája

“…24,25,26,27,28 Az -amiloid peptidek önmaguk is képesek redukálni a Cu(II) és Fe(III)ionokat miközben a benne lévő metionin metionin-szulfoxiddá oxidálódik. 29,30,31 A hisztidin oldalláncokhoz kötött réz -tekintettel a natív enzimek aktív centrumában található rézion multihisztidines koordinációs módjával való hasonlóságára -redoxi reakciók katalizálására lehet képes. A redukált fémionok mennyiségének növekedése pedig további ROS képződést generál.…”