The N-domain of angiotensin-converting enzyme specifically hydrolyzes the Arg-5-His-6 bond of Alzheimer’s Ab-(1-16) peptide and its isoAsp-7 analogue with different efficiency as evidenced by quantitative matrix-assisted laser desorption/ionization time-o

14 сентября 2018
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Контактные данные автора публикации Ilya Yu. Toropygin1 , Elena V. Kugaevskaya1 , Olga A. Mirgorodskaya2 , Yulia E. Elisseeva1 , Yuri P. Kozmin3 , Igor A. Popov1 , Eugene N. Nikolaev1 , Alexander A. Makarov4 and Sergey A. Kozin1*
Ссылка на публикацию в интернете ckp.ibmh.msk.su/work/FILES/18/toropygin.PDF

Аннотация

Chronic imbalance between production and degradation of the human amyloid-beta peptide (Ab) is
assumed to play an important role in pathogenesis of Alzheimer’s disease (AD). Post-translational
modifications of Ab could influence its interactions with specifically cleaving proteases and, therefore,
perturb the Ab homeostasis. The angiotensin-converting enzyme (ACE) was previously shown
to degrade non-modified Ab in vitro and in cells. In the presented work, we investigated the effect of
isomerization of Asp-7, a common non-enzymatic age-related modification found in AD-associated
Ab species, on hydrolysis of Ab by ACE. Two synthetic peptides corresponding to the Ab region 1-16
with either Asp or isoAsp residues in position 7 were examined as monomeric soluble substrates for
the N- as well as for the C-domain of ACE. The use of matrix-assisted laser desorption/ionization
time-of-flight mass spectrometry (MALDI-TOFMS) coupled with the 18O-labeled internal standard
approach has allowed us to show that (i) the N-domain of ACE (N-ACE), but not the C-domain,
selectively cleaves the Arg-5-His-6 bond in both peptides, and that (ii) N-ACE hydrolyzes the
isoAsp-7 analogue more efficiently than the non-modified one. Our results demonstrate a new
endopeptidase activity of N-ACE as well as high preference of the domain to recognize and hydrolyze
the isomerized Ab species that were earlier suggested to promote AD pathogenesis. The results
suggest the need for further analysis of biological effects of isomerized Ab and its interaction with
ACE in AD pathogenesis. Copyright # 2007 John Wiley
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