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Verfasst von:Brings, Sebastian [VerfasserIn]   i
 Mier, Walter [VerfasserIn]   i
 Beijer, Barbro [VerfasserIn]   i
 Kliemank, Elisabeth [VerfasserIn]   i
 Herzig, Stephan [VerfasserIn]   i
 Szendrödi, Julia [VerfasserIn]   i
 Nawroth, Peter Paul [VerfasserIn]   i
 Fleming, Thomas [VerfasserIn]   i
Titel:Non-cross-linking advanced glycation end products affect prohormone processing
Verf.angabe:Sebastian Brings, Walter Mier, Barbro Beijer, Elisabeth Kliemank, Stephan Herzig, Julia Szendroedi, Peter P. Nawroth and Thomas Fleming
E-Jahr:2024
Jahr:January 2024
Umfang:12 S.
Illustrationen:Illustrationen
Fussnoten:Gesehen am 14.03.2024
Titel Quelle:Enthalten in: The biochemical journal
Ort Quelle:London : Portland Press, 1906
Jahr Quelle:2024
Band/Heft Quelle:481(2024), 1 vom: Jan., Seite 33-44
ISSN Quelle:0006-2936
 0306-3275
 0264-6021
Abstract:Advanced glycation end products (AGEs) are non-enzymatic post-translational modifications of amino acids and are associated with diabetic complications. One proposed pathomechanism is the impaired processing of AGE-modified proteins or peptides including prohormones. Two approaches were applied to investigate whether substrate modification with AGEs affects the processing of substrates like prohormones to the active hormones. First, we employed solid-phase peptide synthesis to generate unmodified as well as AGE-modified protease substrates. Activity of proteases towards these substrates was quantified. Second, we tested the effect of AGE-modified proinsulin on the processing to insulin. Proteases showed the expected activity towards the unmodified peptide substrates containing arginine or lysine at the C-terminal cleavage site. Indeed, modification with Nε-carboxymethyllysine (CML) or methylglyoxal-hydroimidazolone 1 (MG-H1) affected all proteases tested. Cysteine cathepsins displayed a reduction in activity by ∼50% towards CML and MG-H1 modified substrates. The specific proteases trypsin, proprotein convertases subtilisin-kexins (PCSKs) type proteases, and carboxypeptidase E (CPE) were completely inactive towards modified substrates. Proinsulin incubation with methylglyoxal at physiological concentrations for 24 h resulted in the formation of MG-modified proinsulin. The formation of insulin was reduced by up to 80% in a concentration-dependent manner. Here, we demonstrate the inhibitory effect of substrate-AGE modifications on proteases. The finding that PCSKs and CPE, which are essential for prohormone processing, are inactive towards modified substrates could point to a yet unrecognized pathomechanism resulting from AGE modification relevant for the etiopathogenesis of diabetes and the development of obesity.
DOI:doi:10.1042/BCJ20230321
URL:Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.

kostenfrei: Volltext: https://doi.org/10.1042/BCJ20230321
 kostenfrei: Volltext: https://portlandpress.com/biochemj/article/481/1/33/233869/Non-cross-linking-advanced-glycation-end-products
 DOI: https://doi.org/10.1042/BCJ20230321
Datenträger:Online-Ressource
Sprache:eng
K10plus-PPN:1883459354
Verknüpfungen:→ Zeitschrift

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