In an in vitro Ca2+-induced cataract model, the progression of opacification is paralleled by a rapid decrease of the endogenous levels of spermidine (SPD) and an increase of transglutaminase type 2 (TG2, EC 2.3.2.13)-catalyzed lens crystallins cross-linking by protein-boundN(1)-N-8-bis(gamma-glutamyl) SPD. This pattern was reversed adding exogenous SPD to the incubation resulting in a delayed loss of transparency of the rabbit lens. The present report shows evidence on the main incorporation of SPD by the catalytic activity of TG2, toward beta H-crystallins and in particular to the beta B2- and mostly in beta B3-crystallins. The increase of endogenous SPD in the cultured rabbit lens showed the activation of a flavin adenine dinucleotide (FAD)-dependent polyamine oxidases (PAO EC 1.5.3.11). As it is known that FAD-PAO degrades theN(8)-terminal reactive portion ofN(1)-mono(gamma-glutamyl) SPD, the protein-boundN(8)-mono(gamma-glutamyl) SPD was found the mainly available derivative for the potential formation of beta B3-crystallins cross-links by protein-boundN(1)-N-8-bis(gamma-glutamyl)SPD. In conclusion, FAD-PAO degradation of theN(8)-terminal reactive residue of the crystallins boundN(1)-mono(gamma-glutamyl)SPD together with the increased concentration of exogenous SPD, leading to saturation of glutamine residues on the substrate proteins, drastically reducesN(1)-N-8-bis(gamma-glutamyl)SPD crosslinks formation, preventing crystallins polymerization and avoiding rabbit lens opacification. The ability of SPD and MDL 72527 to modulate the activities of TG2 and FAD-PAO involved in the mechanism of lens opacification suggests a potential strategy for the prevention of senile cataract.

Mischiati, C., Feriotto, G., Tabolacci, C., Domenici, F., Melino, S., Borromeo, I., et al. (2020). Polyamine oxidase is involved in spermidine reduction of transglutaminase type 2-catalyzed βh-crystallins polymerization in calcium-induced experimental cataract. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 21(15), 1-12 [10.3390/ijms21155427].

Polyamine oxidase is involved in spermidine reduction of transglutaminase type 2-catalyzed βh-crystallins polymerization in calcium-induced experimental cataract

Domenici F.;Melino S.
Investigation
;
Forni C.;De Martino A.;Beninati S.
Writing – Original Draft Preparation
2020-01-01

Abstract

In an in vitro Ca2+-induced cataract model, the progression of opacification is paralleled by a rapid decrease of the endogenous levels of spermidine (SPD) and an increase of transglutaminase type 2 (TG2, EC 2.3.2.13)-catalyzed lens crystallins cross-linking by protein-boundN(1)-N-8-bis(gamma-glutamyl) SPD. This pattern was reversed adding exogenous SPD to the incubation resulting in a delayed loss of transparency of the rabbit lens. The present report shows evidence on the main incorporation of SPD by the catalytic activity of TG2, toward beta H-crystallins and in particular to the beta B2- and mostly in beta B3-crystallins. The increase of endogenous SPD in the cultured rabbit lens showed the activation of a flavin adenine dinucleotide (FAD)-dependent polyamine oxidases (PAO EC 1.5.3.11). As it is known that FAD-PAO degrades theN(8)-terminal reactive portion ofN(1)-mono(gamma-glutamyl) SPD, the protein-boundN(8)-mono(gamma-glutamyl) SPD was found the mainly available derivative for the potential formation of beta B3-crystallins cross-links by protein-boundN(1)-N-8-bis(gamma-glutamyl)SPD. In conclusion, FAD-PAO degradation of theN(8)-terminal reactive residue of the crystallins boundN(1)-mono(gamma-glutamyl)SPD together with the increased concentration of exogenous SPD, leading to saturation of glutamine residues on the substrate proteins, drastically reducesN(1)-N-8-bis(gamma-glutamyl)SPD crosslinks formation, preventing crystallins polymerization and avoiding rabbit lens opacification. The ability of SPD and MDL 72527 to modulate the activities of TG2 and FAD-PAO involved in the mechanism of lens opacification suggests a potential strategy for the prevention of senile cataract.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/10
Settore BIO/06
Settore BIO/01
English
FAD-PAO
TG2
cataract
protein post-translation modification
rabbit eye lens
spermidine
Mischiati, C., Feriotto, G., Tabolacci, C., Domenici, F., Melino, S., Borromeo, I., et al. (2020). Polyamine oxidase is involved in spermidine reduction of transglutaminase type 2-catalyzed βh-crystallins polymerization in calcium-induced experimental cataract. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 21(15), 1-12 [10.3390/ijms21155427].
Mischiati, C; Feriotto, G; Tabolacci, C; Domenici, F; Melino, S; Borromeo, I; Forni, C; De Martino, A; Beninati, S
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/255814
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