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Influence of the N-terminus acetylation of Semax, a synthetic analog of ACTH(4-10), on copper(II) and zinc(II) coordination and biological properties.
J Inorg Biochem. 2016 11; 164:59-69.JI

Abstract

Semax is a heptapeptide (Met-Glu-His-Phe-Pro-Gly-Pro) that encompasses the sequence 4-7 of N-terminal domain of the adrenocorticotropic hormone and a C-terminal Pro-Gly-Pro tripeptide. N-terminal amino group acetylation (Ac-Semax) modulates the chemical and biological properties of parental peptide, modifying the ability of Semax to form complex species with Cu(II) ion. At physiological pH, the main complex species formed by Ac-Semax, [CuLH-2]2-, consists in a distorted CuN3O chromophore with a weak apical interaction of the methionine sulphur. Such a complex differs from the Cu(II)-Semax complex system, which exhibits a CuN4 chromophore. The reduced ligand field affects the [CuLH-2]2- formal redox potential, which is more positive than that of Cu(II)-Semax corresponding species. In the amino-free form, the resulting complex species is redox-stable and unreactive against ascorbic acid, unlike the acetylated form. Semax acetylation did not protect from Cu(II) induced toxicity on a SH-SY5Y neuroblastoma cell line, thus demonstrating the crucial role played by the free NH2 terminus in the cell protection. Since several brain diseases are associated either to Cu(II) or Zn(II) dyshomeostasis, here we characterized also the complex species formed by Zn(II) with Semax and Ac-Semax. Both peptides were able to form Zn(II) complex species with comparable strength. Confocal microscopy imaging confirmed that peptide group acetylation does not affect the Zn(II) influx in neuroblastoma cells. Moreover, a punctuate distribution of Zn(II) within the cells suggests a preferred subcellular localization that might explain the zinc toxic effect. A future perspective can be the use of Ac-Semax as ionophore in antibody drug conjugates to produce a dysmetallostasis in tumor cells.

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Authors+Show Affiliations

Magrì A
Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche (CNR), Via P. Gaifami 18, 95126 Catania, Italy.
Tabbì G
Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche (CNR), Via P. Gaifami 18, 95126 Catania, Italy. Electronic address: giovanni.tabbi@cnr.it.
Giuffrida A
Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche (CNR), Via P. Gaifami 18, 95126 Catania, Italy.
Pappalardo G
Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche (CNR), Via P. Gaifami 18, 95126 Catania, Italy.
Satriano C
Dipartimento di Scienze Chimiche, Università degli Studi di Catania, Viale A. Doria 6, 95125 Catania, Italy.
Naletova I
Dipartimento di Scienze Biomediche, Università degli Studi di Catania, Viale A. Doria 6, 95125 Catania, Italy; Consorzio Interuniversitario C.I.R.C.S.M.B., Via C. Ulpiani 27, 70125 Bari, Italy.
Nicoletti VG
Dipartimento di Scienze Biomediche, Università degli Studi di Catania, Viale A. Doria 6, 95125 Catania, Italy.
Attanasio F
Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale delle Ricerche (CNR), Via P. Gaifami 18, 95126 Catania, Italy. Electronic address: francesco.attanasio@cnr.it.

MeSH

AcetylationAdrenocorticotropic HormoneCell Line, TumorCoordination ComplexesCopperHumansIonophoresPeptide FragmentsZinc

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27586814

Citation

Magrì, Antonio, et al. "Influence of the N-terminus Acetylation of Semax, a Synthetic Analog of ACTH(4-10), On copper(II) and zinc(II) Coordination and Biological Properties." Journal of Inorganic Biochemistry, vol. 164, 2016, pp. 59-69.
Magrì A, Tabbì G, Giuffrida A, et al. Influence of the N-terminus acetylation of Semax, a synthetic analog of ACTH(4-10), on copper(II) and zinc(II) coordination and biological properties. J Inorg Biochem. 2016;164:59-69.
Magrì, A., Tabbì, G., Giuffrida, A., Pappalardo, G., Satriano, C., Naletova, I., Nicoletti, V. G., & Attanasio, F. (2016). Influence of the N-terminus acetylation of Semax, a synthetic analog of ACTH(4-10), on copper(II) and zinc(II) coordination and biological properties. Journal of Inorganic Biochemistry, 164, 59-69. https://doi.org/10.1016/j.jinorgbio.2016.08.013
Magrì A, et al. Influence of the N-terminus Acetylation of Semax, a Synthetic Analog of ACTH(4-10), On copper(II) and zinc(II) Coordination and Biological Properties. J Inorg Biochem. 2016;164:59-69. PubMed PMID: 27586814.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Influence of the N-terminus acetylation of Semax, a synthetic analog of ACTH(4-10), on copper(II) and zinc(II) coordination and biological properties. AU - Magrì,Antonio, AU - Tabbì,Giovanni, AU - Giuffrida,Alessandro, AU - Pappalardo,Giuseppe, AU - Satriano,Cristina, AU - Naletova,Irina, AU - Nicoletti,Vincenzo G, AU - Attanasio,Francesco, Y1 - 2016/08/27/ PY - 2016/03/31/received PY - 2016/08/23/revised PY - 2016/08/25/accepted PY - 2016/9/3/pubmed PY - 2017/9/5/medline PY - 2016/9/3/entrez KW - Biological activity KW - Copper KW - Oxidation KW - Stability constants KW - Voltammetry KW - Zinc SP - 59 EP - 69 JF - Journal of inorganic biochemistry JO - J Inorg Biochem VL - 164 N2 - Semax is a heptapeptide (Met-Glu-His-Phe-Pro-Gly-Pro) that encompasses the sequence 4-7 of N-terminal domain of the adrenocorticotropic hormone and a C-terminal Pro-Gly-Pro tripeptide. N-terminal amino group acetylation (Ac-Semax) modulates the chemical and biological properties of parental peptide, modifying the ability of Semax to form complex species with Cu(II) ion. At physiological pH, the main complex species formed by Ac-Semax, [CuLH-2]2-, consists in a distorted CuN3O chromophore with a weak apical interaction of the methionine sulphur. Such a complex differs from the Cu(II)-Semax complex system, which exhibits a CuN4 chromophore. The reduced ligand field affects the [CuLH-2]2- formal redox potential, which is more positive than that of Cu(II)-Semax corresponding species. In the amino-free form, the resulting complex species is redox-stable and unreactive against ascorbic acid, unlike the acetylated form. Semax acetylation did not protect from Cu(II) induced toxicity on a SH-SY5Y neuroblastoma cell line, thus demonstrating the crucial role played by the free NH2 terminus in the cell protection. Since several brain diseases are associated either to Cu(II) or Zn(II) dyshomeostasis, here we characterized also the complex species formed by Zn(II) with Semax and Ac-Semax. Both peptides were able to form Zn(II) complex species with comparable strength. Confocal microscopy imaging confirmed that peptide group acetylation does not affect the Zn(II) influx in neuroblastoma cells. Moreover, a punctuate distribution of Zn(II) within the cells suggests a preferred subcellular localization that might explain the zinc toxic effect. A future perspective can be the use of Ac-Semax as ionophore in antibody drug conjugates to produce a dysmetallostasis in tumor cells. SN - 1873-3344 UR - https://www.unboundmedicine.com/medline/citation/27586814/Influence_of_the_N_terminus_acetylation_of_Semax_a_synthetic_analog_of_ACTH_4_10__on_copper_II__and_zinc_II__coordination_and_biological_properties_ DB - PRIME DP - Unbound Medicine ER -