Hydrolysis of a mRNA 5′-cap model substrate, 5′,5′-ApppA by di- and trinuclear zinc(II) complexes of a polyamino-polyol ligand

A. Jancsó, Satu Mikkola, Harri Lönnberg, Kaspar Hegetschweiler, T. Gajda

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Copper(II) and zinc(II) complexes of a polyamino-polyol ligand 1,3,5-trideoxy-1,3,5-tris(methylamino)-cis-inositol (tmci) have been investigated as potential candidates for the selective elimination of the 5′-cap structure of mRNA. A cap-model compound ApppA has been utilised as substrate for studying the effect of the different metal ion complex catalysts on the hydrolysis of the triphosphate bridge. Kinetic experiments have been performed by the variation of pH, metal-to-ligand ratio and total concentrations of the metal ion and ligand. The zinc(II) complexes of tmci have been proved to possess a remarkable activity for the hydrolysis of ApppA. The observed rate enhancement compared to the uncatalysed reaction was found to be 12,000-fold, in the presence of 4.5 mM zinc(II) and 1.5 mM tmci at pH ∼ 7.5. In contrast with the copper(II) containing systems, an extra product has also been formed during the cleavage process, beside the expected AMP and ADP. According to the ESI-MS characterisation of the samples, the additional product is a covalent phosphoester adduct of AMP and the ligand. The formation of this species is initiated by a nucleophilic attack of a zinc(II)-bound alcohol or alkoxo group on one of the α phosphate groups of ApppA, which leads to the formation of a phosphodiester bond. In an alternative pathway, the substrate is cleaved into AMP and ADP. According to the pH-potentiometric studies, performed with the tmci-zinc(II) system, di- and trinuclear complexes are responsible for the accelerated ApppA hydrolysis. The copper(II)-tmci 2:1 system showed only a modest kinetic activity. The rate acceleration significantly increased when threefold excess of copper(II) was applied. Although, the detailed investigations above pH ∼ 6.6 have been prevented by precipitate formation during the addition of the substrate into the reaction solution, the activity of the copper(II)-tmci 3:1 system does not exceed that of the zinc(II) complexes. Due to the specific mechanism leading to the covalent extra product, the zinc(II) complexes of tmci provide a comparable rate enhancement for ApppA hydrolysis to the widely studied lanthanide or copper(II) species, in spite of the fact that they are stronger Lewis acids.

Original languageEnglish
Pages (from-to)1283-1293
Number of pages11
JournalJournal of Inorganic Biochemistry
Volume99
Issue number6
DOIs
Publication statusPublished - Jun 2005

Fingerprint

Inositol
Zinc
Hydrolysis
Copper
Ligands
Messenger RNA
Substrates
Adenosine Monophosphate
Adenosine Diphosphate
Metal ions
RNA Caps
Metals
Ions
Lewis Acids
Lanthanoid Series Elements
Kinetics
Coordination Complexes
diadenosine triphosphate
polyol
Precipitates

Keywords

  • Cap-structure
  • Equilibrium studies
  • Kinetics
  • Oligonuclear complexes
  • Triphosphate cleavage

ASJC Scopus subject areas

  • Biochemistry
  • Inorganic Chemistry

Cite this

Hydrolysis of a mRNA 5′-cap model substrate, 5′,5′-ApppA by di- and trinuclear zinc(II) complexes of a polyamino-polyol ligand. / Jancsó, A.; Mikkola, Satu; Lönnberg, Harri; Hegetschweiler, Kaspar; Gajda, T.

In: Journal of Inorganic Biochemistry, Vol. 99, No. 6, 06.2005, p. 1283-1293.

Research output: Contribution to journalArticle

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abstract = "Copper(II) and zinc(II) complexes of a polyamino-polyol ligand 1,3,5-trideoxy-1,3,5-tris(methylamino)-cis-inositol (tmci) have been investigated as potential candidates for the selective elimination of the 5′-cap structure of mRNA. A cap-model compound ApppA has been utilised as substrate for studying the effect of the different metal ion complex catalysts on the hydrolysis of the triphosphate bridge. Kinetic experiments have been performed by the variation of pH, metal-to-ligand ratio and total concentrations of the metal ion and ligand. The zinc(II) complexes of tmci have been proved to possess a remarkable activity for the hydrolysis of ApppA. The observed rate enhancement compared to the uncatalysed reaction was found to be 12,000-fold, in the presence of 4.5 mM zinc(II) and 1.5 mM tmci at pH ∼ 7.5. In contrast with the copper(II) containing systems, an extra product has also been formed during the cleavage process, beside the expected AMP and ADP. According to the ESI-MS characterisation of the samples, the additional product is a covalent phosphoester adduct of AMP and the ligand. The formation of this species is initiated by a nucleophilic attack of a zinc(II)-bound alcohol or alkoxo group on one of the α phosphate groups of ApppA, which leads to the formation of a phosphodiester bond. In an alternative pathway, the substrate is cleaved into AMP and ADP. According to the pH-potentiometric studies, performed with the tmci-zinc(II) system, di- and trinuclear complexes are responsible for the accelerated ApppA hydrolysis. The copper(II)-tmci 2:1 system showed only a modest kinetic activity. The rate acceleration significantly increased when threefold excess of copper(II) was applied. Although, the detailed investigations above pH ∼ 6.6 have been prevented by precipitate formation during the addition of the substrate into the reaction solution, the activity of the copper(II)-tmci 3:1 system does not exceed that of the zinc(II) complexes. Due to the specific mechanism leading to the covalent extra product, the zinc(II) complexes of tmci provide a comparable rate enhancement for ApppA hydrolysis to the widely studied lanthanide or copper(II) species, in spite of the fact that they are stronger Lewis acids.",
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AU - Mikkola, Satu

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AU - Hegetschweiler, Kaspar

AU - Gajda, T.

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KW - Equilibrium studies

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