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. 2020 Jul 20;59(14):9739-9755.
doi: 10.1021/acs.inorgchem.0c00969. Epub 2020 Jun 25.

ESI-MS Study of the Interaction of Potential Oxidovanadium(IV) Drugs and Amavadin with Model Proteins

Valeria Ugone  1 , Daniele Sanna  2 , Giuseppe Sciortino  1   3 , Debbie C Crans  4 , Eugenio Garribba  1
Affiliations

ESI-MS Study of the Interaction of Potential Oxidovanadium(IV) Drugs and Amavadin with Model Proteins

Valeria Ugone et al. Inorg Chem. .

Abstract

In this study, the binding to lysozyme (Lyz) of four important VIV compounds with antidiabetic and/or anticancer activity, [VIVO(pic)2(H2O)], [VIVO(ma)2], [VIVO(dhp)2], and [VIVO(acac)2], where pic-, ma-, dhp-, and acac- are picolinate, maltolate, 1,2-dimethyl-3-hydroxy-4(1H)-pyridinonate, and acetylacetonate anions, and of the vanadium-containing natural product amavadin ([VIV(hidpa)2]2-, with hidpa3- N-hydroxyimino-2,2'-diisopropionate) was investigated by ElectroSpray Ionization-Mass Spectrometry (ESI-MS). Moreover, the interaction of [VIVO(pic)2(H2O)], chosen as a representative VIVO2+ complex, was examined with two additional proteins, myoglobin (Mb) and ubiquitin (Ub), to compare the data. The examined vanadium concentration was in the range 15-150 μM, i.e., very close to that found under physiological conditions. With pic-, dhp-, and hidpa3-, the formation of adducts n[VIVOL2]-Lyz or n[VIVL2]-Lyz is favored, while with ma- and acac- the species n[VIVOL]-Lyz are detected, with n dependent on the experimental VIV/protein ratio. The behavior of the systems with [VIVO(pic)2(H2O)] and Mb or Ub is very similar to that of Lyz. The results suggested that under physiological conditions, the moiety cis-VIVOL2 (L = pic-, dhp-) is bound by only one accessible side-chain protein residue that can be Asp, Glu, or His, while VIVOL+ (L = ma-, acac-) can interact with the two equatorial and axial sites. If the VIV complex is thermodynamically stable and does not have available coordination positions, such as amavadin, the protein cannot interact with it through the formation of coordination bonds and, in such cases, noncovalent interactions are predicted. The formation of the adducts is dependent on the thermodynamic stability and geometry in aqueous solution of the VIVO2+ complex and affects the transport, uptake, and mechanism of action of potential V drugs.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Structure in Aqueous Solution of the VCs Studied in This Work: cis-[VIVO(pic)2(H2O)], [VIVO(acac)2], [VIVO(dhp)2] ⇄ cis-[VIVO(dhp)2(H2O)], cis-[VIVO(ma)2(H2O)], and [VIV(hidpa)2]2– (amavadin)
The charges of the ligands and V=O ion (2+) are omitted for clarity.
Figure 1
Figure 1
ESI-MS spectrum of lysozyme (concentration 5 μM).
Figure 2
Figure 2
Deconvoluted ESI-MS spectrum of lysozyme (concentration 5 μM).
Figure 3
Figure 3
ESI-MS spectra recorded on the system containing [VIVO(pic)2(H2O)] and lysozyme (5 μM): molar ratios 3:1 (top) and 5:1 (bottom).
Figure 4
Figure 4
Deconvoluted ESI-MS spectra recorded on the system containing [VIVO(pic)2(H2O)] and lysozyme (5 μM): molar ratios 3:1 (top) and 5:1 (bottom). L indicates the picolinato ligand.
Figure 5
Figure 5
Deconvoluted ESI-MS spectra recorded on the system containing [VIVO(pic)2(H2O)] and lysozyme (50 μM): molar ratios 3:1 (top) and 5:1 (bottom). L indicates the picolinato ligand. With the asterisks, the peaks of the adducts {[VIVOL]+ + n[VIVOL2]}–Lyz with n = 0–2 (ratio 3:1) and n = 0–4 (ratio 5:1) are denoted.
Figure 6
Figure 6
Deconvoluted ESI-MS spectra recorded on the system containing [VIVO(ma)2] and lysozyme (50 μM): molar ratios 3:1 (top) and 5:1 (bottom). L indicates the maltolato ligand.
Figure 7
Figure 7
Deconvoluted ESI-MS spectra recorded on the system containing [VIVO(dhp)2] and lysozyme (5 μM): molar ratios 3:1 (top) and 5:1 (bottom). L indicates the 1,2-dimethyl-3-hydroxy-4(1H)-pyridinonato ligand.
Figure 8
Figure 8
Deconvoluted ESI-MS spectra recorded on the system containing [VIVO(acac)2] and lysozyme with a molar ratio of 5:1 and a protein concentration of 5 μM (top) and 50 μM (bottom). L indicates the acetylacetonato ligand.
Figure 9
Figure 9
Deconvoluted ESI-MS spectra recorded on the system containing [VIV(hidpa)2]2– and lysozyme with a molar ratio of 5:1 and a protein concentration of 5 μM (top) and 50 μM (bottom). L indicates the N-hydroxyimino-2,2′-diisopropionato ligand.
Figure 10
Figure 10
Deconvoluted ESI-MS spectrum of myoglobin (concentration 5 μM).
Figure 11
Figure 11
Deconvoluted ESI-MS spectra recorded on the system containing [VIVO(pic)2(H2O)] and myoglobin (50 μM): molar ratios 3:1 (top) and 5:1 (bottom). L indicates the picolinato ligand. With the asterisks, the peaks of the adducts {[VIVOL] + n[VIVOL2]}–Mb with n = 0–3 (ratio 3:1) and n = 0–4 (ratio 5:1) are denoted.
Figure 12
Figure 12
Deconvoluted ESI-MS spectrum of ubiquitin (concentration 5 μM).
Figure 13
Figure 13
Experimental (top) and calculated (bottom) isotopic pattern for the peak revealed in the ESI-MS spectrum of ubiquitin, C378H639N105O118S (i.e., [Ub+9H+]) at m/z 952.63 with z = 9.
Figure 14
Figure 14
Deconvoluted ESI-MS spectra recorded on the system containing [VIVO(pic)2(H2O)] and ubiquitin (5 μM): molar ratios 3:1 (top), 5:1 (center), and 10:1 (bottom). L indicates the picolinato ligand.
Figure 15
Figure 15
ESI-MS spectrum recorded on the system containing [VIVO(ma)2] (150 μM) and lysozyme (50 μM). The region in the m/z range 180–350 is presented in the inset.
Scheme 2
Scheme 2. Adducts Formed at the Physiological Vanadium Concentration by [VIVO(pic)2(H2O)], [VIVO(ma)2], [VIVO(dhp)2], [VIVO(acac)2], and [VIV(hidpa)2]2–,
When more than one adduct is formed in aqueous solution, it is indicated with minor or major species. In round parentheses, the less probable binding of an axial residue Z is denoted. The charges of the ligands and V=O ion (2+) are omitted for clarity.
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