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Enhancing Tris(pyrazolyl)borate-Based Models of Cysteine/Cysteamine Dioxygenases through Steric Effects: Increased Reactivities, Full Product Characterization and Hints to Initial Superoxide Formation.

ABSTRACT: The design of biomimetic model complexes for the cysteine dioxygenase (CDO) and cysteamine dioxygenase (ADO) is reported, where the 3-His coordination of the iron ion is simulated by three pyrazole donors of a trispyrazolyl borate ligand (Tp) and protected cysteine and cysteamine represent substrate ligands. It is found that the replacement of phenyl groups-attached at the 3-positions of the pyrazole units in a previous model-by mesityl residues has massive consequences, as the latter arrange to a more spacious reaction pocket. Thus, the reaction with O2 proceeds much faster and afterwards the first structural characterization of an iron(II) η2 -O,O-sulfinate product became possible. If one of the three Tp-mesityl groups is placed in the 5-position, an even larger reaction pocket results, which leads to yet faster rates and accumulation of a reaction intermediate at low temperatures, as shown by UV/Vis and Mössbauer spectroscopy. After comparison with the results of investigations on the cobalt analogues this intermediate is tentatively assigned to an iron(III) superoxide species.

SUBMITTER: Muller L

PROVIDER: S-EPMC7540079 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Enhancing Tris(pyrazolyl)borate-Based Models of Cysteine/Cysteamine Dioxygenases through Steric Effects: Increased Reactivities, Full Product Characterization and Hints to Initial Superoxide Formation.

Müller Lars L Hoof Santina S Keck Matthias M Herwig Christian C Limberg Christian C

Chemistry (Weinheim an der Bergstrasse, Germany) 20200813 51

The design of biomimetic model complexes for the cysteine dioxygenase (CDO) and cysteamine dioxygenase (ADO) is reported, where the 3-His coordination of the iron ion is simulated by three pyrazole donors of a trispyrazolyl borate ligand (Tp) and protected cysteine and cysteamine represent substrate ligands. It is found that the replacement of phenyl groups-attached at the 3-positions of the pyrazole units in a previous model-by mesityl residues has massive consequences, as the latter arrange to ...[more]

PMID: 32432367

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Project description:The unique ability of nitrone spin traps to detect and characterize transient free radicals by electron paramagnetic resonance (EPR) spectroscopy has fueled the development of new spin traps with improved properties. Among a variety of free radicals in chemical and biological systems, superoxide radical anion (O(2)(•-)) plays a critical role as a precursor to other more oxidizing species such as hydroxyl radical (HO(•)), peroxynitrite (ONOO(-)), and hypochlorous acid (HOCl), and therefore the direct detection of O(2)(•-) is important. To overcome the limitations of conventional cyclic nitrones, that is, poor reactivity with O(2)(•-), instability of the O(2)(•-) adduct, and poor cellular target specificity, synthesis of disubstituted nitrones has become attractive. Disubstituted nitrones offer advantages over the monosubstituted ones because they allow bifunctionalization of spin traps, therefore accommodating all the desired spin trap properties in one molecular design. However, because of the high number of possible disubstituted analogues as candidate, a systematic computational study is needed to find leads for the optimal spin trap design for biconjugation. In this paper, calculation of the energetics of O(2)(•-) and HO(2)(•) adduct formation from various disubstituted nitrones at PCM/B3LYP/6-31+G(d,p)//B3LYP/6-31G(d) level of theory was performed to determine the most favorable disubstituted nitrones for this reaction. In addition, our results provided general trends of radical reactivity that is dependent upon but not exclusive to the charge densities of nitronyl-C, the position of substituents including stereoselectivities, and the presence of intramolecular H-bonding interaction. Unusually high exoergic ΔG(298K,aq)'s for O(2)(•-) and HO(2)(•) adduct formation were predicted for (3S,5S)-5-methyl-3,5-bis(methylcarbamoyl)-1-pyrroline N-oxide (11-cis) and (4S,5S)-5-dimethoxyphosphoryl-5-methyl-4-ethoxycarbonyl-1-pyrroline N-oxide (29-trans) with ΔG(298K,aq) = -3.3 and -9.4 kcal/mol, respectively, which are the most exoergic ΔG(298K,aq) observed thus far for any nitrone at the level of theory employed in this study.

Dataset Information

Enhancing Tris(pyrazolyl)borate-Based Models of Cysteine/Cysteamine Dioxygenases through Steric Effects: Increased Reactivities, Full Product Characterization and Hints to Initial Superoxide Formation.

Publications

Enhancing Tris(pyrazolyl)borate-Based Models of Cysteine/Cysteamine Dioxygenases through Steric Effects: Increased Reactivities, Full Product Characterization and Hints to Initial Superoxide Formation.

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