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Theoretical and experimental studies of tyrosyl hydroperoxide formation in the presence of H-bond donors.

ABSTRACT: Oxidative damage to biomolecules such as lipids, proteins, nucleotides, and sugars has been implicated in the pathogenesis of various diseases. Superoxide radical anion (O 2 (*-)) addition to nitrones bearing an amide N-H has been shown to be more favored as compared to other nitrones [ Villamena, F. A. , ( 2007) J. Am. Chem. Soc. 129, 8177- 8191 ]. It has also been demonstrated by others [ Winterbourn, C. C. , ( 2004) Biochem. J. 381, 241- 248 ] that O 2 (*-) addition to tyrosine to form hydroperoxide is favored in the presence of basic amino groups, but the mechanism for this observation remains obscure. We, therefore, hypothesized that the alpha-effect resulting from the interaction of O 2 (*-) with N-H can play a crucial role in the enhancement of hydroperoxide formation. Understanding this phenomenon is important in the elucidation of mechanisms leading to oxidative stress in cellular systems. Computational (at the PCM/B3LYP/6-31+G**//B3LYP/6-31G level of theory) as well as experimental studies were carried out to shed insights into the effect of amide or amino N-H on the enhancement (or stabilization) of hydroperoxide formation in tyrosine. H-bond interaction of amino acid group with O 2 (*-) results in the perturbation of the spin and charge densities of O 2 (*-). A similar phenomenon has been predicted for non-amino acids bearing H-bond donor groups. Using the FOX assay, tyrosyl hydroperoxide formation was enhanced in the presence of H-bond donors from amino acids and non-amino acids. The role of H-bonding in either stabilizing the hydroperoxide adduct or facilitating O 2 (*-) addition via an alpha-effect was further theoretically investigated, and results show that the latter mechanism is more thermodynamically preferred. This study provides new mechanistic insights in the initiation of oxidative modification to tyrosyl radical.

SUBMITTER: Field SM

PROVIDER: S-EPMC2666260 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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Theoretical and experimental studies of tyrosyl hydroperoxide formation in the presence of H-bond donors.

Field Steven M SM Villamena Frederick A FA

Chemical research in toxicology 20080925 10

Oxidative damage to biomolecules such as lipids, proteins, nucleotides, and sugars has been implicated in the pathogenesis of various diseases. Superoxide radical anion (O 2 (*-)) addition to nitrones bearing an amide N-H has been shown to be more favored as compared to other nitrones [ Villamena, F. A. , ( 2007) J. Am. Chem. Soc. 129, 8177- 8191 ]. It has also been demonstrated by others [ Winterbourn, C. C. , ( 2004) Biochem. J. 381, 241- 248 ] that O 2 (*-) addition to tyrosine to form hydrop ...[more]

PMID: 18816073

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Project description:G protein coupled receptors (GPCRs), also called 7TM receptors, form a huge superfamily of membrane proteins that, upon activation by extracellular agonists, pass the signal to the cell interior. Ligands can bind either to extracellular N-terminus and loops (e.g. glutamate receptors) or to the binding site within transmembrane helices (Rhodopsin-like family). They are all activated by agonists although a spontaneous auto-activation of an empty receptor can also be observed. Biochemical and crystallographic methods together with molecular dynamics simulations and other theoretical techniques provided models of the receptor activation based on the action of so-called "molecular switches" buried in the receptor structure. They are changed by agonists but also by inverse agonists evoking an ensemble of activation states leading toward different activation pathways. Switches discovered so far include the ionic lock switch, the 3-7 lock switch, the tyrosine toggle switch linked with the nPxxy motif in TM7, and the transmission switch. The latter one was proposed instead of the tryptophan rotamer toggle switch because no change of the rotamer was observed in structures of activated receptors. The global toggle switch suggested earlier consisting of a vertical rigid motion of TM6, seems also to be implausible based on the recent crystal structures of GPCRs with agonists. Theoretical and experimental methods (crystallography, NMR, specific spectroscopic methods like FRET/BRET but also single-molecule-force-spectroscopy) are currently used to study the effect of ligands on the receptor structure, location of stable structural segments/domains of GPCRs, and to answer the still open question on how ligands are binding: either via ensemble of conformational receptor states or rather via induced fit mechanisms. On the other hand the structural investigations of homoand heterodimers and higher oligomers revealed the mechanism of allosteric signal transmission and receptor activation that could lead to design highly effective and selective allosteric or ago-allosteric drugs.

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Theoretical and experimental studies of tyrosyl hydroperoxide formation in the presence of H-bond donors.

Publications

Theoretical and experimental studies of tyrosyl hydroperoxide formation in the presence of H-bond donors.

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