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• W1974343642 endingPage "3870" @default.
• W1974343642 startingPage "3864" @default.
• W1974343642 abstract "Monoamine oxidase (MAO), which exists in two isozymic forms, MAO A and MAO B, is an important flavoenzyme responsible for the metabolism of amine neurotransmitters such as dopamine, serotonin, and norepinephrine. Despite extensive research effort, neither the catalytic nor the inhibition mechanisms of MAO have been completely understood. There has also been dispute with regard to the protonation state of the substrate upon entering the active site, as well as the identity of residues that are important for the initial deprotonation of irreversible acetylenic inhibitors, in accordance with the recently proposed mechanism. Therefore, in order to investigate features essential for the modes of action of MAO, we have calculated pKa values of three relevant tyrosine residues in the MAO B active site, with and without dopamine bound as the substrate (as well as the pKa of the dopamine itself in the active site). The calculated pKa values for Tyr188, Tyr398, and Tyr435 in the complex are found to be shifted upward to 13.0, 13.7, and 14.7, respectively, relative to 10.1 in aqueous solution, ruling out the likelihood that they are viable proton acceptors. The altered tyrosine pKa values could be rationalized as an interplay of two opposing effects: insertion of positively charged bulky dopamine that lowers tyrosine pKa values, and subsequent removal of water molecules from the active site that elevates tyrosine pKa values, in which the latter prevails. Additionally, the pKa value of the bound dopamine (8.8) is practically unchanged compared to the corresponding value in aqueous solution (8.9), as would be expected from a charged amine placed in a hydrophobic active site consisting of aromatic moieties. We also observed potentially favorable cation−π interactions between the −NH3+ group on dopamine and aromatic moieties, which provide a stabilizing effect to the charged fragment. Thus, we offer here theoretical evidence that the amine is most likely to be present in the active site in its protonated form, which is similar to the conclusion from experimental studies of MAO A (Jones et al. J. Neural Trans.2007, 114, 707–712). However, the free energy cost of transferring the proton from the substrate to the bulk solvent is only 1.9 kcal mol–1, leaving open the possibility that the amine enters the chemical step in its neutral form. In conjunction with additional experimental and computational work, the data presented here should lead toward a deeper understanding of mechanisms of the catalytic activity and irreversible inhibition of MAO B, which can allow for the design of novel and improved MAO B inhibitors." @default.
• W1974343642 created "2016-06-24" @default.
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• W1974343642 creator A5081106233 @default.
• W1974343642 date "2012-04-25" @default.
• W1974343642 modified "2023-09-23" @default.
• W1974343642 title "Computational Study of the p<i>K</i>_a Values of Potential Catalytic Residues in the Active Site of Monoamine Oxidase B" @default.
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• W1974343642 cites W1511840847 @default.
• W1974343642 cites W1626371877 @default.
• W1974343642 cites W1862441471 @default.
• W1974343642 cites W1966041739 @default.
• W1974343642 cites W1967529010 @default.
• W1974343642 cites W1968257988 @default.
• W1974343642 cites W1971046411 @default.
• W1974343642 cites W1972046258 @default.
• W1974343642 cites W1973291438 @default.
• W1974343642 cites W1974678298 @default.
• W1974343642 cites W1974694453 @default.
• W1974343642 cites W1976360756 @default.
• W1974343642 cites W1976394766 @default.
• W1974343642 cites W1977196954 @default.
• W1974343642 cites W1977397081 @default.
• W1974343642 cites W1978997652 @default.
• W1974343642 cites W1979220864 @default.
• W1974343642 cites W1979951279 @default.
• W1974343642 cites W1980075159 @default.
• W1974343642 cites W1981470146 @default.
• W1974343642 cites W1982680156 @default.
• W1974343642 cites W1983731524 @default.
• W1974343642 cites W1984485922 @default.
• W1974343642 cites W1988695791 @default.
• W1974343642 cites W1992850079 @default.
• W1974343642 cites W1998247230 @default.
• W1974343642 cites W1999497935 @default.
• W1974343642 cites W2001998268 @default.
• W1974343642 cites W2003516919 @default.
• W1974343642 cites W2003940515 @default.
• W1974343642 cites W2007059164 @default.
• W1974343642 cites W2007820637 @default.
• W1974343642 cites W2010842568 @default.
• W1974343642 cites W2013999225 @default.
• W1974343642 cites W2020425958 @default.
• W1974343642 cites W2023209169 @default.
• W1974343642 cites W2023442763 @default.
• W1974343642 cites W2024337271 @default.
• W1974343642 cites W2028266622 @default.
• W1974343642 cites W2029389595 @default.
• W1974343642 cites W2032237219 @default.
• W1974343642 cites W2032486811 @default.
• W1974343642 cites W2033015524 @default.
• W1974343642 cites W2038684398 @default.
• W1974343642 cites W2038937822 @default.
• W1974343642 cites W2042386533 @default.
• W1974343642 cites W2045179269 @default.
• W1974343642 cites W2057571164 @default.
• W1974343642 cites W2063544942 @default.
• W1974343642 cites W2064589622 @default.
• W1974343642 cites W2070223984 @default.
• W1974343642 cites W2079604571 @default.
• W1974343642 cites W2081674263 @default.
• W1974343642 cites W2084352362 @default.
• W1974343642 cites W2091101912 @default.
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• W1974343642 cites W2101936319 @default.
• W1974343642 cites W2107433905 @default.
• W1974343642 cites W2108364115 @default.
• W1974343642 cites W2120586432 @default.
• W1974343642 cites W2122450959 @default.
• W1974343642 cites W2128330262 @default.
• W1974343642 cites W2128952454 @default.
• W1974343642 cites W2130890126 @default.
• W1974343642 cites W2131713387 @default.
• W1974343642 cites W2144757830 @default.
• W1974343642 cites W2145624846 @default.
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• W1974343642 doi "https://doi.org/10.1021/ct300119u" @default.
• W1974343642 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/26593027" @default.
• W1974343642 hasPublicationYear "2012" @default.
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