Evidence for alternative binding modes in the interaction of benzylamine analogues with bovine liver monoamine oxidase B

Edmondson, Dale E.; Bhattacharrya, Anjan K; Xu, Jianjun

doi:10.1016/s0167-4838(00)00055-8

Cited by 14 publications

(8 citation statements)

References 13 publications

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“…Therefore, conformational constraints imposed by β-methylation in combination with the restricted interaction displayed by the p-chlorine substituent and the breaking of the water network place p-CMP in the substrate pocket but with features that do not allow the oxidation to occur. These results are in agreement with previous conclusions of Edmondson et al [ 46 ] who argue that the para-position of the bound substrate is in a hydrophobic domain of limited size. With these restrictions, bound p-MMP can adopt an orientation that favors its substrate character.…”

Section: Resultssupporting

confidence: 94%

Why p-OMe- and p-Cl-β-Methylphenethylamines Display Distinct Activities upon MAO-B Binding

et al. 2016

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Despite their structural and chemical commonalities, p-chloro-β-methylphenethylamine and p-methoxy-β-methylphenethylamine display distinct inhibitory and substrate activities upon MAO-B binding. Density Functional Theory (DFT) quantum chemical calculations reveal that β-methylation and para-substitution underpin the observed activities sustained by calculated transition state energy barriers, attained conformations and key differences in their interactions in the enzyme’s substrate binding site. Although both compounds meet substrate requirements, it is clear that β-methylation along with the physicochemical features of the para-substituents on the aromatic ring determine the activity of these compounds upon binding to the MAO B-isoform. While data for a larger set of compounds might lend generality to our conclusions, our experimental and theoretical results strongly suggest that the contrasting activities displayed depend on the conformations adopted by these compounds when they bind to the enzyme.

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Section: Resultssupporting

confidence: 94%

Why p-OMe- and p-Cl-β-Methylphenethylamines Display Distinct Activities upon MAO-B Binding

et al. 2016

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“…The p K a is dependent in large part on the electrostatic stabilization (solvation) of the charged species. If the binding modes of various substrates differ substantially as suggested by Edmondson, which is unlikely due to the very limited space in the active site, then it would be possible to alter the p K a values. For example, interaction of the tyrosine hydroxyl group with an amino group of the substrate would certainly perturb the p K a values of both hydrogen-bonded partners.…”

Section: Resultsmentioning

confidence: 99%

Examining Electrostatic Preorganization in Monoamine Oxidases A and B by Structural Comparison and pK_aCalculations

et al. 2014

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Monoamine oxidases (MAO) A and B are important flavoenzymes involved in the metabolism of amine neurotransmitters. Orru et al. ( J. Neural Transm. 2013 , 120 , 847 - 851 ) recently presented experimental results that have challenged the prevailing assumption that MAO A and MAO B employ an identical catalytic mechanism. We compared the spatial configuration of ionizable groups in both isozymes and estimated the time-averaged electrostatic potential by calculating the pKa values of five active site residues. Superimposition of both experimental structures shows very close overlap and the RMSD in placements of ionizable groups within 16 Å of the reaction center is only 0.847 Å. This similarity is also reflected in the calculated pKa values, where the largest difference between the MAO A and MAO B pKa values was found for residues Tyr188 in MAO B and the corresponding Tyr197 in MAO A assuming 1.23 units. The pKa values for the other four studied residues differ by less than 0.75 units. The results show that the electrostatic preorganizations in both active sites are very similar, supporting the idea that both enzymes work by the same mechanism.

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“…More recent work indicates that it is strongly preferred by rat liver MAO-B, suggesting that it "is unlikely to be deaminated by intestinal MAO" and "is likely to be absorbed and could affect the sympathetic nervous system, by virtue of its action as an inhibitor of noradrenaline uptake" [34]. Nevertheless, regarding the intake of hordenine by humans, these results should be taken with caution in view of the considerable functional differences between rat and human MAOs [43][44][45].…”

Section: Alkaloids Of the Cactaceaementioning

confidence: 99%

Alkaloids of the Cactaceae — The Classics

Cassels

2019

Natural Product Communications

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Alkaloids of the Cactaceae have been studied for the last 120 years. The first half of that period provided the "classic" compounds, after which a large number of usually very similar analogs were isolated or determined with modern methods. Although some unusual synthetic approaches have been developed, their preparation is generally quite straightforward. Their biosynthesis has been studied but, particularly in the case of the isoquinoline compounds, important aspects have not been addressed. Due to its striking effects, the pharmacology of mescaline has been studied more intensely than that of the other phenethylamines present in cacti, followed only by hordenine. The many 1,2,3,4-tetrahydroisoquinoline alkaloids have attracted much less interest and have often been considered practically inactive. Nevertheless, some recorded activities of this group of compounds suggests a need for additional studies, especially in connection with their co-administration with mescaline, as in dried cacti and in beverages prepared from them.

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Evidence for alternative binding modes in the interaction of benzylamine analogues with bovine liver monoamine oxidase B

Cited by 14 publications

References 13 publications

Why p-OMe- and p-Cl-β-Methylphenethylamines Display Distinct Activities upon MAO-B Binding

Why p-OMe- and p-Cl-β-Methylphenethylamines Display Distinct Activities upon MAO-B Binding

Examining Electrostatic Preorganization in Monoamine Oxidases A and B by Structural Comparison and pK_aCalculations

Alkaloids of the Cactaceae — The Classics

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Evidence for alternative binding modes in the interaction of benzylamine analogues with bovine liver monoamine oxidase B

Cited by 14 publications

References 13 publications

Why p-OMe- and p-Cl-β-Methylphenethylamines Display Distinct Activities upon MAO-B Binding

Why p-OMe- and p-Cl-β-Methylphenethylamines Display Distinct Activities upon MAO-B Binding

Examining Electrostatic Preorganization in Monoamine Oxidases A and B by Structural Comparison and pKaCalculations

Alkaloids of the Cactaceae — The Classics

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Product

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Examining Electrostatic Preorganization in Monoamine Oxidases A and B by Structural Comparison and pK_aCalculations