Stereochemistry of oxidation of benzylamine by the amine oxidase from beef plasma

Battersby, Alan R.; Staunton, James; Klinman, Judith P.; Summers, Michael C.

doi:10.1016/0014-5793(79)80976-x

Cited by 19 publications

(15 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Likewise, if there is a Ca methyl group, only one of the two enantiomers will be processed. The finding that different amine oxidases display opposite stereochemical preferences for the same substrates [53] is strong evidence that the respective active-sites engender significant differences in binding modes, consistent with our observations here of rank order reversals in the inhibitory activity of the four compounds studied.…”

Section: Discussionsupporting

confidence: 88%

Towards the development of selective amine oxidase inhibitors

Shepard

Smith

Elmore

et al. 2002

European Journal of Biochemistry

View full text Add to dashboard Cite

Four substrate analogs, 4-(2-naphthyloxy)-2-butyn-1-amine (1), 1,4-diamino-2-chloro-2-butene (2), 1,6-diamino-2,4-hexadiyne (3), and 2-chloro-5-phthalimidopentylamine (4) have been tested as inhibitors against mammalian, plant, bacterial, and fungal copper-containing amine oxidases: bovine plasma amine oxidase (BPAO), equine plasma amine oxidase (EPAO), pea seedling amine oxidase (PSAO), Arthrobacter globiformis amine oxidase (AGAO), Escherichia coli amine oxidase (ECAO), and Pichia pastoris lysyl oxidase (PPLO). Reactions of 1,4-diamino-2-butyne with selected amine oxidases were also examined. Each substrate analog contains a functional group that chemical precedent suggests could produce mechanism-based inactivation. Striking differences in selectivity and rates of inactivation were observed. For example, between two closely related plasma enzymes, BPAO is more sensitive than EPAO to 1 and 3, while the reverse is true for 2 and 4. In general, inactivation appears to arise in some cases from TPQ cofactor modification and in other cases from alkylation of protein residues in a manner that blocks access of substrate to the active site. Notably, 1 completely inhibits AGAO at stoichiometric concentrations and is not a substrate, but is an excellent substrate of PSAO and inhibition is observed only at very high concentrations. Structural models of 1 in Schiff base linkage to the TPQ cofactor in AGAO and PSAO (for which crystal structures are available) reveal substantial differences in the degree of interaction of bound 1 with sidechain residues, consistent with the widely divergent activities. Collectively, these results suggest that the development of highly selective amine oxidase inhibitors is feasible.Keywords: copper; amine oxidase; enzyme inhibition; mechanism-based inhibition.The copper-containing amine oxidases play a crucial role in metabolic oxidative deamination of primary amines to the corresponding aldehydes, with the concomitant production of hydrogen peroxide and ammonia [1]. The reaction proceeds through a transamination mechanism mediated by an active site 2,4,5-trihydroxyphenylalanine quinone (TPQ) cofactor. The TPQ cofactor is formed from the posttranslational self-processing of a tyrosine residue within the highly conserved sequence Ser/Thr-X aa -X aa -Asn-Tyr(TPQ)-Asp/Glu-Tyr [1] that requires both copper and molecular oxygen [2][3][4][5][6][7]. The key step in catalysis (Scheme 1) is the conversion of the initial quinoneimine Ôsubstrate Schiff baseÕ (step 2) to a quinolaldimine Ôproduct Schiff baseÕ (step 3), facilitated by Ca proton abstraction by an absolutely conserved active-site aspartate acting as general base [8][9][10][11][12]. Hydrolytic release of aldehyde product gives a Cu(II)-aminoresorcinol (step 4), in equilibrium with Cu(I)-semiquinone (step 5), that is reoxidized to TPQ in the presence of O 2 , with release of H 2 O 2 and NH 4 + [13].Scheme 1. Proposed catalytic mechanism of turnover for amine oxidases.

show abstract

Section: Discussionsupporting

confidence: 88%

Towards the development of selective amine oxidase inhibitors

Shepard

Smith

Elmore

et al. 2002

European Journal of Biochemistry

View full text Add to dashboard Cite

show abstract

“…Even though docking studies suggested that both, RP101075 and the R-enantiomer (RP101074) occupied the MAO B active site similarly (Figure 5B and 5C) (Supplementary Table S1), RP101074 was not converted to CC112273. These results were consistent with reports from earlier studies that showed stereospecific conversion of only the S-(-2 H)-deuteroamines (Belleau et al, 1960;Belleau and Moran, 1963;Battersby et al, 1979;Yu and Davis, 1988). Mechanistic studies on MAO catalyzed deamination suggest C-H bond cleavage to be a requisite and rate determining step in the oxidation process (Belleau et al, 1960;Yu et al, 1986;Yu and Davis, 1988;Ottoboni et al, 1989;Silverman et al, 1993;Edmondson et al, 2004;Edmondson et al, 2007;Orru et al, 2013).…”

Section: Discussionsupporting

confidence: 91%

Investigation into MAO B–Mediated Formation of CC112273, a Major Circulating Metabolite of Ozanimod, in Humans and Preclinical Species: Stereospecific Oxidative Deamination of (S)-Enantiomer of Indaneamine (RP101075) by MAO B

et al. 2021

View full text Add to dashboard Cite

Ozanimod, recently approved for treating relapsing MS, produced a disproportionate, active, MAO B-catalyzed metabolite (CC112273) that showed remarkable interspecies differences and led to challenges in safety testing. This study explored the kinetics of CC112273 formation from its precursor RP101075. Incubations with human liver mitochondrial fractions revealed K Mapp , V max and Cl int for CC112273 formation to be 4.8 M, 50.3 pmol/min/mg protein and 12 l/min/mg, respectively, while K M with human recombinant MAO B was 1.1 M. Studies with liver mitochondrial fractions from preclinical species led to K Mapp , V max and Cl int estimates of 3.0, 35 and 33 M, 80.6, 114, 37.3 pmol/min/mg and 27.2, 3.25 and 1.14 l/min/mg in monkey, rat and mouse, respectively, and revealed marked differences between rodents and primates, primarily attributable to differences in the K M . Comparison of Cl int estimates revealed monkey to be ~two-fold more efficient and the mouse and rat to be 11 and 4-fold less efficient than humans in CC112273 formation. The influence of stereochemistry on MAO B-mediated oxidation was also investigated using the R-isomer of RP101075 (RP101074). This showed marked selectivity towards catalysis of the S-isomer (RP101075) only. Docking into MAO B crystal structure suggested that even though both the isomers occupied its active site, only the orientation of RP101075 presented the C-H on the -carbon that was ideal for the C-H bond cleavage, which is a requisite for oxidative deamination. These studies explain the basis for the observed interspecies differences in the metabolism of ozanimod as well as the substrate stereospecificity for formation of CC112273.

show abstract

“…Parallel studies indicate that benzylamine oxidation involves the stereospecific loss of the p r o 3 hydrogen at C-1 (Battersby, A. R., Staunton, J., Klinman, J. P., & Summers, M. C., 1979: Suva & Abeles, 1978, analogous to the stereochemistry observed for the pea seedling amine oxidase reaction (Battersby et al, 1976a,b). Surprisingly, we find that dopamine oxidation involves nonstereospecific loss of tritium from both C-1 and C-2.…”

Section: Substratesmentioning

confidence: 88%

“…Previous studies of the amine oxidase catalyzed oxidation of benzylamine indicate that both the pea seedling (Battersby et al, 1976b) and bovine plasma (Battersby, A. R., Staunton, J., Klinman, J. P., & Summers, M. C., 1979;Suva & Abeles, 1978) enzymes catalyze the abstraction of the pro-S hydrogen a t C-1 of substrate. A major finding of the present study is that hydrogen loss from dopamine, stereospecifically labeled with tritium at both C-1 and C-2, occurs nonstereospecifically (Tables I and IV).…”

Section: Discussionmentioning

confidence: 99%

Stereochemistry and kinetic isotope effects in the bovine plasma amine oxidase catalyzed oxidation of dopamine

Summers¹,

Marković²,

Klinman³

1979

Biochemistry

View full text Add to dashboard Cite

The stereochemistry of the bovine plasma amine oxidase catalyzed oxidation of 2-(3,4-dihydroxyphenyl)-ethylamine (domapine) has been investigated by comparing 3H/14C ratios of 3,4-dibenzyloxyphenethyl alcohols, derived from 3,4-dihydroxyphenylacetaldehydes, to starting dopamines chirally labeled at C-1 and C-2. The oxidation of [2RS-3H]-, [2R-3H]-, and [2S-3H]dopamine leads to products which have retained 53, 59, and 47% of their tritium. Similarly, oxidation of [1RS-3H]-, [1R-3H]-, and [1S-3H]dopamine leads to an 80, 80, and 92% retention of tritium. The configurational purity of tritium at C-2 of dopamine and C-1 of the dopamine precursor 3-methoxy-4-hydroxyphenethylamine has been confirmed employing dopamine-beta-hydroxylase (specific for the pro-R hydrogen at C-2) and pea seedling amine oxidase (specific for the pro-S hydrogen at C-1). In addition, chromatographically resolved isozymes of bovine plasma amine oxidase have been demonstrated to lead to the same stereochemical result as pooled enzyme fractions. We have been able to rule out carbon interchange and tritium transfer in the ethylamine side chain of dopamine as the source of the apparent nonstereospecificity. Estimated primary tritium isotope effects are 1 for [2-3H]dopamines and 5--6 and 26--34 for [1R-3H]- and [1S-3H]dopamine, respectively. We propose the presence of alternate dopamine binding modes, characterized by absolute but opposing stereochemistries and differential primary tritium isotope effects at C-1.

show abstract

Stereochemistry of oxidation of benzylamine by the amine oxidase from beef plasma

Cited by 19 publications

References 7 publications

Towards the development of selective amine oxidase inhibitors

Towards the development of selective amine oxidase inhibitors

Investigation into MAO B–Mediated Formation of CC112273, a Major Circulating Metabolite of Ozanimod, in Humans and Preclinical Species: Stereospecific Oxidative Deamination of (S)-Enantiomer of Indaneamine (RP101075) by MAO B

Stereochemistry and kinetic isotope effects in the bovine plasma amine oxidase catalyzed oxidation of dopamine

Contact Info

Product

Resources

About