Publications

• Visualization of dioxygen bound to copper during enzyme catalysis.

  Wilmot C.M., Hajdu J., McPherson M.J., Knowles P.F., Phillips S.E.

  X-ray crystal structures of three species related to the oxidative half of the reaction of the copper-containing quinoprotein amine oxidase from Escherichia coli have been determined. Crystals were freeze-trapped either anaerobically or aerobically after exposure to substrate, and structures were ... >> More

  X-ray crystal structures of three species related to the oxidative half of the reaction of the copper-containing quinoprotein amine oxidase from Escherichia coli have been determined. Crystals were freeze-trapped either anaerobically or aerobically after exposure to substrate, and structures were determined to resolutions between 2.1 and 2.4 angstroms. The oxidation state of the quinone cofactor was investigated by single-crystal spectrophotometry. The structures reveal the site of bound dioxygen and the proton transfer pathways involved in oxygen reduction. The quinone cofactor is regenerated from the iminoquinone intermediate by hydrolysis involving Asp383, the catalytic base in the reductive half-reaction. Product aldehyde inhibits the hydrolysis, making release of product the rate-determining step of the reaction in the crystal. << Less

  Science 286:1724-1728(1999) [PubMed] [EuropePMC]

• Multiscale simulation of monoamine oxidase catalyzed decomposition of phenylethylamine analogs.

  Oanca G., Stare J., Vianello R., Mavri J.

  Phenylethylamine (PEA) is an endogenous amphetamine and its levels are increased by physical activity. As other biogenic monoamines, it is decomposed by monoamine oxidase (MAO) enzymes. The chemical mechanism of MAO, and flavoenzymes in general, is a subject of heated debate. We have previously sh ... >> More

  Phenylethylamine (PEA) is an endogenous amphetamine and its levels are increased by physical activity. As other biogenic monoamines, it is decomposed by monoamine oxidase (MAO) enzymes. The chemical mechanism of MAO, and flavoenzymes in general, is a subject of heated debate. We have previously shown that the rate-limiting step of MAO catalysis involves a hydride transfer from the substrate methylene group vicinal to the amino group to the N5 atom of the lumiflavin co-factor moiety. By using multiscale simulation on the Empirical Valence Bond (EVB) level, we studied the chemical reactivity of the monoamine oxidase B catalyzed decomposition of PEA and its two derivatives: p-chloro-β-methylphenylamine (p-CMP) and p-methoxy-β-methylphenethylamine (p-MMP). We calculated activation free energies of 17.1kcal/mol (PEA), 18.4kcal/mol (p-MMP) and 20.0kcal/mol (p-CMP), which are in excellent agreement with the experimental values of 16.7kcal/mol for PEA and 18.3kcal/mol for p-MMP, while the experimental value for p-CMP is not available. This gives strong support to the validity of our hydride transfer mechanism for both MAO A and B isoforms. The results are discussed in the context of the interplay between MAO point mutations and neuropsychiatric disorders. << Less

  Eur J Pharmacol 817:46-50(2017) [PubMed] [EuropePMC]

• 90 years of monoamine oxidase: some progress and some confusion.

  Tipton K.F.

  It would not be practical to attempt to deal with all the advances that have informed our understanding of the behavior and functions of this enzyme over the past 90 years. This account concentrates key advances that explain why the monoamine oxidases remain of pharmacological and biochemical inte ... >> More

  It would not be practical to attempt to deal with all the advances that have informed our understanding of the behavior and functions of this enzyme over the past 90 years. This account concentrates key advances that explain why the monoamine oxidases remain of pharmacological and biochemical interest and on some areas of continuing uncertainty. Some issues that remain to be understood or are in need of further clarification are highlighted. << Less

  J Neural Transm (Vienna) 125:1519-1551(2018) [PubMed] [EuropePMC]

  This publication is cited by 6 other entries.

• Substrate-specific enhancement of the oxidative half-reaction of monoamine oxidase.

  Tan A.K., Ramsay R.R.

  Monoamine oxidases A and B have identical flavin sites but different, although overlapping, amine substrate specificity. Reoxidation of ternary complexes containing substrate is much faster than of free enzyme, and the enhancement is greater in the A form than the B form. The oxidative half-reacti ... >> More

  Monoamine oxidases A and B have identical flavin sites but different, although overlapping, amine substrate specificity. Reoxidation of ternary complexes containing substrate is much faster than of free enzyme, and the enhancement is greater in the A form than the B form. The oxidative half-reaction was studied with a variety of substrates to elucidate the specificity of the effect and to probe the different influences of substrate on the flavin reoxidation in the two forms of the enzyme. The second-order rate constant for the reoxidation was highest with monoamine oxidase A when kynuramine was the ligand (508 x 10(3) M-1 s-1) compared to 4 x 10(3) M-1 s-1 in its absence. MPTP (166 x 10(3) M-1 s-1) also enhanced reoxidation well, but indole substrates stimulated only poorly (e.g., tryptamine, 29 x 10(3) M-1 s-1; serotonin, 50 x 10(3) M-1 s-1). For the A form, the reduction of the flavin was rate-limiting in all cases. For the B form, reoxidation was rate-limiting for beta-phenylethylamine and contributed to the determination of the overall rate with several substrates. The ratio of the enhanced rate of oxidation to the rate of reduction correlated with the redox state of the enzyme in turnover experiments. All the observations are consistent with alternate paths of reoxidation, via either free enzyme or a reduced enzyme-substrate complex. The flux through each path is determined by the relative dissociation constants and rate constants. << Less

  Biochemistry 32:2137-2143(1993) [PubMed] [EuropePMC]

  This publication is cited by 5 other entries.

• A key amino acid responsible for substrate selectivity of monoamine oxidase A and B.

  Tsugeno Y., Ito A.

  Monoamine oxidase (MAO) oxidizes biologically important amines including neurotransmitters and plays a central role in the regulation of intracellular level of these amines. Two distinct forms of MAO (MAO A and MAO B) were defined based on differences in substrate and inhibitor specificities. We e ... >> More

  Monoamine oxidase (MAO) oxidizes biologically important amines including neurotransmitters and plays a central role in the regulation of intracellular level of these amines. Two distinct forms of MAO (MAO A and MAO B) were defined based on differences in substrate and inhibitor specificities. We earlier reported that the region between about residues 120 and 220 of rat MAO is responsible for determination of the substrate selectivity of MAO A and B (Tsugeno, Y. Hirashiki, I., Ogata, F., and Ito, A. (1995) J. Biochem. (Tokyo) 118, 974-980). To determine the essential amino acids in this region that participate in substrate recognition, a series of mutant enzymes in which amino acid residues that are conserved among various species but are different between the two forms of the enzyme were replaced with the corresponding amino acids of the counterpart and were engineered from the cDNAs of rat liver MAO A and B, and affinities for several substrates were examined. A single mutation in which Phe-208 in MAO A was substituted by the corresponding residue of Ile in MAO B was sufficient to convert the A-type substrate selectivity, and the reverse was exactly the case. Phe at this position was replaceable with Tyr for the A-type specificity and Ile was replaceable with Val and Ala for the B-type. Thus, aromatic and aliphatic residues seem to contribute to render substrate selectivity of MAO A and MAO B, respectively. << Less

  J. Biol. Chem. 272:14033-14036(1997) [PubMed] [EuropePMC]

  This publication is cited by 3 other entries.

• The unique substrate specificity of human AOC2, a semicarbazide-sensitive amine oxidase.

  Kaitaniemi S., Elovaara H., Groen K., Kidron H., Liukkonen J., Salminen T., Salmi M., Jalkanen S., Elima K.

  Semicarbazide-sensitive amine oxidases (SSAOs) catalyze oxidative deamination of primary amines, but the true physiological function of these enzymes is still poorly understood. Here, we have studied the functional and structural characteristics of a human cell-surface SSAO, AOC2, which is homolog ... >> More

  Semicarbazide-sensitive amine oxidases (SSAOs) catalyze oxidative deamination of primary amines, but the true physiological function of these enzymes is still poorly understood. Here, we have studied the functional and structural characteristics of a human cell-surface SSAO, AOC2, which is homologous to the better characterized family member, AOC3. The preferred in vitro substrates of AOC2 were found to be 2-phenylethylamine, tryptamine and p-tyramine instead of methylamine and benzylamine, the favored substrates of AOC3. Molecular modeling suggested structural differences between AOC2 and AOC3, which provide AOC2 with the capability to use the larger monoamines as substrates. Even though AOC2 mRNA was expressed in many tissues, the only tissues with detectable AOC2-like enzyme activity were found in the eye. Characterization of AOC2 will help in evaluating the contribution of this enzyme to the pathological processes attributed to the SSAO activity and in designing specific inhibitors for the individual members of the SSAO family. << Less

  Cell. Mol. Life Sci. 66:2743-2757(2009) [PubMed] [EuropePMC]

  This publication is cited by 4 other entries.

• The oxidation of adrenaline and noradrenaline by the two forms of monoamine oxidase from human and rat brain.

  O'Carroll A.M., Bardsley M.E., Tipton K.F.

  The selective monoamine oxidase inhibitors clorgyline and (?)-deprenyl were used to study the distribution of monoamine oxidase-A and -B (MAO-A, MAO-B) activities towards (?)-noradrenaline and (+),(?)-adrenaline in homogenates from seven different regions of human brain. The activities towards 5-h ... >> More

  The selective monoamine oxidase inhibitors clorgyline and (?)-deprenyl were used to study the distribution of monoamine oxidase-A and -B (MAO-A, MAO-B) activities towards (?)-noradrenaline and (+),(?)-adrenaline in homogenates from seven different regions of human brain. The activities towards 5-hydroxytryptamine and 2-phenethylamine, which are essentially specific substrates for the A- and B-forms, respectively, under the conditions used in this work, were also determined. Noradreanline and adrenaline were substrates for both forms of the enzyme in all regions studied. The total MAO activity was found to be highest in the hypothalamus and lowest in the cerebellar cortex. Use of the selective MAO inhibitors clorgyline and (?)-deprenyl also showed adrenaline and noradrenaline to be substrates for both forms of the enzyme in rat brain. In human cerebral cortex and rat brain the two forms were found to have similar K(m)-values and maximum velocities towards adrenaline. These values for the two forms were also found to be similar in human cerebral cortex when noradrenaline was used as the substrate. In contrast MAO-A showed a significantly lower K(m) and a higher maximum velocity towards noradrenaline in rat brain. These results suggest that the rat may not provide a close model of the human for studies on the effects of MAO inhibitors on brain noradrenaline metabolism. << Less

  Neurochem. Int. 8:493-500(1986) [PubMed] [EuropePMC]

  This publication is cited by 5 other entries.