Determination of regions important for Monoamine Oxidase (MAO) A and B substrate and inhibitor selectivities

Shih, Jean C.; Chen, K.; Geha, Rani Maurice

doi:10.1007/978-3-7091-6499-0_1

Cited by 18 publications

(6 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The primary sequence is highly critical for the differences in catalytic activity between MAO A and MAO B. In mutagenesis studies, we and others established that the internal segment (between aminoacids 152 and 366) confers inhibitor and substrate specificities [5,6]. Both proteins are predominantly located in the outer membrane of mitochondria, to which they are anchored by the C-terminal domain [7].…”

Section: Molecular Characteristics Of Maomentioning

confidence: 99%

Monoamine oxidase inactivation: From pathophysiology to therapeutics

Bortolato

Chen

Shih

2008

Advanced Drug Delivery Reviews

535

329

View full text Add to dashboard Cite

Monoamine oxidases (MAOs) A and B are mitochondrial bound isoenzymes which catalyze the oxidative deamination of dietary amines and monoamine neurotransmitters, such as serotonin, norepinephrine, dopamine, β-phenylethylamine and other trace amines. The rapid degradation of these molecules ensures the proper functioning of synaptic neurotransmission and is critically important for the regulation of emotional behaviors and other brain functions. The byproducts of MAO-mediated reactions include several chemical species with neurotoxic potential, such as hydrogen peroxide, ammonia and aldehydes. As a consequence, it is widely speculated that prolonged excessive activity of these enzymes may be conducive to mitochondrial damages and neurodegenerative disturbances. In keeping with these premises, the development of MAO inhibitors has led to important breakthroughs in the therapy of several neuropsychiatric disorders, ranging from mood disorders to Parkinson’s disease. Furthermore, the characterization of MAO knockout (KO) mice has revealed that the inactivation of this enzyme produces a number of functional and behavioral alterations, some of which may be harnessed for therapeutic aims. In this article, we discuss the intriguing hypothesis that the attenuation of the oxidative stress induced by the inactivation of either MAO isoform may contribute to both antidepressant and antiparkinsonian actions of MAO inhibitors. This possibility further highlights MAO inactivation as a rich source of novel avenues in the treatment of mental disorders.

show abstract

Section: Molecular Characteristics Of Maomentioning

confidence: 99%

Monoamine oxidase inactivation: From pathophysiology to therapeutics

Bortolato

Chen

Shih

2008

Advanced Drug Delivery Reviews

535

329

View full text Add to dashboard Cite

show abstract

“…Our understanding of the MAO structure, regulation, and function has progressed significantly on the basis of cloning and site-directed mutagenesis studies, , but recently the availability of X-ray crystal structures of purified recombinant human MAO-A and MAO-B, − in complex with irreversible and reversible inhibitors, has provided a structural basis to MAOs' selective enzyme−ligand recognition and useful information for inhibitor design. , Due to the relevance to the design and development of MAO-B Is, some of us have recently investigated the impact on inhibitor screening of species-dependent differences between human and rat MAO-B, which have 88.6% sequence identity and differ by only one residue in the binding site (I316 in hMAO-B instead of V316 in rMAO-B) …”

Section: Introductionmentioning

confidence: 99%

Synthesis and Monoamine Oxidase Inhibitory Activity of New Pyridazine-, Pyrimidine- and 1,2,4-Triazine-Containing Tricyclic Derivatives

et al. 2007

View full text Add to dashboard Cite

A number of condensed azines, mostly belonging to the families of indeno-fused pyridazines (1), pyrimidines (2, 3), and 1,2,4-triazines (4, 5), were synthesized and evaluated in vitro as monoamine oxidase (MAO) A and B inhibitors. Most of them showed higher inhibition potency toward MAO-B, the most effective one being 3-(3-nitrophenyl)-9H-indeno[1,2-e] [1,2,4]triazin-9-one (4c), which displayed an IC50 value of 80 nM and proved to be 10-fold more potent than its [2,1-e] fusion isomer 5. Replacing the 3-phenyl group of the known indeno[1,2-c]pyridazin-5-one MAO-B inhibitors with a flexible phenoxymethyl group enhanced the inhibitory potency. The inhibition data highlighted the importance of the aza-heterocyclic scaffold in affecting the MAO isoform selectivity. The 3-phenyl derivatives with type 1, 4, and 5 scaffolds were inhibitors of MAO-B with little or no MAO-A effect, whereas 2- or 3-phenyl derivatives of type 2 and 3 pyrimidine-containing fusion isomers inhibited both isoenzymes with a structure-dependent preference toward MAO-A.

show abstract

“…In contrast to the large number of CYP isozymes, only two forms of MAO – MAO‐A and ‐B, differing in their substrate specificities and inhibitor sensitivity – are presently known to exist in mammalian tissues. They are actually different proteins encoded by separate genes on the X‐chromosome and which share approximately 70% amino acid identity [21,22]. MAO consists of two sub‐units tightly associated but not covalently bound together.…”

Section: Monoamine Oxidasesmentioning

confidence: 99%

Biotransformation of xenobiotics by amine oxidases

Benedetti

2001

Fundamemntal Clinical Pharma

View full text Add to dashboard Cite

Although the cytochrome P450 (CYP) system ranks first in terms of catalytic versatility and the wide range of xenobiotics it detoxifies or activates to reactive intermediates, the contribution of amine oxidases and in particular of monoamine oxidases (MAOs) to the metabolism of xenobiotics is far from negligible but has been largely neglected. In this review on the involvement of amine oxidases in the metabolism of xenobiotics, the major characteristics reported for the CYP system (protein, reaction, tissue distribution, subcellular localisation, substrates, inhibitors, inducers, genetic polymorphism, impact of different physiopathological conditions on the activity, turnover) will be compared, whenever possible, with the corresponding characteristics of amine oxidases (MAOs in particular). The knowledge of the involvement of MAO-A, -B or both in the metabolism of a drug allows us to predict interactions with selective or non-selective MAO inhibitors (e.g. the metabolism of a drug deaminated by both forms of MAO is not necessarily inhibited in vivo by a selective MAO-A or -B inhibitor). If a drug is metabolized by MAOs, competitive interactions can occur with other drugs that are MAO substrates, e.g. with beta-adrenoceptor agonists and antagonists, prodrugs of dopamine, serotonin 5-HT1-receptor agonists as well as with primaquine, flurazepam and citalopram. Moreover, the knowledge of the involvement of MAOs in the metabolism of a drug may suggest possible, although not obligatory, interactions with tyramine-containing food or drink, with over the counter medicines sold to relieve the symptoms of coughs and colds (generally containing the indirectly-acting sympathomimetic amine phenylpropanolamine) or with phenylephrine-containing preparations. Finally, biotransformation by amine oxidases, as by CYP, does not always lead to detoxication but can produce toxic compounds.

show abstract

Determination of regions important for Monoamine Oxidase (MAO) A and B substrate and inhibitor selectivities

Cited by 18 publications

References 9 publications

Monoamine oxidase inactivation: From pathophysiology to therapeutics

Monoamine oxidase inactivation: From pathophysiology to therapeutics

Synthesis and Monoamine Oxidase Inhibitory Activity of New Pyridazine-, Pyrimidine- and 1,2,4-Triazine-Containing Tricyclic Derivatives

Biotransformation of xenobiotics by amine oxidases

Contact Info

Product

Resources

About