Mitochondrial monoamine oxidase

Mitochondrial monoamine oxidase, 1, 253 Mitomycin synthesis, 7, 658, 659 Mitomycin-A, 7, 93 Mitomycin-B, 7, 93 Mitomycin-C, 7, 93 as antitumor drug, 4, 374 Mixed function oxidases, 1, 224 Mobam... 

Ubiquitous mitochondrial monoamine oxidase [monoamine oxygen oxidoreductase (deaminating) (flavin-containing) EC 1.4.3.4 MAO] exists in two forms, namely type A and type B [ monoamine oxidase (MAO) A and B]. They are responsible for oxidative deamination of primary, secondary, and tertiary amines, including neurotransmitters, adrenaline, noradrenaline, dopamine (DA), and serotonin and vasoactive amines, such as tyramine and phenylethylamine. Their nonselec-tive and selective inhibitors ( selective MAO-A and -B inhibitors) are employed for the treatment of depressive illness and Parkinson s disease (PD). 

Binda C, Li M, Hubalek E, Restelli N, Edmondson DE, Mattevi A. Insights into the mode of inhibition of human mitochondrial monoamine oxidase B from high-resolution crystal structures. Proc Natl Acad Sci USA 2003 100 9750-5. 

M.C. Walker, D.E. Edmondson, Structure-activity relationships in the oxidation of benzylamine analogues by bovine liver mitochondrial monoamine oxidase B, Biochemistry 33 (1994) 7088-7098. 

Monoamine oxidase (MAO) serves as a marker enzyme for outer membrane. There is some MAO activity in the inner membrane and therefore also in SMPs however, a high level of monoamine oxidase in the SMP preparation indicates a large contamination by outer membrane. Mitochondrial monoamine oxidase is an FAD-dependent enzyme that catalyzes the oxidation of amines to aldehydes (Equation E10.2). A convenient assay for this enzyme uses benzylamine as substrate and monitors the rate of ben-zaldehyde production at 250 nm. 

As shown in Fig. 3 (Top Panel), dietary tyrosine is transported into axon terminals of DA neurons and converted in the cytoplasm to DOPA by the rate limiting enzyme TH. DOPA is then rapidly decarboxylated by DDC to DA which is taken up and stored in synaptic vesicles until release. Excess newly synthesized DA is metabolized by mitochondrial monoamine oxidase (MAO) to DOPAC which rapidly diffuses out of neurons and is taken up and converted to homovanillic acid (HVA) by catechol-O-methyltransferase (COMT)-containing glial cells in the neuropil (Hansson and Sellstrom, 1983 Kimelberg, 1986). Upon arrival of an action potential at the axon terminal, vesicular DA is released into the synapse via calcium-dependent exocytosis where it is free to interact with stimulatory Di and/or inhibitory D2 DA receptors on postsynaptic target cells and inhibitory D2 autoreceptors on presynaptic terminals. A major portion of DA is removed from the synapse by high affinity DA transporters located on presynaptic terminals, and recaptured DA is either metabolized to DOPAC by mitochondrial MAO or stored in synaptic vesicles for subsequent re-release. A small portion of DA can also be taken up from the synapse by glia and metabolized to 3-methoxytyramine (3MT) and HVA. 

As mentioned, the mildness of NaBHaCN (coupled with its effectiveness and stability in aqueous media) has attracted considerable interest for applications in biochemical areas. Examples include the trapping of suspected imine intermediates produced in enzyme (mitochondrial monoamine oxidase) inactivation by amines, the establishment by reduction of the positions of imine-forming amines in 2-keto-3-deoxy-6-phosphogluconate aldolase, and the transfer labeling of methionyl-tRNA synthetase and methionyl-tRNA transformalase by treatment with periodate-treated tRNA. In fact, most biochemical applications of NaBHaCN have utilized in situ imine formation-reduction (i.e. reductive amination) conditions and will be further discussed in Section 1.2.2.3.1. 

The FAD-requiring enzymes in mammalian systems include the D- and L-amino acid oxidases, mono- and diamine oxidases, glucose oxidase, succinate dehydrogenase, a-glycerophosphate dehydrogenase, and glutathione reductase. FMN is a cofactor for renal L-amino acid oxidase, NADH reductase, and a-hydroxy acid oxidase. In succinate dehydrogenase, FAD is linked to a histidyl residue in liver mitochondrial monoamine oxidase, to a cysteinyl residue. In other cases, the attachment is nonco-valent but the dissociation constant is very low. 

I DA is also metabolised by mitochondrial monoamine oxidase (MAO) and by the membrane-bound catechol-O-methyltransferase (COMT) enzyme to form the endproduct homovallinic acid (HVA) (Table 1.2). 

Molderings et al., 1991). Two sub-types of specific IBS were proposed. The I,-subtype is sensitive to cloni-dine and idazoxan whereas the 12-subtype, suggested being associated with the mitochondrial monoamine oxidase, is sensitive to idazoxan but poorly sensitive to clonidine (Bousquet et al., 1995 Molderings, 1997). 

Figure 16.7-11. Various neurotransmitters as substrates for mitochondrial monoamine oxidase (MAO).

Many pyridazine derivatives were tested for analgesic activity,162,487,834-840 for antimicrobial,841-845 tuberculostatic,846,847 and hypoglycemic activity as antidiabetics,848,849 for activity on the central nervous system,850 for anticoccidial,851 insecticidal.852 and fugicidal activity,853 for inhibition of mitochondrial monoamine oxidase,854 for their action on the metabolism of rat cerebral cortex slices,855,856 and against the enzyme... 

Of the reduced indoxazenes, attention is drawn to the hydrazide of 4,5,6,7-tetrahydroindoxazene-3-carboxylic acid which, as the hydrochloride, is more potent than iproniazid as an inhibitor of mitochondrial monoamine oxidase.126... 

Table 17. Inhibition of human liver mitochondrial monoamine oxidase by various aliphatic amines and alcohols at different pH values [175]...

Gorkin VZ (1964) Current progress in the study of the nature and physiological role of mitochondrial monoamine oxidase. Voprosy med-itsinskoi khimii (10) 115-134 (in Russian)... 

Nelson DR, Strobel HW (1987) Evolution of cytochrome P-450 proteins. Molec Biol Evolut 4 572-593 Nicotra A (1982) A radiochemical evaluation of mitochondrial monoamine oxidase activity towards serotonin in sea urchin eggs and embryos. Int J Invert Reprod 5 283-288 Nicotra A, Naccarato MN (1982) Monoamine oxidase activity in Paracentrotus lividus sperm cells. Int J Invert Reprod 5 101-105... 

These enzymes are highly susceptible to inactivation by y3,y-acetylenic amines. Flavin-linked mitochondrial monoamine oxidase is irreversibly inhibited by the antidepressant drug pargyline. Structure activity studies have shown that the acetylenic unit is crucial and that it has to be /3,y to the nitrogen. ... 

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