Monoamine oxidase b: Difference between revisions

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<scene name='User:Martha_Blakely/Sandbox_1/Monoamine_oxidase_b_front/1'>Monoamine oxidase B</scene> (MAO-B) is a mitochondrial outer-membrane flavoenzyme.  It is one of two isozymes (MOA-A is the other), which catalyzes the oxidative deamination of amine neurotransmitters, including [http://en.wikipedia.org/wiki/Serotonin serotonin], [http://en.wikipedia.org/wiki/Dopamine dopamine], and [http://en.wikipedia.org/wiki/Epinephrine epinephrine].  Selectivity is as follows: MAO-A oxidizes serotonin and epinephrine, MAO-B oxidizes benzylamine and phenylethylamine, and both enzymes oxidize dopamine.  The flavin-dependent enzymes use O₂ as an electron acceptor in the catalytic pathway which includes hydrogen peroxide, H₂O₂, as a product. Increased H₂O₂ levels promote apoptotic signaling of cells. Thus, researchers have found that increased levels of MAO-B, whose levels in the brain increase at least 3-fold on aging, are related to decreased levels of neuronal cells.  The cells in the brain particularly targeted are dopamine-producing cells, which results in the development of [http://en.wikipedia.org/wiki/Parkinson%27s_disease Parkinson’s disease]. A popular example related to the development of Parkinsonian symptoms based on MAO-B levels is the oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to 1-methyl-4-phenylpyridinium (MPP+) which destroys glial cells.  The inhibition of MAO-B prevents against this cell death behavior.

== Structure ==

Structurally, MAO-B is a dimer with each monomer composed of 520 amino acids.  The sequence <scene name='User:Martha_Blakely/Sandbox_1/Alpha_helices/1'>489-520</scene> forms a helix on each monomer that is responsible for the attachment to the outer-membrane of mitochondria.  This α-helix resides in the lipid bilayer. In addition to the C-terminal helices, other hydrophobic side chains such as <scene name='User:Martha_Blakely/Sandbox_1/Pro109ile110/1'>Pro109 and Ile110</scene> also contribute to attachment.

==Inhibition==

Both reversible and irreversible inhibitors have been developed for MAO-B.  Irreversible inhibitors form a covalent bond to the FAD cofactor in the enzyme active site, permanently deactivating it.  Concentrations of the inhibitor and the possible substrates determine whether a reversible inhibitor binds to the enzyme. <scene name='1gos/Rasagiline_bound_to_mao-b/1'>Rasagiline</scene> and <scene name='1gos/Deprenyl_bound_to_mao-b/2'>deprenyl</scene> (also seleginine) are both FDA-approved irreversible inhibitors used for the inhibition of MAO-B.  They both are categorized as propargylamines.  Rasagiline is much more selective for MAO-B than MAO-A.  Only its R isomer is pharmacologically active while its S isomer is not.  Under normal administration, deprenyl is selective for MAO-B, but when deprenyl is administered in large amounts, its selectivity for MAO-B decreases.  In this case, it also inhibits MAO-A.  <scene name='1gos/Bound_with_safinamide/2'>Safinamide</scene> is an example of a reversible inhibitor for MAO-B.  Other known inhibitors are derived from pyrazole, xanthone, and pirlindole.