User:Martha Blakely/Sandbox 1
From Proteopedia
| Line 3: | Line 3: | ||
Monoamine oxidase B (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]. The flavin-dependent enzymes use O<sub>2</sub> as an electron acceptor in the catalytic pathway which includes hydrogen peroxide, H<sub>2</sub>O<sub>2</sub>, as a product. Increased H<sub>2</sub>O<sub>2</sub> 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]. | Monoamine oxidase B (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]. The flavin-dependent enzymes use O<sub>2</sub> as an electron acceptor in the catalytic pathway which includes hydrogen peroxide, H<sub>2</sub>O<sub>2</sub>, as a product. Increased H<sub>2</sub>O<sub>2</sub> 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]. | ||
| - | Inhibitors of MAO-B such as [http://en.wikipedia.org/wiki/Deprenyl deprenyl] and [http://en.wikipedia.org/wiki/Rasagiline rasagiline] have been developed in order to protect the brain. Deprenyl is used in L-dopa therapy which acts as treatment for | + | Inhibitors of MAO-B such as [http://en.wikipedia.org/wiki/Deprenyl deprenyl] and [http://en.wikipedia.org/wiki/Rasagiline rasagiline] have been developed in order to protect the brain from neurological disorders. Deprenyl is used in L-dopa therapy which acts as treatment and protection for Parkinson's and pre-Parkinson's patients. |
== Structure == | == Structure == | ||
Revision as of 11:23, 24 June 2010
|
Monoamine oxidase B (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 serotonin, dopamine, and epinephrine. 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 Parkinson’s Disease.
Inhibitors of MAO-B such as deprenyl and rasagiline have been developed in order to protect the brain from neurological disorders. Deprenyl is used in L-dopa therapy which acts as treatment and protection for Parkinson's and pre-Parkinson's patients.
Contents |
Structure
Structurally, MAO-B is a dimer with each monomer composed of 520 amino acids. The sequence 489-520 form 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 Pro 109 and Ile 110 also contribute to attachment.
The active site of MAO-B is a flat hydrophobic cavity that is separated into two parts, the entrance cavity and the substrate cavity. The dual nature of the active site allows for binding of differently sized substrates. Some are large enough to fill both cavities, some only fill the substrate cavity, and other substrates are even smaller. The wide range of substrate size can partially be contributed to a boundary between the two cavities. Four residues (Tyr326, Ile199, Leu 171 and Phe168) form this boundary. Ile 199 is a gating residue that can be in the “open” or “closed” positions. Entrance into the connected cavities is determined by the movement of a loop of amino acids (residues 99-112) located at the protein surface near the membrane attachment. This loop prevents solvent from entering the active site. Its location relative to the mitochondrial outer-membrane implies that passage into the active site must be done near the membrane.
Catalytic Pathway
Inhibition
References, for further information on Monoamine oxidase B
- Binda, Newton-Vinson, Hubalek, Edmondson, and Mattevi (2002) "Structure of human monoamine oxidase B, a drug target for the treatment of neurological disorders", Nature Structural Biology 9: 22-26.
- Edmondson, Binda, Wang, Upadhyay, Mattevi (2009) "Molecular and Mechanistic Poperties of the Membrane-Bound Mitochondrial Monoamine Oxidases", Biochemistry 48: 4220-4230.
- Youdim, Edmondson, Tipton (2006) "The therapeutic potential of monoamine oxidase inhibitors", Nature Reviews 7:295-309.
