User:Martha Blakely/Sandbox 1: Difference between revisions
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[[Image:FAD.jpg]] FAD cofactor with an empty N5 bond. | [[Image:FAD.jpg]] FAD cofactor with an empty N5 bond. | ||
Each monomer has its own <scene name='User:Martha_Blakely/Sandbox_1/Fad_cofactors/2'>FAD cofactor</scene> covalently bonded. | Each monomer has its own <scene name='User:Martha_Blakely/Sandbox_1/Fad_cofactors/2'>FAD cofactor</scene> covalently bonded. The FAD molecule is situated on the opposite end of the active site away from the entrance into the cavity. It aids in binding substrates and inhibitors which seem to be situated between Tyr398 and Tyr435 when bonded to the N5 position of the FAD cofactor (generally called “flavin moiety”). Inhibitors and substrates must maneuver past these tyrosine residues, which contain phenol side chains, in order to bond to the N5 position of the FAD cofactor. These three together, the flavin, Tyr398, and Tyr435, form an aromatic cage. | ||
The implications of these residues are important to know for their own effects on substrate binding. These important residues also show that further knowledge of the three-dimensional structure of MAO-B is important in the development of enzyme inhibitors. | |||
==Difference from MAO-A== | ==Difference from MAO-A== | ||
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The oxidative deamination of amine neurotransmitters is catalyzed by both monoamine oxidases. The image above shows the two generally proposed and accepted catalytic pathways for this oxidation; the lower loop is the case for most substrates. In this loop, the enzyme-imine compound (E.FAD<sub>red</sub>--Imine) reacts with oxygen (O<sub>2</sub>) to create H<sub>2</sub>O<sub>2</sub> and the oxidized enzyme-imine compound (E.FAD<sub>ox</sub>). The imine is then reduced to the ammonium ion (NH<sub>4</sub><sup>+</sup>) and its respective aldehyde. The cycle goes around the loop another time when an amine (S) binds to the active site within the enzyme (E.FAD<sub>ox</sub> + S). | The oxidative deamination of amine neurotransmitters is catalyzed by both monoamine oxidases. The image above shows the two generally proposed and accepted catalytic pathways for this oxidation; the lower loop is the case for most substrates. In this loop, the enzyme-imine compound (E.FAD<sub>red</sub>--Imine) reacts with oxygen (O<sub>2</sub>) to create H<sub>2</sub>O<sub>2</sub> and the oxidized enzyme-imine compound (E.FAD<sub>ox</sub>). The imine is then reduced to the ammonium ion (NH<sub>4</sub><sup>+</sup>) and its respective aldehyde. The cycle goes around the loop another time when an amine (S) binds to the active site within the enzyme (E.FAD<sub>ox</sub> + S). | ||
Hydrogen peroxide is shown as a product in this catalytic pathway. | Hydrogen peroxide is shown as a product in this catalytic pathway. Due to hydrogen peroxide's association with health problems such as Parkinson's disease and Alzheimer's disease, MAO inhibitors have been created with the intention of neuroprotective functions. The inhibitors must be bound to the active site of the enzyme, which means that knowledge of enzyme binding during the catalytic pathway with neurotransmitters is important for the development of these inhibitors. | ||
==Inhibition== | ==Inhibition== | ||
Both reversible and irreversible inhibitors have been developed for MAO-B. Irreversible inhibitors bind to the enzyme in such a way that permanently deactivates it. Concentrations of the inhibitor and the possible substrates determine whether a reversible inhibitor binds to the enzyme. Rasagiline and deprenyl (also seleginine) are both irreversible inhibitors used for the inhibition of MAO-B. Rasagiline is much more selective for MAO-B than MAO-A. 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. Safinamide is an example of a reversible inhibitor for MAO-B. | |||
==References | ==References== | ||
*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. | *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. | *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. | *Youdim, Edmondson, Tipton (2006) "The therapeutic potential of monoamine oxidase inhibitors", Nature Reviews 7:295-309. | ||
