User:Martha Blakely/Sandbox 1: Difference between revisions
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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. | 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. | ||
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 others are too small to fit either. The wide range of substrate size can partially be contributed to a boundary between the two cavities. Four residues (<scene name='User:Martha_Blakely/Sandbox_1/Boundary_between_cavities/2'>Tyr326, Leu171, Ile199, and Phe168</scene>) form this boundary between cavities. Ile199 is a gating residue that can be in the “open” or “closed” positions. | 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 others are too small to fit either. The wide range of substrate size can partially be contributed to a boundary between the two cavities. Four residues (<scene name='User:Martha_Blakely/Sandbox_1/Boundary_between_cavities/2'>Tyr326, Leu171, Ile199, and Phe168</scene>) form this boundary between cavities. The positioning of these four residues affects which substrates and inhibitors are able to bind to MAO-B. Ile199 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 (<scene name='User:Martha_Blakely/Sandbox_1/Loop_99-112_in_attachment/1'>residues 99-112</scene>) located at the protein surface near the membrane attachment. This loop prevents solvent from entering the active site. The loop’s location is near the region of the protein that binds with the mitochondrial outer-membrane. This proximity implies that passage into the active site can only occur near the membrane. | Entrance into the connected cavities is determined by the movement of a loop of amino acids (<scene name='User:Martha_Blakely/Sandbox_1/Loop_99-112_in_attachment/1'>residues 99-112</scene>) located at the protein surface near the membrane attachment. This loop prevents solvent from entering the active site. The loop’s location is near the region of the protein that binds with the mitochondrial outer-membrane. This proximity implies that passage into the active site can only occur near the membrane. | ||
[[Image:FAD.jpg]] FAD cofactor with an empty N5 bond. | [[Image:FAD.jpg]] Flavin moiety of 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 | Each monomer has its own <scene name='User:Martha_Blakely/Sandbox_1/Fad_cofactors/2'>FAD cofactor</scene> covalently bound. 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. | 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. | ||
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==Comparative to MAO-A== | ==Comparative to MAO-A== | ||
Both are flavoenzymes found attached to the outer-membrane of mitochondria. The amino acid sequences of the two are about 70% | Both are flavoenzymes found attached to the outer-membrane of mitochondria. The amino acid sequences of the two are about 70% identical and are encoded by separate genes on the X-chromosome. Both catalyze the oxidative deamination of amine neurotransmitters, but the enzyme selectivity of the neurotransmitters varies. In their crystalline form, MAO-A is a monomer, whereas MAO-B is a dimer. Depression and mood swings are related to higher levels of MAO-A, rather than diseases like Parkinson’s and Alzheimer’s that are associated with higher levels of MAO-B. Serotonin, a neurotransmitter related to mood elevation, is specific to MAO-A. The residues that correspond to binding are also different between these two enzymes. | ||
==Catalytic Pathway== | ==Catalytic Pathway== | ||
