User:Nicholas Bantz/Sandbox 1

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[[Image:LSD1Mechanism.png|700 px|right|thumb|Figure 3: Hydride transfer mechanism of LSD-1 active site via FAD cofactor.]]
[[Image:LSD1Mechanism.png|700 px|right|thumb|Figure 3: Hydride transfer mechanism of LSD-1 active site via FAD cofactor.]]
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The mechanism of lysine demethylation is highly dependent on the presence of the <scene name='81/811089/Fadcofactor/4'>FAD cofactor</scene>. The FAD cofactor, positioned closely to the substrate lysine in the active site, acts as an oxidizing agent and initiates catalysis (Figure 3). A two-electron transfer occurs between the substrate lysine and FAD in the form of a [https://en.wikipedia.org/wiki/Hydride hydride]; the lysine is oxidized and the FAD is reduced <ref name="Stavropolous"/>. The FAD cofactor forms an anion and is stabilized by the positively charged <scene name='81/811088/Lys661/3'>Lys661</scene> positioned in the catalytic pocket of the active site <ref name="Stavropolous"/>. The oxidized lysine forms an aminium cation that is hydrolyzed into the carbinolamine intermediate <ref name="Stavropolous"/>. The carbinolamine intermediate readily decomposes into formaldehyde and the demethylated lysine substrate <ref name="Stavropolous"/>.
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The mechanism of lysine demethylation is highly dependent on the presence of the <scene name='81/811089/Fadcofactor/4'>FAD cofactor</scene>. The FAD cofactor, positioned closely to the substrate lysine in the active site, acts as an oxidizing agent and initiates catalysis (Figure 3). A two-electron transfer occurs between the substrate lysine and FAD in the form of a [https://en.wikipedia.org/wiki/Hydride hydride]; the lysine is oxidized and the FAD is reduced <ref name="Stavropolous"/>. The FAD cofactor forms an anion and is stabilized by the positively charged <scene name='81/811088/Lys661/3'>Lys661</scene> positioned in the catalytic pocket of the active site <ref name="Stavropolous"/>. The oxidized lysine forms an iminium cation that is hydrolyzed into the carbinolamine intermediate <ref name="Stavropolous"/>. The carbinolamine intermediate readily decomposes into formaldehyde and the demethylated lysine substrate <ref name="Stavropolous"/>.
===Inhibition by Tri-Methylated Lysine===
===Inhibition by Tri-Methylated Lysine===
[[Image:Tri-methylated Lysine.png|90 px|right|thumb|Figure 4: Tri-methylated lysine.]]
[[Image:Tri-methylated Lysine.png|90 px|right|thumb|Figure 4: Tri-methylated lysine.]]
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The proposed LSD-1 mechanism is supported by the fact that tri-methylated lysine substrates (Figure 4) competitively inhibit the enzyme. A substrate lysine that is tri-methylated binds to the active site but does not undergo catalysis; the inhibition is not steric (the active site is large enough to accommodate tri-methylated lysines), but is rather chemical in nature. Tri-methylated lysines do not have a free lone pair to form an aminium cation as is necessitated by the proposed mechanism, resulting in chemical inhibition of LSD-1 <ref name="Stavropolous"/>. Thus, the mechanism of LSD-1 contributes to its specificity for mono- or di-methylated lysine substrates (Figure 4).
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The proposed LSD-1 mechanism is supported by the fact that tri-methylated lysine substrates (Figure 4) competitively inhibit the enzyme. A substrate lysine that is tri-methylated binds to the active site but does not undergo catalysis; the inhibition is not steric (the active site is large enough to accommodate tri-methylated lysines), but is rather chemical in nature. Tri-methylated lysines do not have a free lone pair to form an iminium cation as is necessitated by the proposed mechanism, resulting in chemical inhibition of LSD-1 <ref name="Stavropolous"/>. Thus, the mechanism of LSD-1 contributes to its specificity for mono- or di-methylated lysine substrates (Figure 4).
== Medical Implications ==
== Medical Implications ==

Revision as of 20:30, 16 April 2019

LSD-1: Human lysine-specific demethylase 1

LSD-1 (PDB: 2H94) overall 3D structure: Tower domain (blue), SWIRM domain (yellow), Oxidase domain (red), and FAD cofactor (green).

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  • Nicholas Bantz
  • Cody Carley
  • Michael Thomas

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Nicholas Bantz

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