User:Steve Klimcak/Sandbox 1 - Revision history

Steve Klimcak at 18:42, 25 April 2019

Steve Klimcak — Thu, 25 Apr 2019 18:42:39 GMT

←Older revision		Revision as of 18:42, 25 April 2019
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	==Application==		==Application==
-	LSD1 plays a pivital role in many biological processes such as cell growth, epithelial-mesenchymal transition, stem cell biology, malignant transformation of cells, and cell differentiation. Malfunctioning of these processes can lead to life threatening diseases including but not limited to myeloid leukemia and acute lymphoblastic leukemia. Evidence has shown that these activities have ties to prostate and small cell lung cancer so studies have been done to find a reliable inhibitor for LSD1. Monamine oxidases utilize the FAD co-factor much like LSD1 and inhibitors of monamaine oxidase have proven to be successful in inhibiting the activity of LSD1. A patent for 5-cyano indole derivatives(compound similar in structure to monoamine oxidase inhibitors) has been proposed to be a potential inhibitor for LSD1. More specifically trans-2-Phenylcyclopropylamine has been shown the best representation of this inhibition. The formation of a product via an addition reaction through the flavin ring can restrict LSD1's activity with subsequent one‐electron oxidation and cyclopropyl ring opening. However due to the selective nature of 2-PCPA it does not present a strong enough affinity for LSD1's activity. Alternative structures using the foundation of 2-PCPA are continually being researched to find the best fit inhibitor for LSD1. An article published in Wiley Online Library discusses a number of potential LSD1 inhibitors based on monoamine oxidase inhibitors. Thus inhibition of LSD1 opens new pathways for possible treatments for cancers and disorders.	+	LSD1 plays a pivital role in many biological processes such as cell growth, epithelial-mesenchymal transition, stem cell biology, malignant transformation of cells, and cell differentiation. Malfunctioning of these processes can lead to life threatening diseases including but not limited to myeloid leukemia and acute lymphoblastic leukemia. Evidence has shown that these activities have ties to prostate and small cell lung cancer so studies have been done to find a reliable inhibitor for LSD1. Monamine oxidases utilize the FAD co-factor much like LSD1 and inhibitors of monamaine oxidase have proven to be successful in inhibiting the activity of LSD1. A patent for 5-cyano indole derivatives(compound similar in structure to monoamine oxidase inhibitors) has been proposed to be a potential inhibitor for LSD1. More specifically trans-2-Phenylcyclopropylamine has been shown the best representation of this inhibition. The formation of a product via an addition reaction through the flavin ring can restrict LSD1's activity with subsequent one‐electron oxidation and cyclopropyl ring opening. However due to the selective nature of 2-PCPA it does not present a strong enough affinity for LSD1's activity. Alternative structures using the foundation of 2-PCPA are continually being researched to find the best fit inhibitor for LSD1. An article published in Wiley Online Library discusses a number of potential LSD1 inhibitors based on monoamine oxidase inhibitors [https://onlinelibrary.wiley.com/doi/full/10.1002/med.21350]. Thus inhibition of LSD1 opens new pathways for possible treatments for cancers and disorders.
	[[Image:FAD-PCPA.jpg\|400px\|right\|thumb\|Figure 2]]		[[Image:FAD-PCPA.jpg\|400px\|right\|thumb\|Figure 2]]

Steve Klimcak at 18:40, 25 April 2019

Steve Klimcak — Thu, 25 Apr 2019 18:40:47 GMT

←Older revision		Revision as of 18:40, 25 April 2019
Line 21:		Line 21:
	==Application==		==Application==
	LSD1 plays a pivital role in many biological processes such as cell growth, epithelial-mesenchymal transition, stem cell biology, malignant transformation of cells, and cell differentiation. Malfunctioning of these processes can lead to life threatening diseases including but not limited to myeloid leukemia and acute lymphoblastic leukemia. Evidence has shown that these activities have ties to prostate and small cell lung cancer so studies have been done to find a reliable inhibitor for LSD1. Monamine oxidases utilize the FAD co-factor much like LSD1 and inhibitors of monamaine oxidase have proven to be successful in inhibiting the activity of LSD1. A patent for 5-cyano indole derivatives(compound similar in structure to monoamine oxidase inhibitors) has been proposed to be a potential inhibitor for LSD1. More specifically trans-2-Phenylcyclopropylamine has been shown the best representation of this inhibition. The formation of a product via an addition reaction through the flavin ring can restrict LSD1's activity with subsequent one‐electron oxidation and cyclopropyl ring opening. However due to the selective nature of 2-PCPA it does not present a strong enough affinity for LSD1's activity. Alternative structures using the foundation of 2-PCPA are continually being researched to find the best fit inhibitor for LSD1. An article published in Wiley Online Library discusses a number of potential LSD1 inhibitors based on monoamine oxidase inhibitors. Thus inhibition of LSD1 opens new pathways for possible treatments for cancers and disorders.		LSD1 plays a pivital role in many biological processes such as cell growth, epithelial-mesenchymal transition, stem cell biology, malignant transformation of cells, and cell differentiation. Malfunctioning of these processes can lead to life threatening diseases including but not limited to myeloid leukemia and acute lymphoblastic leukemia. Evidence has shown that these activities have ties to prostate and small cell lung cancer so studies have been done to find a reliable inhibitor for LSD1. Monamine oxidases utilize the FAD co-factor much like LSD1 and inhibitors of monamaine oxidase have proven to be successful in inhibiting the activity of LSD1. A patent for 5-cyano indole derivatives(compound similar in structure to monoamine oxidase inhibitors) has been proposed to be a potential inhibitor for LSD1. More specifically trans-2-Phenylcyclopropylamine has been shown the best representation of this inhibition. The formation of a product via an addition reaction through the flavin ring can restrict LSD1's activity with subsequent one‐electron oxidation and cyclopropyl ring opening. However due to the selective nature of 2-PCPA it does not present a strong enough affinity for LSD1's activity. Alternative structures using the foundation of 2-PCPA are continually being researched to find the best fit inhibitor for LSD1. An article published in Wiley Online Library discusses a number of potential LSD1 inhibitors based on monoamine oxidase inhibitors. Thus inhibition of LSD1 opens new pathways for possible treatments for cancers and disorders.
		+	[[Image:FAD-PCPA.jpg\|400px\|right\|thumb\|Figure 2]]

	== Disease ==		== Disease ==

Steve Klimcak at 18:38, 25 April 2019

Steve Klimcak — Thu, 25 Apr 2019 18:38:09 GMT

←Older revision		Revision as of 18:38, 25 April 2019
Line 20:		Line 20:

	==Application==		==Application==
-	LSD1 plays a pivital role in many biological processes such as cell growth, epithelial-mesenchymal transition, stem cell biology, malignant transformation of cells, and cell differentiation. Malfunctioning of these ~~activities~~ can lead to life threatening diseases ~~such as acute~~ myeloid leukemia and acute lymphoblastic leukemia. Evidence has shown that these activities have ties to prostate and small cell lung cancer so studies have been done to find a reliable inhibitor for LSD1. Monamine oxidases utilize the FAD co-factor much like LSD1 and inhibitors of monamaine oxidase have proven to be successful in inhibiting the activity of LSD1. Thus inhibition of LSD1 opens new pathways for possible treatments for cancers and disorders.	+	LSD1 plays a pivital role in many biological processes such as cell growth, epithelial-mesenchymal transition, stem cell biology, malignant transformation of cells, and cell differentiation. Malfunctioning of these processes can lead to life threatening diseases including but not limited to myeloid leukemia and acute lymphoblastic leukemia. Evidence has shown that these activities have ties to prostate and small cell lung cancer so studies have been done to find a reliable inhibitor for LSD1. Monamine oxidases utilize the FAD co-factor much like LSD1 and inhibitors of monamaine oxidase have proven to be successful in inhibiting the activity of LSD1. A patent for 5-cyano indole derivatives(compound similar in structure to monoamine oxidase inhibitors) has been proposed to be a potential inhibitor for LSD1. More specifically trans-2-Phenylcyclopropylamine has been shown the best representation of this inhibition. The formation of a product via an addition reaction through the flavin ring can restrict LSD1's activity with subsequent one‐electron oxidation and cyclopropyl ring opening. However due to the selective nature of 2-PCPA it does not present a strong enough affinity for LSD1's activity. Alternative structures using the foundation of 2-PCPA are continually being researched to find the best fit inhibitor for LSD1. An article published in Wiley Online Library discusses a number of potential LSD1 inhibitors based on monoamine oxidase inhibitors. Thus inhibition of LSD1 opens new pathways for possible treatments for cancers and disorders.
		+
	== Disease ==		== Disease ==

Steve Klimcak at 16:48, 25 April 2019

Steve Klimcak — Thu, 25 Apr 2019 16:48:23 GMT

←Older revision		Revision as of 16:48, 25 April 2019
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	===Hydrophobic Pocket===		===Hydrophobic Pocket===
	The hydrophobic pocket located in the active site cavity of LSD1, forms a catalytic chamber where the substrate lysine is oriented and positioned to interact with the		The hydrophobic pocket located in the active site cavity of LSD1, forms a catalytic chamber where the substrate lysine is oriented and positioned to interact with the
-	FAD co-factor to initiate demethylation. The specific residues making up the pocket include valine-317, glycine-330, alanine-331, methionine 332, valine-333, phenylalanine-338, leucine-569, asparagine-660, lysine-661, tryptophan 695, serine 749, serine 760, and tyrosine-761. These residues in the <scene name='81/811712/Hydrophobic_pocket/4'>hydrophobic pocket</scene> shown in green surrounds the FAD in a way such that it exposes the catalytic nitrogen(N5) that is responsible for the two electron demethylation. The <scene name='81/811712/Fad_n5/3'>catalytic nitrogen</scene> depicted as a sphere is approximately 3.5Å away from the substrate lysine. Lysine 661 shown 4.98Å is responsible for anchoring the FAD in place to efficiently bind the substrate lysine. Another three seperate pockets help bind the histone tail residues to the substrate lysine which is essential for identifying different modifications of the histone tail.	+	FAD co-factor to initiate demethylation. The specific residues making up the pocket include valine-317, glycine-330, alanine-331, methionine 332, valine-333, phenylalanine-338, leucine-569, asparagine-660, lysine-661, tryptophan 695, serine 749, serine 760, and tyrosine-761. These residues in the <scene name='81/811712/Hydrophobic_pocket/4'>hydrophobic pocket</scene> shown in green surrounds the FAD in a way such that it exposes the catalytic nitrogen(N5) that is responsible for the two electron demethylation. The <scene name='81/811712/Fad_n5/3'>catalytic nitrogen</scene> depicted as a sphere is approximately 3.5Å away from the substrate lysine. Lysine 661 shown 4.98Å is responsible for anchoring the FAD in place to efficiently bind the substrate lysine. A structure complex of LSD1 with the a substrate lysine encased in has yet to be crystallized. Another three seperate pockets help bind the histone tail residues to the substrate lysine which is essential for identifying different modifications of the histone tail.

	==Application==		==Application==

Steve Klimcak at 16:41, 25 April 2019

Steve Klimcak — Thu, 25 Apr 2019 16:41:35 GMT

←Older revision		Revision as of 16:41, 25 April 2019
Line 17:		Line 17:
	===Hydrophobic Pocket===		===Hydrophobic Pocket===
	The hydrophobic pocket located in the active site cavity of LSD1, forms a catalytic chamber where the substrate lysine is oriented and positioned to interact with the		The hydrophobic pocket located in the active site cavity of LSD1, forms a catalytic chamber where the substrate lysine is oriented and positioned to interact with the
-	FAD co-factor to initiate demethylation. The specific residues making up the pocket include valine-317, glycine-330, alanine-331, methionine 332, valine-333, phenylalanine-338, leucine-569, asparagine-660, lysine-661, tryptophan 695, serine 749, serine 760, and tyrosine-761. These residues in the <scene name='81/811712/Hydrophobic_pocket/1'>hydrophobic pocket</scene> shown in green surrounds the FAD in a way such that it exposes the catalytic nitrogen(N5) that is responsible for the two electron demethylation. The <scene name='81/811712/Fad_n5/3'>catalytic nitrogen</scene> depicted as a sphere is approximately 3.5Å away from the substrate lysine. Lysine 661 shown 4.98Å is responsible for anchoring the FAD in place to efficiently bind the substrate lysine. Another three seperate pockets help bind the histone tail residues to the substrate lysine which is essential for identifying different modifications of the histone tail.	+	FAD co-factor to initiate demethylation. The specific residues making up the pocket include valine-317, glycine-330, alanine-331, methionine 332, valine-333, phenylalanine-338, leucine-569, asparagine-660, lysine-661, tryptophan 695, serine 749, serine 760, and tyrosine-761. These residues in the <scene name='81/811712/Hydrophobic_pocket/4'>hydrophobic pocket</scene> shown in green surrounds the FAD in a way such that it exposes the catalytic nitrogen(N5) that is responsible for the two electron demethylation. The <scene name='81/811712/Fad_n5/3'>catalytic nitrogen</scene> depicted as a sphere is approximately 3.5Å away from the substrate lysine. Lysine 661 shown 4.98Å is responsible for anchoring the FAD in place to efficiently bind the substrate lysine. Another three seperate pockets help bind the histone tail residues to the substrate lysine which is essential for identifying different modifications of the histone tail.

	==Application==		==Application==

Steve Klimcak at 18:27, 23 April 2019

Steve Klimcak — Tue, 23 Apr 2019 18:27:50 GMT

←Older revision		Revision as of 18:27, 23 April 2019
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	===Mechanism===		===Mechanism===
	The demethylation of lysine via LSD1 occurs through oxidation via a hydride transfer. Shown in Figure 2 the first step involves the <scene name='81/811710/Fad_highlight/1'>Flavin Adenine Dinucleotide cofactor</scene> initiating a hydride transfer from the one of the two methyl groups bound to the nitrogen at the lysine tail, via a N5 on the flavin group. An imine cation is then formed at the end of the lysine tail to compensate for the loss of hydride. The FAD co-factor is also negatively charged and lysine residue 661 provides stability by drawing that charge away. In the next step the imine is hydrolyzed and transitions to an hemiaminal. This then breaks down to formaldehyde and the product lysine.		The demethylation of lysine via LSD1 occurs through oxidation via a hydride transfer. Shown in Figure 2 the first step involves the <scene name='81/811710/Fad_highlight/1'>Flavin Adenine Dinucleotide cofactor</scene> initiating a hydride transfer from the one of the two methyl groups bound to the nitrogen at the lysine tail, via a N5 on the flavin group. An imine cation is then formed at the end of the lysine tail to compensate for the loss of hydride. The FAD co-factor is also negatively charged and lysine residue 661 provides stability by drawing that charge away. In the next step the imine is hydrolyzed and transitions to an hemiaminal. This then breaks down to formaldehyde and the product lysine.
-	[[Image:~~LSD1 Mech1~~.jpg\|400px\|right\|thumb\|Figure 2]]	+	[[Image:LSD1Mech2.jpg\|400px\|right\|thumb\|Figure 2]]

	===Hydrophobic Pocket===		===Hydrophobic Pocket===

Steve Klimcak at 18:12, 19 April 2019

Steve Klimcak — Fri, 19 Apr 2019 18:12:57 GMT

←Older revision		Revision as of 18:12, 19 April 2019
Line 13:		Line 13:
	===Mechanism===		===Mechanism===
	The demethylation of lysine via LSD1 occurs through oxidation via a hydride transfer. Shown in Figure 2 the first step involves the <scene name='81/811710/Fad_highlight/1'>Flavin Adenine Dinucleotide cofactor</scene> initiating a hydride transfer from the one of the two methyl groups bound to the nitrogen at the lysine tail, via a N5 on the flavin group. An imine cation is then formed at the end of the lysine tail to compensate for the loss of hydride. The FAD co-factor is also negatively charged and lysine residue 661 provides stability by drawing that charge away. In the next step the imine is hydrolyzed and transitions to an hemiaminal. This then breaks down to formaldehyde and the product lysine.		The demethylation of lysine via LSD1 occurs through oxidation via a hydride transfer. Shown in Figure 2 the first step involves the <scene name='81/811710/Fad_highlight/1'>Flavin Adenine Dinucleotide cofactor</scene> initiating a hydride transfer from the one of the two methyl groups bound to the nitrogen at the lysine tail, via a N5 on the flavin group. An imine cation is then formed at the end of the lysine tail to compensate for the loss of hydride. The FAD co-factor is also negatively charged and lysine residue 661 provides stability by drawing that charge away. In the next step the imine is hydrolyzed and transitions to an hemiaminal. This then breaks down to formaldehyde and the product lysine.
-	[[Image:LSD1 ~~Mech~~.jpg\|400px\|right\|thumb\|Figure 2]]	+	[[Image:LSD1 Mech1.jpg\|400px\|right\|thumb\|Figure 2]]

	===Hydrophobic Pocket===		===Hydrophobic Pocket===

Steve Klimcak at 17:51, 19 April 2019

Steve Klimcak — Fri, 19 Apr 2019 17:51:47 GMT

←Older revision		Revision as of 17:51, 19 April 2019
Line 17:		Line 17:
	===Hydrophobic Pocket===		===Hydrophobic Pocket===
	The hydrophobic pocket located in the active site cavity of LSD1, forms a catalytic chamber where the substrate lysine is oriented and positioned to interact with the		The hydrophobic pocket located in the active site cavity of LSD1, forms a catalytic chamber where the substrate lysine is oriented and positioned to interact with the
-	FAD co-factor to initiate demethylation. The specific residues making up the pocket include valine-317, glycine-330, alanine-331, methionine 332, valine-333, phenylalanine-338, leucine-569, asparagine-660, lysine-661, tryptophan 695, serine 749, serine 760, and tyrosine-761. These residues in the <scene name='81/811712/Hydrophobic_pocket/1'>hydrophobic pocket</scene> shown in green surrounds the FAD in a way such that it exposes the catalytic nitrogen(N5) that is responsible for the two electron demethylation. The <scene name='81/811712/Fad_n5/2'>catalytic nitrogen</scene> depicted as a sphere is approximately 3.5Å away from the substrate lysine. Lysine 661 shown 4.98Å is responsible for anchoring the FAD in place to efficiently bind the substrate lysine. Another three seperate pockets help bind the histone tail residues to the substrate lysine which is essential for identifying different modifications of the histone tail.	+	FAD co-factor to initiate demethylation. The specific residues making up the pocket include valine-317, glycine-330, alanine-331, methionine 332, valine-333, phenylalanine-338, leucine-569, asparagine-660, lysine-661, tryptophan 695, serine 749, serine 760, and tyrosine-761. These residues in the <scene name='81/811712/Hydrophobic_pocket/1'>hydrophobic pocket</scene> shown in green surrounds the FAD in a way such that it exposes the catalytic nitrogen(N5) that is responsible for the two electron demethylation. The <scene name='81/811712/Fad_n5/3'>catalytic nitrogen</scene> depicted as a sphere is approximately 3.5Å away from the substrate lysine. Lysine 661 shown 4.98Å is responsible for anchoring the FAD in place to efficiently bind the substrate lysine. Another three seperate pockets help bind the histone tail residues to the substrate lysine which is essential for identifying different modifications of the histone tail.

	==Application==		==Application==

Steve Klimcak at 17:48, 19 April 2019

Steve Klimcak — Fri, 19 Apr 2019 17:48:50 GMT

←Older revision		Revision as of 17:48, 19 April 2019
Line 17:		Line 17:
	===Hydrophobic Pocket===		===Hydrophobic Pocket===
	The hydrophobic pocket located in the active site cavity of LSD1, forms a catalytic chamber where the substrate lysine is oriented and positioned to interact with the		The hydrophobic pocket located in the active site cavity of LSD1, forms a catalytic chamber where the substrate lysine is oriented and positioned to interact with the
-	FAD co-factor to initiate demethylation. The specific residues making up the pocket include valine-317, glycine-330, alanine-331, methionine 332, valine-333, phenylalanine-338, leucine-569, asparagine-660, lysine-661, tryptophan 695, serine 749, serine 760, and tyrosine-761. These residues in the <scene name='81/811712/Hydrophobic_pocket/1'>hydrophobic pocket</scene> shown in green surrounds the FAD in a way such that it exposes the catalytic nitrogen(N5) that is responsible for the two electron demethylation. The <scene name='81/811712/Fad_n5/1'>catalytic nitrogen</scene> depicted as a sphere is approximately 3.5Å away from the substrate lysine. Another three seperate pockets help bind the histone tail residues to the substrate lysine which is essential for identifying different modifications of the histone tail.	+	FAD co-factor to initiate demethylation. The specific residues making up the pocket include valine-317, glycine-330, alanine-331, methionine 332, valine-333, phenylalanine-338, leucine-569, asparagine-660, lysine-661, tryptophan 695, serine 749, serine 760, and tyrosine-761. These residues in the <scene name='81/811712/Hydrophobic_pocket/1'>hydrophobic pocket</scene> shown in green surrounds the FAD in a way such that it exposes the catalytic nitrogen(N5) that is responsible for the two electron demethylation. The <scene name='81/811712/Fad_n5/2'>catalytic nitrogen</scene> depicted as a sphere is approximately 3.5Å away from the substrate lysine. Lysine 661 shown 4.98Å is responsible for anchoring the FAD in place to efficiently bind the substrate lysine. Another three seperate pockets help bind the histone tail residues to the substrate lysine which is essential for identifying different modifications of the histone tail.

	==Application==		==Application==

Steve Klimcak at 17:09, 19 April 2019

Steve Klimcak — Fri, 19 Apr 2019 17:09:52 GMT

←Older revision		Revision as of 17:09, 19 April 2019
Line 17:		Line 17:
	===Hydrophobic Pocket===		===Hydrophobic Pocket===
	The hydrophobic pocket located in the active site cavity of LSD1, forms a catalytic chamber where the substrate lysine is oriented and positioned to interact with the		The hydrophobic pocket located in the active site cavity of LSD1, forms a catalytic chamber where the substrate lysine is oriented and positioned to interact with the
-	FAD co-factor to initiate demethylation. The specific residues making up the pocket include valine-317, glycine-330, alanine-331, methionine 332, valine-333, phenylalanine-338, leucine-569, asparagine-660, lysine-661, tryptophan 695, serine 749, serine 760, and tyrosine-761. These residues in the <scene name='81/811712/Hydrophobic_pocket/1'>hydrophobic pocket</scene> shown in green surrounds the FAD in a way such that it exposes the catalytic nitrogen(N5) that is responsible for the two electron demethylation. The <scene name='81/811712/Fad_n5/1'>catalytic nitrogen</scene> depicted as a sphere is approximately 3.5Å away from the substrate lysine ~~which through its imine intermediate can stabilize the negative charge on the FAD~~. Another three seperate pockets help bind the histone tail residues to the substrate lysine which is essential for identifying different modifications of the histone tail.	+	FAD co-factor to initiate demethylation. The specific residues making up the pocket include valine-317, glycine-330, alanine-331, methionine 332, valine-333, phenylalanine-338, leucine-569, asparagine-660, lysine-661, tryptophan 695, serine 749, serine 760, and tyrosine-761. These residues in the <scene name='81/811712/Hydrophobic_pocket/1'>hydrophobic pocket</scene> shown in green surrounds the FAD in a way such that it exposes the catalytic nitrogen(N5) that is responsible for the two electron demethylation. The <scene name='81/811712/Fad_n5/1'>catalytic nitrogen</scene> depicted as a sphere is approximately 3.5Å away from the substrate lysine. Another three seperate pockets help bind the histone tail residues to the substrate lysine which is essential for identifying different modifications of the histone tail.

	==Application==		==Application==