User:Jacob Holt/Sandbox 1: Difference between revisions

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== Introduction ==

[[Image:SCD1_rxn.png|500 px|right|thumb|Figure 1. Overall reaction completed by the SCD1 enzyme. It introduces a double bond between carbons 9 and 10 on the ligand Stearoyl CoA, converting it into Oleoyl CoA]]Stearyol CoA Desaturase (SCD1) functions as a lipogenic enzyme which is essential for fatty acid metabolism. SCD1 desaturates the sigma bond, within the 18-carbon acyl-CoA ligand, that attaches carbons 9 and 10<ref name="Bai">PMID: 26098370 </ref>. The primary role of SCD1 is to catalyze the biosynthesis of monounsaturated fatty acids (MUFAs) via saturated [https://en.wikipedia.org/wiki/Acyl-CoA acyl-CoAs] with an acyl chain length of 14-19 carbons<ref name="Paton">PMID: 19066317 </ref><ref name="Shen">PMID: 32470559 </ref>. Variations of the monounsaturated fatty acids function as precursors for the biosynthesis of [https://en.wikipedia.org/wiki/Phospholipid phospholipids], [https://en.wikipedia.org/wiki/Cholesteryl_ester cholesteryl esters], and [https://en.wikipedia.org/wiki/Triglyceride triglycerides]; therefore, SCD1 is a promising candidate for drug targeting<ref name="Bai" />.

[[Image:SCD1_rxn.png|500 px|right|thumb|Figure 1. Overall reaction completed by the SCD1 enzyme. It introduces a double bond between carbons 9 and 10 on the ligand Stearoyl CoA, converting it into Oleoyl CoA.]]Stearyol CoA Desaturase (SCD1) functions as a lipogenic enzyme which is essential for fatty acid metabolism. SCD1 desaturates the sigma bond, within the 18-carbon acyl-CoA ligand, that attaches carbons 9 and 10<ref name="Bai">PMID: 26098370 </ref>. The primary role of SCD1 is to catalyze the biosynthesis of monounsaturated fatty acids (MUFAs) via saturated [https://en.wikipedia.org/wiki/Acyl-CoA acyl-CoAs] with an acyl chain length of 14-19 carbons<ref name="Paton">PMID: 19066317 </ref><ref name="Shen">PMID: 32470559 </ref>. Variations of the monounsaturated fatty acids function as precursors for the biosynthesis of [https://en.wikipedia.org/wiki/Phospholipid phospholipids], [https://en.wikipedia.org/wiki/Cholesteryl_ester cholesteryl esters], and [https://en.wikipedia.org/wiki/Triglyceride triglycerides]; therefore, SCD1 is a promising candidate for drug targeting<ref name="Bai" />.

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== Proposed Mechanism ==

[[Image:SCD1_New.jpeg|450 px|right|thumb|Figure 4: A proposed mechanism for SCD1 desaturase. The catalytic water molecule reacts with Fe2+ and O2 to create oxygen radicals on the iron ions. Electrons are brought in via an electron transport chain; this lowers the oxidation state of the iron ions and forms the reactive species. The first hydrogen is abstracted creating a radical intermediate that is then deprotonated again to make the final desaturated product. Electrons are transferred in again to allow for the iron ions to go back to their original oxidation state because enzymes must end a reaction in the same state, they started it. Figure was a modification of scheme 1 proposed by Yu M. and Chen S.5 ]]

[[Image:SCD1_New.jpeg|450 px|right|thumb|Figure 4: A proposed mechanism for SCD1 desaturase. The catalytic water molecule reacts with Fe2+ and O2 to create oxygen radicals on the iron ions. Electrons are brought in via an electron transport chain; this lowers the oxidation state of the iron ions and forms the reactive species. The first hydrogen is abstracted creating a radical intermediate that is then deprotonated again to make the final desaturated product. Electrons are transferred in again to allow for the iron ions to go back to their original oxidation state because enzymes must end a reaction in the same state, they started it. Figure was a modification of scheme 1 proposed by Yu M. and Chen S.5.]]

The mechanism used by the SCD1 enzyme is different than most desaturase enzymes because it does not use an oxo-bridge. This was confirmed based on the distance between the metal ions (~6.4Å) and the lack of electron density that should be present with two oxygens<ref name="Shen" />. There have been multiple proposed mechanisms, but the mechanism shown below is a shortened version of the mechanism that is the most accurate<ref name="Yu" />.

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== Biological Relevance ==

[[Image:scd_in_membrane.jpeg|500 px|thumb|Figure 5. Position of SCD within the biological membrane. It is part of an electron transport chain involving cytochrome b5 reductase (PDB: 5GV8) and cytochrome b5 (PDB: 3NER) to allow for the activation of the catalytic molecule coordinated by the two ions in the center of SCD]]The electron transport chain allows for the mechanism of SCD1 to be carried out by providing electrons via either a Cytochrome B5 electron shuttle or an exchange through a [https://en.wikipedia.org/wiki/Ternary_complex#:~:text=A%20ternary%20complex%20can%20be,type%20of%20enzyme%2Dcatalyzed%20reactions ternary complex]<ref name="Shen" />. The electrons will be shuttled from complex to complex and then eventually be accepted by the SCD1 enzyme which will allow for activation of the catalytic molecule (Figure 5). The placement of SCD1 in the ER membrane is believed to prevent inhibition by allowing better flow of products/side products to their later pathways<ref name="Shen" />.

[[Image:scd_in_membrane.jpeg|500 px|thumb|Figure 5. Position of SCD within the biological membrane. The protein is part of an electron transport chain involving cytochrome b5 reductase (PDB: 5GV8) and cytochrome b5 (PDB: 3NER) to allow for the activation of the catalytic molecule coordinated by the two ions in the center of SCD. SCD is colored according to the hydrophobicities of each helix, shown in figures 2 and 3.]]The electron transport chain allows for the mechanism of SCD1 to be carried out by providing electrons via either a Cytochrome B5 electron shuttle or an exchange through a [https://en.wikipedia.org/wiki/Ternary_complex#:~:text=A%20ternary%20complex%20can%20be,type%20of%20enzyme%2Dcatalyzed%20reactions ternary complex]<ref name="Shen" />. The electrons will be shuttled from complex to complex and then eventually be accepted by the SCD1 enzyme which will allow for activation of the catalytic molecule (Figure 5). The placement of SCD1 in the ER membrane is believed to prevent inhibition by allowing better flow of products/side products to their later pathways<ref name="Shen" />.

Absence or a deficit of SCD1 in the body is associated with obesity and insulin resistance which is a main cause of [https://en.wikipedia.org/wiki/Type_2_diabetes type 2 diabetes]<ref name="Shen" />. Cancer sites in the body tend to show a much higher expression rate of SCD1<ref name="Shen" />. Focusing on SCD1 as a drug target could lead to advancements in treatment of obesity, diabetes, and other metabolic diseases<ref name="Bai" />.

@@ Line 4: / Line 4: @@
 == Introduction ==
-[[Image:SCD1_rxn.png|500 px|right|thumb|Figure 1. Overall reaction completed by the SCD1 enzyme. It introduces a double bond between carbons 9 and 10 on the ligand Stearoyl CoA, converting it into Oleoyl CoA]]Stearyol CoA Desaturase (SCD1) functions as a lipogenic enzyme which is essential for fatty acid metabolism. SCD1 desaturates the sigma bond, within the 18-carbon acyl-CoA ligand, that attaches carbons 9 and 10<ref name="Bai">PMID: 26098370 </ref>.  The primary role of SCD1 is to catalyze the biosynthesis of monounsaturated fatty acids (MUFAs) via saturated [https://en.wikipedia.org/wiki/Acyl-CoA acyl-CoAs] with an acyl chain length of 14-19 carbons<ref name="Paton">PMID: 19066317 </ref><ref name="Shen">PMID: 32470559 </ref>. Variations of the monounsaturated fatty acids function as precursors for the biosynthesis of [https://en.wikipedia.org/wiki/Phospholipid phospholipids], [https://en.wikipedia.org/wiki/Cholesteryl_ester cholesteryl esters], and [https://en.wikipedia.org/wiki/Triglyceride triglycerides]; therefore, SCD1 is a promising candidate for drug targeting<ref name="Bai" />.
+[[Image:SCD1_rxn.png|500 px|right|thumb|Figure 1. Overall reaction completed by the SCD1 enzyme. It introduces a double bond between carbons 9 and 10 on the ligand Stearoyl CoA, converting it into Oleoyl CoA.]]Stearyol CoA Desaturase (SCD1) functions as a lipogenic enzyme which is essential for fatty acid metabolism. SCD1 desaturates the sigma bond, within the 18-carbon acyl-CoA ligand, that attaches carbons 9 and 10<ref name="Bai">PMID: 26098370 </ref>.  The primary role of SCD1 is to catalyze the biosynthesis of monounsaturated fatty acids (MUFAs) via saturated [https://en.wikipedia.org/wiki/Acyl-CoA acyl-CoAs] with an acyl chain length of 14-19 carbons<ref name="Paton">PMID: 19066317 </ref><ref name="Shen">PMID: 32470559 </ref>. Variations of the monounsaturated fatty acids function as precursors for the biosynthesis of [https://en.wikipedia.org/wiki/Phospholipid phospholipids], [https://en.wikipedia.org/wiki/Cholesteryl_ester cholesteryl esters], and [https://en.wikipedia.org/wiki/Triglyceride triglycerides]; therefore, SCD1 is a promising candidate for drug targeting<ref name="Bai" />.
@@ Line 62: / Line 62: @@
 == Proposed Mechanism ==
-[[Image:SCD1_New.jpeg|450 px|right|thumb|Figure 4: A proposed mechanism for SCD1 desaturase. The catalytic water molecule reacts with Fe2+ and O2 to create oxygen radicals on the iron ions. Electrons are brought in via an electron transport chain; this lowers the oxidation state of the iron ions and forms the reactive species. The first hydrogen is abstracted creating a radical intermediate that is then deprotonated again to make the final desaturated product. Electrons are transferred in again to allow for the iron ions to go back to their original oxidation state because enzymes must end a reaction in the same state, they started it. Figure was a modification of scheme 1 proposed by Yu M. and Chen S.5 ]]
+[[Image:SCD1_New.jpeg|450 px|right|thumb|Figure 4: A proposed mechanism for SCD1 desaturase. The catalytic water molecule reacts with Fe2+ and O2 to create oxygen radicals on the iron ions. Electrons are brought in via an electron transport chain; this lowers the oxidation state of the iron ions and forms the reactive species. The first hydrogen is abstracted creating a radical intermediate that is then deprotonated again to make the final desaturated product. Electrons are transferred in again to allow for the iron ions to go back to their original oxidation state because enzymes must end a reaction in the same state, they started it. Figure was a modification of scheme 1 proposed by Yu M. and Chen S.5.]]
 The mechanism used by the SCD1 enzyme is different than most desaturase enzymes because it does not use an oxo-bridge. This was confirmed based on the distance between the metal ions (~6.4Å) and the lack of electron density that should be present with two oxygens<ref name="Shen" />.  There have been multiple proposed mechanisms, but the mechanism shown below is a shortened version of the mechanism that is the most accurate<ref name="Yu" />.
@@ Line 88: / Line 88: @@
 == Biological Relevance ==
-[[Image:scd_in_membrane.jpeg|500 px|thumb|Figure 5. Position of SCD within the biological membrane.  It is part of an electron transport chain involving cytochrome b5 reductase (PDB: 5GV8) and cytochrome b5 (PDB: 3NER) to allow for the activation of the catalytic molecule coordinated by the two ions in the center of SCD]]The electron transport chain allows for the mechanism of SCD1 to be carried out by providing electrons via either a Cytochrome B5 electron shuttle or an exchange through a [https://en.wikipedia.org/wiki/Ternary_complex#:~:text=A%20ternary%20complex%20can%20be,type%20of%20enzyme%2Dcatalyzed%20reactions ternary complex]<ref name="Shen" />.  The electrons will be shuttled from complex to complex and then eventually be accepted by the SCD1 enzyme which will allow for activation of the catalytic molecule (Figure 5). The placement of SCD1 in the ER membrane is believed to prevent inhibition by allowing better flow of products/side products to their later pathways<ref name="Shen" />.
+[[Image:scd_in_membrane.jpeg|500 px|thumb|Figure 5. Position of SCD within the biological membrane.  The protein is part of an electron transport chain involving cytochrome b5 reductase (PDB: 5GV8) and cytochrome b5 (PDB: 3NER) to allow for the activation of the catalytic molecule coordinated by the two ions in the center of SCD.  SCD is colored according to the hydrophobicities of each helix, shown in figures 2 and 3.]]The electron transport chain allows for the mechanism of SCD1 to be carried out by providing electrons via either a Cytochrome B5 electron shuttle or an exchange through a [https://en.wikipedia.org/wiki/Ternary_complex#:~:text=A%20ternary%20complex%20can%20be,type%20of%20enzyme%2Dcatalyzed%20reactions ternary complex]<ref name="Shen" />.  The electrons will be shuttled from complex to complex and then eventually be accepted by the SCD1 enzyme which will allow for activation of the catalytic molecule (Figure 5). The placement of SCD1 in the ER membrane is believed to prevent inhibition by allowing better flow of products/side products to their later pathways<ref name="Shen" />.
 Absence or a deficit of SCD1 in the body is associated with obesity and insulin resistance which is a main cause of [https://en.wikipedia.org/wiki/Type_2_diabetes type 2 diabetes]<ref name="Shen" />. Cancer sites in the body tend to show a much higher expression rate of SCD1<ref name="Shen" />.  Focusing on SCD1 as a drug target could lead to advancements in treatment of obesity, diabetes, and other metabolic diseases<ref name="Bai" />.