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Stearoyl-CoA Desaturase 1 from Mus musculus

1 Introduction
2 Structure
3 Mechanism
4 Disease

Introduction

Stearoyl-CoA Desaturase is an enzyme essential for the biosynthesis of monosaturated fatty acids from saturated fatty acids ^[1]. SCD catalyzes the rate-limiting step in the conversion of Stearoyl-CoA to oleic acid, an essential substrate in the biosynthesis of phospholipids, triacyclglycerols, and cholesterol ^[2]. SCD is highly conserved in eukaryotes and has different gene isoforms. Mice have four isoforms: SCD1, SCD2, SCD3, and SCD4. Humans have two different isoforms: SCD1 and SCD5 ^[2]. The SCD isoform discussed in this page is Stearoyl-CoA Desaturase 1 (SCD1) found in mice. SCD is believed to have once been an anaerobic pathway found in cartilaginous fish about 450 million years ago ^[3]. The enzyme’s mechanism is now aerobic and favorable. The structure of SCD1 was found using X-ray crystallography ^[2].

Structure

Overall Structure

SCD1 is an integral membrane protein embedded within the endoplasmic reticulum and consists of 4 transmembrane alpha helices, arranged in a cone-like shape. The cytosolic domain of the enzyme consists of 11 alpha helices and contains the carboxy and amino termini ^[2]. Its substrate, Stearoyl-CoA, binds to the cytosolic region which contains a "kink" that properly orients Stearoyl-CoA to undergo a dehydrogenation reaction between the of Stearoyl-CoA ^[2].

Binding of Substrate

Stearoyl-CoA is the substrate that binds to the enzyme, SCD1. The binding of the substrate is stabilized by specific residues on the exterior and interior of the protein. Stearoyl-CoA is a long-chain fatty acyl-CoA. The head group of the substrate is composed of an adenine, ribose, phosphate groups, and polar atoms such as of nitrogen, oxygen, and sulfur. The head of stearoyl-CoA is attached to the exterior of the protein by polar residues. The adenine, ribose, and phosphate are attached by the residues . The remaining exterior of the substrate is attached by the residues ^[2]. All the conserved residues are attached to the Stearoyl-CoA via hydrogen bonds. The fatty acid tail of Stearoyl-CoA is a 17-carbon chain which reaches into the interior of the protein. The fatty acid chain dives into the interior hydrophobic tunnel which is long, narrow, and approximately 24 Angstroms long ^[2]. The geometry of the tunnel and formation of bound acyl chain are the structural basis for the stereospecificity of the desaturation reaction ^[2].

Kink of Substrate

The chain is kinked at where the double bond is generated. The kink is induced through the interactions of four conserved residues. Three out of four of these residues are not bound to the chain, but are hydrogen bonded to each other: . T257 is hydrogen bonded to Q143, and Q143 is hydrogen bonded to W149 ^[2]. These residues are directly below the kink and will be hydrolyzed when the enzymatic product is ready to be released. Specifically, if the hydrogen bond between T257 and Q143 is broken, a large opening would allow for the product to be released into the bilayer ^[2]. The residue that is directly hydrogen bonded to the chain is . This residue is highly conserved and stabilizes the chain so it will be in the correct orientation in the active site. The enzyme will be effective on acyl chains that are between 17 to 19 carbons long. The residue that has a role in determining substrate length is . Y104 is a capping residue that has approximately 4 Angstroms between its' hydroxyl oxygen and the end of the chain ^[2].

Active Site

Mechanism

Disease

References

^[2] ^[4] ^[3] ^[1]

↑ ^1.0 ^1.1 Paton CM, Ntambi JM. Biochemical and physiological function of stearoyl-CoA desaturase. Am J Physiol Endocrinol Metab. 2009 Jul;297(1):E28-37. doi:, 10.1152/ajpendo.90897.2008. Epub 2008 Dec 9. PMID:19066317 doi:http://dx.doi.org/10.1152/ajpendo.90897.2008
↑ ^2.00 ^2.01 ^2.02 ^2.03 ^2.04 ^2.05 ^2.06 ^2.07 ^2.08 ^2.09 ^2.10 ^2.11 Bai Y, McCoy JG, Levin EJ, Sobrado P, Rajashankar KR, Fox BG, Zhou M. X-ray structure of a mammalian stearoyl-CoA desaturase. Nature. 2015 Jun 22. doi: 10.1038/nature14549. PMID:26098370 doi:http://dx.doi.org/10.1038/nature14549
↑ ^3.0 ^3.1 Castro LF, Wilson JM, Goncalves O, Galante-Oliveira S, Rocha E, Cunha I. The evolutionary history of the stearoyl-CoA desaturase gene family in vertebrates. BMC Evol Biol. 2011 May 19;11:132. doi: 10.1186/1471-2148-11-132. PMID:21595943 doi:http://dx.doi.org/10.1186/1471-2148-11-132
↑ Shen J, Wu G, Tsai AL, Zhou M. Structure and Mechanism of a Unique Diiron Center in Mammalian Stearoyl-CoA Desaturase. J Mol Biol. 2020 May 27. pii: S0022-2836(20)30367-3. doi:, 10.1016/j.jmb.2020.05.017. PMID:32470559 doi:http://dx.doi.org/10.1016/j.jmb.2020.05.017

Student Contributors

Abbey Wells
Josey McKinley
Anthony Durand

Proteopedia Page Contributors and Editors (what is this?)

Abbey Wells

Retrieved from "http://52.214.119.220/wiki/index.php/User:Abbey_Wells/Sandbox_1"

@@ Line 2: / Line 2: @@
 <StructureSection load='6WF2' size='350' frame = 'true' side='right' caption='Structure of SCD1' scene='87/877606/Introduction-di-iron-image/1'>
-==Introduction==
+== Introduction ==
-SCD stands for Stearoyl-CoA Desaturase. This enzyme is highly conserved in eukaryotes and has different isoforms. Mice have four isoforms: SCD1, SCD2, SCD3, and SCD4. Humans have two different isoforms: SCD1 and SCD5. The SCD discussed in this page is the SCD-1 found in mice. SCD was thought to have once been an anaerobic pathway found in cartilaginous fish about 450 million years ago. The enzyme’s mechanism is now aerobic and this aerobic pathway is favored. The structure of SCD1 was found using X-ray crystallography. This enzyme is embedded in the membrane of the Endoplasmic Reticulum. SCD is made up of 15 alpha helices; four helices are embedded in the membrane and 11 helices in the cytosol. The substrate binds to the helices in the cytosol.
+Stearoyl-CoA Desaturase is an enzyme essential for the biosynthesis of monosaturated fatty acids from saturated fatty acids <ref name="Paton">doi: 10.1152/ajpendo.90897.2008</ref>. SCD catalyzes the rate-limiting step in the conversion of [http://en.wikipedia.org/wiki/Stearoyl-CoA Stearoyl-CoA] to [http://en.wikipedia.org/wiki/Oleic_acid oleic acid], an essential substrate in the biosynthesis of phospholipids, triacyclglycerols, and cholesterol <ref name="Bai">PMID:26098370</ref>. SCD is highly conserved in eukaryotes and has different gene isoforms. Mice have four isoforms: SCD1, SCD2, SCD3, and SCD4. Humans have two different isoforms: SCD1 and SCD5 <ref name="Bai">PMID:26098370</ref>. The SCD isoform discussed in this page is [http://en.wikipedia.org/wiki/Stearoyl-CoA_desaturase-1 Stearoyl-CoA Desaturase 1 (SCD1)] found in mice. SCD is believed to have once been an anaerobic pathway found in cartilaginous fish about 450 million years ago <ref name="Filipe">doi: 10.1186/1471-2148-11-132</ref>. The enzyme’s mechanism is now aerobic and favorable. The structure of SCD1 was found using X-ray crystallography <ref name="Bai">PMID:26098370</ref>.
+== Structure ==
+=== Overall Structure ===
+SCD1 is an integral membrane protein embedded within the [http://micro.magnet.fsu.edu/cells/endoplasmicreticulum/endoplasmicreticulum.html endoplasmic reticulum] and consists of 4 transmembrane alpha helices, arranged in a cone-like shape. The cytosolic domain of the enzyme consists of 11 alpha helices and contains the carboxy and amino termini <ref name="Bai">PMID:26098370</ref>. Its substrate, Stearoyl-CoA, binds to the cytosolic region which contains a "kink" that properly orients Stearoyl-CoA to undergo a [http://en.wikipedia.org/wiki/Dehydrogenation#:~:text=Dehydrogenation%20is%20the%20a%20chemical,reaction%20and%20a%20serious%20problem.&text=Enzymes%20that%20catalyze%20dehydrogenation%20are%20called%20dehydrogenases. dehydrogenation] reaction between the <scene name='87/877602/C9_and_c103'>carbon 9 and carbon 10</scene> of Stearoyl-CoA <ref name="Bai">PMID:26098370</ref>.
-[http://en.wikipedia.org/wiki/Stearoyl-CoA_desaturase-1 Stearoyl-CoA Desaturase 1 (SCD1)] is an iron-containing [http://en.wikipedia.org/wiki/Fatty_acid_desaturase Δ-9-desaturase]  that is a key regulator of fatty-acid metabolism where it catalyzes the rate-limiting step in the conversion of [http://en.wikipedia.org/wiki/Stearoyl-CoA Stearoyl-CoA] to [http://en.wikipedia.org/wiki/Oleic_acid oleic acid], an essential substrate in the biosynthesis of phospholipids, triacyclglycerols, and cholesterol. SCD1 is embedded within the membrane of the [http://micro.magnet.fsu.edu/cells/endoplasmicreticulum/endoplasmicreticulum.html endoplasmic reticulum] and consists of 4 transmembrane alpha helices and 11 cytosolic helices.
+=== Binding of Substrate ===
+[http://en.wikipedia.org/wiki/Stearoyl-CoA Stearoyl-CoA] is the substrate that binds to the enzyme, SCD1. The binding of the substrate is stabilized by specific residues on the exterior and interior of the protein. Stearoyl-CoA is a long-chain fatty [http://en.wikipedia.org/wiki/Acyl-CoA#:~:text=Acyl%2DCoA%20is%20a%20group,forming%20several%20equivalents%20of%20ATP. acyl-CoA]. The head group of the substrate is composed of an adenine, ribose, phosphate groups, and polar atoms such as of nitrogen, oxygen, and sulfur. The head of stearoyl-CoA is attached to the exterior of the protein by polar residues. The adenine, ribose, and phosphate  are attached by the residues <scene name='87/877602/Hydrophillic_top_t/4'>R151, D152, K185</scene>. The remaining exterior of the substrate is attached by the residues <scene name='87/877602/Hydrophillic_bottom_labeled_t/5'>N144, N71, R184</scene> <ref name="Bai">PMID:26098370</ref>. All the conserved residues are attached to the Stearoyl-CoA via hydrogen bonds. The fatty acid tail of Stearoyl-CoA is a 17-carbon chain which reaches into the interior of the protein.  The fatty acid chain dives into the interior hydrophobic tunnel which is long, narrow, and approximately 24 Angstroms long <ref name="Bai">PMID:26098370</ref>. The geometry of the tunnel and formation of bound acyl chain are the structural basis for the stereospecificity of the desaturation reaction <ref name="Bai">PMID:26098370</ref>.
+=== Kink of Substrate ===
+The chain is kinked at <scene name='87/877602/C9_and_c10/3'>carbon 9 and carbon 10</scene> where the double bond is generated. The kink is induced through the interactions of four conserved residues. Three out of four of these residues are not bound to the chain, but are hydrogen bonded to each other: <scene name='87/877602/Kink_build/4'>T257, Q143, W149</scene>. T257 is hydrogen bonded to Q143, and Q143 is hydrogen bonded to W149 <ref name="Bai">PMID:26098370</ref>. These residues are directly below the kink and will be hydrolyzed when the enzymatic product is ready to be released. Specifically, if the hydrogen bond between T257 and Q143 is broken, a large opening would allow for the product to be released into the bilayer <ref name="Bai">PMID:26098370</ref>. The residue that is directly hydrogen bonded to the chain is <scene name='87/877602/W258/4'>W258</scene>. This residue is highly conserved and stabilizes the chain so it will be in the correct orientation in the active site. The enzyme will be effective on acyl chains that are between 17 to 19 carbons long. The residue that has a role in determining substrate length is <scene name='87/877602/Cap/5'>Y104</scene>. Y104 is a capping residue that has approximately 4 [http://en.wikipedia.org/wiki/Angstrom Angstroms] between its' hydroxyl oxygen and the end of the chain <ref name="Bai">PMID:26098370</ref>.
-Its substrate, Stearoyl-CoA, binds to the cytosolic region which contains a "kink" that properly orients Stearoyl-CoA to undergo a [http://en.wikipedia.org/wiki/Dehydrogenation#:~:text=Dehydrogenation%20is%20the%20a%20chemical,reaction%20and%20a%20serious%20problem.&text=Enzymes%20that%20catalyze%20dehydrogenation%20are%20called%20dehydrogenases. dehydrogenation] reaction between the <scene name='87/877606/Ligand-highlighted/3'>9th and 10th carbons</scene> of Stearoyl-CoA. This reaction is catalyzed by <scene name='87/877606/Di-iron-ions/2'>two iron ions</scene> that reside within the catalytic center of SCD1 which are oriented by 8 essential histidine residues.
+=== Active Site ===
-Mechanistically, this reaction involves a molecular oxygen, water molecule, and the transport of electrons down an [http://en.wikipedia.org/wiki/Electron_transport_chain electron transport chain] consisting of cytochrome b5 reductase, cytochrome b5, and NADH to the irons ions within SCD1 which then through a series of redox reactions introduces a double bond between the 9th and 10th carbons of Stearoyl-CoA forming oleic acid.
-== Function ==
-== Binding of Substrate ==
-[[Image:SC.jpg|300px|thumb|right|]]
-Stearoyl-CoA is the substrate that binds to the enzyme, SCD1. The binding of the substrate is stabilized by specific residues on the exterior and interior of the protein. Stearoyl-CoA is a long-chain fatty acyl-CoA. The head group of the substrate is composed of an adenine, ribose, phosphate groups, and many atoms of Nitrogen, oxygen, and sulfur. The fatty acid tail is a 17-carbon chain which reaches into the interior of the protein. The head of stearoyl-CoA is attached to the exterior of the protein by polar residues. The adenine, ribose, and phosphate  are attached via <scene name='87/877602/Hydrophillic_top/2'>Hydrophilic Top</scene> groups that include R151, D152, and K185. The rest of the exterior of the substrate is attached via <scene name='87/877602/Hydrophillic_bottom_labeled/2'>Hydrophilic Bottom</scene> groups that include R184, N144, and N71. The fatty acid chain dives into the interior of the enzyme. The acyl chain is enclosed in a tunnel (24 ang) buried in the cytosolic domain. The geometry of the tunnel and formation of bound acyl chain are the structural basis for the stereospecificity of the desaturation reaction. The chain is kinked at carbon 9-carbon 10 where the double bond is generated. The <scene name='87/877602/Full_kink/2'>Kink</scene> is induced through the interactions of four conserved residues. Three out of four of these residues are not bound to the chain, but are hydrogen bonded to each other: <scene name='87/877602/Kink/2'>W149, T257, Q143</scene>. T257 is hydrogen bonded to Q143, and Q143 is hydrogen bonded to W149. These residues are directly below the kink and will be hydrolyzed when the substrate is ready to be released. The residue that is directly hydrogen bonded to the chain is <scene name='87/877602/Trp258/2'>Trp258</scene>. This residue is highly conserved and stabilizes the chain so it will be in the correct orientation in the active site.
-== Active Site ==
-Two structures of SCD known. One structure shows the substrate, water molecule, and zinc (4YMK). The second structure shows the product and iron (6WF2). For the pictures below, the structure is shown with two zinc ions in order to demonstrate how is <scene name='87/877627/Zn_and_water/1'>water</scene> coordination with the ions. Water is used in the mechanism, which is why we chose to use the structure with zinc to explain the active site.
-The two  <scene name='87/877627/Just_zn/1'>zinc</scene>ions are 6.4 Angstroms apart. The ions sit above the kink in the active site. They are stabilized by the  <scene name='87/877627/His_box2/1'>his box</scene>. The ion closest to C9 is 5.2 angstroms from it. This ion interacts with 4 histidines, H156, H265, H294, H298, and one water molecule. The ion closest to C10 is 4.7 angstroms away from it. This ion interacts with 5 histidines, H116, H121, H153, H157, and H297. These 9 total Histidine residues form a  <scene name='87/877627/His_box2/1'>his box</scene>.The his box is used to stabilize the ions into the active site, forming a prosthetic group. The his box is highly conserved among the other isoforms of SCD. Other residues around the his box are used to hydrogen bond to the histidines to stabilize them. These residues include:  <scene name='87/877627/E161/1'>E161,</scene>
- <scene name='87/877627/N261/1'>N261,</scene> <scene name='87/877627/D165/1'>D165,</scene> <scene name='87/877627/E291/1'>and E291</scene>
@@ Line 26: / Line 19: @@
 [[Image:SCDMech.jpg|300px|thumb|left|]]
 == Disease ==
 </StructureSection>
 == References ==
-<ref name="Ransey">PMID:28504306</ref>
+<ref name="Bai">PMID:26098370</ref>
+<ref name="Shen">PMID:32470559</ref>
+<ref name="Filipe">doi: 10.1186/1471-2148-11-132</ref>
+<ref name="Paton">doi: 10.1152/ajpendo.90897.2008</ref>
 <references/>
 == Student Contributors ==