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Contents 1 Stearoyl-CoA Desaturase 1 from Mus musculus 1.1 Introduction 1.2 Function 1.3 Disease 1.4 Binding of Substrate 1.5 Active Site 1.6 Mechanism 1.7 Disease 1.8 References 1.9 Student Contributors

Stearoyl-CoA Desaturase 1 from Mus musculus

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.

Function

Disease

Alopecia

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 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 hydrophilic top groups that include R151, D152, and K185. The rest of the exterior of the substrate is attached via hydrophilic bottom 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 formormation 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 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: W149, T257, and Q143. 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 W258. 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 (ADD HERE). For the pictures below, the structure is shown with two zinc ions to show the water in coordination with the ions. Water is used in the mechanism, which is why we chose to use zinc for our page. The two zinc ions are 6.4 Angstroms apart. The ions sit above the kink in the active site. They are stabilized by the His box. The ion closest to C9 is 5.2 angstroms from it. This ion interacts with 4 histidines, H (list here) and one water molecule. The ion closest to C10 is 4.7 angstroms away from it. This ion interacts with 5 histidines, H (LIST HERE). These 9 total Histidine residues form a his box (ADD GREEN LINK). 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: E291, E161, D165, and N261

Mechanism

Disease

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References

^[1]

1. ↑ Ransey E, Paredes E, Dey SK, Das SR, Heroux A, Macbeth MR. Crystal structure of the Entamoeba histolytica RNA lariat debranching enzyme EhDbr1 reveals a catalytic Zn(2+) /Mn(2+) heterobinucleation. FEBS Lett. 2017 Jul;591(13):2003-2010. doi: 10.1002/1873-3468.12677. Epub 2017, Jun 14. PMID:28504306 doi:http://dx.doi.org/10.1002/1873-3468.12677

Student Contributors

• Abbey Wells
• Josey McKinley
• Anthony Durand