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Desaturation of Fatty Stearoyl-CoA by SCD

1 Introduction
- 1.1 Overview
2 Structure
- 2.1 Binding Pocket
- 2.2 Metal Cations
3 Function
- 3.1 Desaturation Mechanism
- 3.2 Release of Product
4 Related Disease

Introduction

Overview

Stearoyl-CoA Desaturase (SCD) is an integral membrane protein located in the endoplasmic reticulum and is conserved across all eukaryotes ^[1]. SCD-1 is expressed in Mus musculus. The human homolog, SCD1, shares 85% sequence identity with all four SCD’s found in M. musculus (Scd1-Scd4). The expression of SCD is seen mainly in the liver and brain ^[2].

SCD is an enzyme which catalyzes desaturation of a double bond within a fatty acid hydrocarbon chain. The addition of a double bond is necessary for the biosynthesis of monounsaturated fatty acids such as: cholesterol, phospholipids, and triglycerides. The enzyme’s main function is lipid biosynthesis as well as regulating gene expression for lipogenesis ^[1]. SCD is regulated by transcription and its promoter has multiple binding sites for transcription factors that assist in regulation of lipogenesis ^[2]. It was discovered that when M. musculus were SCD-deficient, there was no obesity seen in the mice ^[1] This is why SCD is a popular target in treating metabolic diseases. Functioning SCD creates the balance between the accumulation and use of fats in the body.

SCD-1 is interacts with either of the two different substrates: stearoyl-CoA or palmitoyl-CoA. When SCD interacts with stearoyl-CoA and performs desaturation, the product is oleoyl-CoA and has the first cis-double bond introduced into the fatty acid chain. The introduction of the cis-double bond into the hydrocarbon chain will increase fluidity of the lipid bilayer. The process of desaturation is tightly regulated by multiple transcription factors.

The desaturase enzyme also works in combat with inhibitors. SCD is affected by hormones, growth factors, and nutritional status ^[2]. Leptin is a hormone that plays a role in regulation of energy homeostasis and is also able to stop SCD-1 expression by activating specific transcription factors to bind to SCD promoter and overpower the insulin signals ^[2]. Other negative regulators of SCD include estrogen and glucagon. Interestingly enough, SCD can also be inhibited by one’s nutritional status because of the production of polyunsaturated fatty acids (PUFAs).

Structure

Binding Pocket

Metal Cations

Function

Palmitoyl and Stearoyl CoA are substrates of SCD1. These substrates enter the hydrophobic V-shaped tunnel inside SCD1. The tunnel is regioselective and stereospecific such that the substrate’s binding site lines up C9 and C10 at the kink of the V-shaped tunnel with the di-iron center that consists of an oxygen molecule bound to one of the metals. The kink is formed by two conserved Trp149 and Thr257 residues. It is at this kink of the tunnel that desaturation occurs. Hydrogens are removed at the C9, then C10 to introduce the double bond through mechanism (link to mechanism section?). Precise placement of the C9-C10 atoms near the two iron metals provides the tunnel with regioselectivity and stereospecificity, stabilizing the substrate for oxygen to extract the hydrogens in order to form the double bond.

Desaturation Mechanism

Release of Product

Related Disease

References

↑ ^1.0 ^1.1 ^1.2 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
↑ ^2.0 ^2.1 ^2.2 ^2.3 Tracz-Gaszewska Z, Dobrzyn P. Stearoyl-CoA Desaturase 1 as a Therapeutic Target for the Treatment of Cancer. Cancers (Basel). 2019 Jul 5;11(7). pii: cancers11070948. doi:, 10.3390/cancers11070948. PMID:31284458 doi:http://dx.doi.org/10.3390/cancers11070948

Student Contributors

Brianna M. Avery
William J. Harris III
Emily M. Royston

Proteopedia Page Contributors and Editors (what is this?)

Brianna Avery

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

@@ Line 10: / Line 10: @@
 SCD is an enzyme which catalyzes desaturation of a double bond within a fatty acid hydrocarbon chain. The addition of a double bond is necessary for the biosynthesis of monounsaturated fatty acids such as: cholesterol, phospholipids, and triglycerides. The enzyme’s main function is lipid biosynthesis as well as regulating gene expression for lipogenesis <ref name="Bai" />. SCD is regulated by transcription and its promoter has multiple binding sites for transcription factors that assist in regulation of lipogenesis <ref name="Dobrzyn" />.  It was discovered that when M. musculus were SCD-deficient, there was no obesity seen in the mice <ref name="Bai" /> This is why SCD  is a popular target in treating metabolic diseases. Functioning SCD creates the balance between the accumulation and use of fats in the body.
-SCD-1 is interacts with either of the two different substrates: [https://pubchem.ncbi.nlm.nih.gov/compound/94140 stearoyl-CoA] or [https://pubchem.ncbi.nlm.nih.gov/compound/644109 palmitoyl-CoA]. Once the enzyme performs the desaturase mechanism, the product is oleoyl-CoA and has the first cis-double bond introduced into the fatty acid chain. The introduction of the cis-double bond into the hydrocarbon chain will increase fluidity of the lipid bilayer. The process of desaturation is tightly regulated by multiple transcription factors.
+SCD-1 is interacts with either of the two different substrates: [https://pubchem.ncbi.nlm.nih.gov/compound/94140 stearoyl-CoA] or [https://pubchem.ncbi.nlm.nih.gov/compound/644109 palmitoyl-CoA]. When SCD interacts with stearoyl-CoA and performs desaturation, the product is oleoyl-CoA and has the first cis-double bond introduced into the fatty acid chain. The introduction of the cis-double bond into the hydrocarbon chain will increase fluidity of the lipid bilayer. The process of desaturation is tightly regulated by multiple transcription factors.
 The desaturase enzyme also works in combat with inhibitors. SCD is affected by hormones, growth factors, and nutritional status <ref name="Dobrzyn" />. Leptin is a hormone that plays a role in regulation of energy homeostasis and is also able to stop SCD-1 expression by activating specific transcription factors to bind to SCD promoter and overpower the insulin signals <ref name="Dobrzyn" />. Other negative regulators of SCD include estrogen and glucagon. Interestingly enough, SCD can also be inhibited by one’s nutritional status because of the production of polyunsaturated fatty acids (PUFAs).