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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
- 4.1 Diabetes and Obesity
- 4.2 Cancer

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

Diabetes and Obesity

The deficiency and/or inhibition of SCD1 results in increased insulin sensitivity, reduced body obesity and resistance to diet-induced obesity. SCD1 is a target for treatment of obesity, diabetes, and other metabolic diseases ^[1].

Cancer

Increased expression levels of SCD1 has shown to enhance cancer cell proliferation. The concentration of monounsaturated fatty acids (MUFAs) is much higher in a cancer cell versus a healthy cell. When expression of SCD1 in breast cancer patients was examined, results proved that increased expression of SCD1 was associated with shorter survival ^[3].

Inhibition of SCD1 can stop cancer cell propagation both directly and indirectly ^[2]. The enzyme directly regulates signaling pathways, and indirectly interrupts the ratio of monounsaturated to saturated fatty acids. SCD1 is proving as a positive anticancer therapy, considering the difficulty many patients face when going through multiple rounds of chemotherapy. The reason cancer cells often are able to become resistant to chemotherapeutic drugs is because they possess stem cell-like phenotypes ^[2]. SCD1 inhibition has shown to repress tumor growth from cancer stem cells (CSC) and prevent any new proliferation of the CSC ^[4].

References

↑ ^1.0 ^1.1 ^1.2 ^1.3 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 ^2.4 ^2.5 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
↑ Holder AM, Gonzalez-Angulo AM, Chen H, Akcakanat A, Do KA, Fraser Symmans W, Pusztai L, Hortobagyi GN, Mills GB, Meric-Bernstam F. High stearoyl-CoA desaturase 1 expression is associated with shorter survival in breast cancer patients. Breast Cancer Res Treat. 2013 Jan;137(1):319-27. doi: 10.1007/s10549-012-2354-4. , Epub 2012 Dec 4. PMID:23208590 doi:http://dx.doi.org/10.1007/s10549-012-2354-4
↑ Li J, Condello S, Thomes-Pepin J, Ma X, Xia Y, Hurley TD, Matei D, Cheng JX. Lipid Desaturation Is a Metabolic Marker and Therapeutic Target of Ovarian Cancer Stem Cells. Cell Stem Cell. 2017 Mar 2;20(3):303-314.e5. doi: 10.1016/j.stem.2016.11.004., Epub 2016 Dec 29. PMID:28041894 doi:http://dx.doi.org/10.1016/j.stem.2016.11.004

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 5: / Line 5: @@
 ==Introduction==
-===Overview===
+====Overview====
 [https://en.wikipedia.org/wiki/Stearoyl-CoA_desaturase-1 Stearoyl-CoA Desaturase] (SCD) is an integral membrane protein located in the endoplasmic reticulum and is conserved across all eukaryotes <ref name="Bai">DOI: 10.1038/nature14549</ref>. 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 <ref name="Dobrzyn">PMID: 31284458</ref>.
@@ Line 18: / Line 18: @@
 <scene name='87/877504/Trp_thr_creation_of_kink/1'>Creation of C9-C10 Double Bond</scene>
-===Binding Pocket===
+====Binding Pocket====
-===Metal Cations===
+====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===
+====Desaturation Mechanism====
 <scene name='87/877504/Zn_h_bond_stabilization_2/7'>C9-C10 Double Bond</scene>
-===Release of Product===
+====Release of Product====
 ==Related Disease==
-===Diabetes and Obesity===
+====Diabetes and Obesity====
 The deficiency and/or inhibition of SCD1 results in increased insulin sensitivity, reduced body obesity and resistance to diet-induced obesity. SCD1 is a target for treatment of obesity, diabetes, and other metabolic diseases <ref name="Bai" />.
-===Cancer===
+====Cancer====
 Increased expression levels of SCD1 has shown to enhance cancer cell proliferation. The concentration of monounsaturated fatty acids (MUFAs) is much higher in a cancer cell versus a healthy cell. When expression of SCD1 in breast cancer patients was examined, results proved that increased expression of SCD1 was associated with shorter survival <ref name="Holder">PMID: 23208590</ref>.
-Inhibition of SCD1 can stop cancer cell propagation both directly and indirectly <ref name="Dobrzyn" />. The enzyme directly regulates signaling pathways, and indirectly interrupts the ratio of monounsaturated to saturated fatty acids. SCD1 is proving as a positive anticancer therapy, considering the difficulty many patients face when going through multiple rounds of chemotherapy.
+Inhibition of SCD1 can stop cancer cell propagation both directly and indirectly <ref name="Dobrzyn" />. The enzyme directly regulates signaling pathways, and indirectly interrupts the ratio of monounsaturated to saturated fatty acids. SCD1 is proving as a positive anticancer therapy, considering the difficulty many patients face when going through multiple rounds of chemotherapy. The reason cancer cells often are able to become resistant to chemotherapeutic drugs is because they possess stem cell-like phenotypes <ref name="Dobrzyn" />. SCD1 inhibition has shown to repress tumor growth from cancer stem cells (CSC) and prevent any new proliferation of the CSC <ref name="Li">PMID: 28041894</ref>.
-The reason cancer cells often are able to become resistant to chemotherapeutic drugs is because they posses stem cell-like phenotypes <ref name="Dobrzyn" />. SCD1 inhibition has shown to repress tumor growth from cancer stem cells (CSC) and prevent any new proliferation of the CSC <ref name="Li">PMID: 28041894</ref>.
 </StructureSection>