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Introduction

Stearoyl-CoA Desaturase 1 (SCD1) is an iron-containing Δ-9-desaturase that is a key regulator of fatty-acid metabolism where it 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. SCD1 is embedded within the membrane of the endoplasmic reticulum and consists of 4 transmembrane alpha helices and 11 cytosolic helices.

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. This reaction is catalyzed by two iron ions that reside within the catalytic center of SCD1 which are oriented by 8 essential histidine residues.

Mechanistically, this reaction involves a molecular oxygen, water molecule, and the transport of electrons down an 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.

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.

Binding of the 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 groups that include R151, D152, and K185. The rest of the exterior of the substrate is attached via 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 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. 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 . This residue is highly conserved and stabilizes the chain so it will be in the correct orientation in the active site.

Function

Disease

Relevance

Structural highlights