Stearoyl-CoA desaturase (Δ-9-desaturase or SCD-1) is an endoplasmic reticulum enzyme that catalyzes the rate-limiting step in the formation of monounsaturated fatty acids (MUFAs), specifically oleate and palmitoleate from stearoyl-CoA and palmitoyl-CoA. Oleate and palmitoleate are major components of membrane phospholipids, cholesterol esters and alkyl-diacylglycerol. In humans, the enzyme is present in two isoforms, encoded respectively by the SCD1 and SCD5 genes. Stearoyl-CoA desaturase is a key enzyme in fatty acid metabolism. It is responsible for forming a double bond in stearoyl-CoA. This is how the monounsaturated fatty acid oleic acid is produced from the saturated fatty acid, stearic acid. A series of redox reactions, during which two electrons flow from NADH to flavoprotein cytochrome b5, then to the electron acceptor cytochrome b5 as well as molecular oxygen introduces a single double bond within a row of methylene fatty acyl-CoA substrates. The complexed enzyme adds a single double bond between the C9 and C10 of long-chain acyl-CoAs from de-novo synthesis. This enzyme belongs to the family of oxidoreductases, specifically those acting on paired donors, with O2 as oxidant and incorporation or reduction of oxygen. The oxygen incorporated need not be derived from O2 with oxidation of a pair of donors resulting in the reduction of O to two molecules of water. The systematic name of this enzyme class is stearoyl-CoA,ferrocytochrome-b5:oxygen oxidoreductase (9,10-dehydrogenating). This enzyme participates in polyunsaturated fatty acid biosynthesis and PPAR signaling pathway. It employs one cofactor, iron. It is found in animals and fungi.
Function
Stearoyl-CoA desaturase (SCD; EC 1.14.19.1) is an iron-containing enzyme that catalyzes a rate-limiting step in the synthesis of unsaturated fatty acids. The principal product of SCD is oleic acid, which is formed by desaturation of stearic acid. It catalyzes the chemical reaction
stearoyl-CoA + 2 ferrocytochrome b5 + O2 + 2 H+ ⇌ {\displaystyle \rightleftharpoons } oleoyl-CoA + 2 ferricytochrome b5 + 2 H2O The 4 substrates of this enzyme are stearoyl-CoA, ferrocytochrome b5, O2, and H+, whereas its 3 products are oleoyl-CoA, ferricytochrome b5, and H2O. Promiscuous reactions include:
Efficient conversion of vaccenyl-CoA into rumenyl-CoA in humans and rats.
Biochemical role The ratio of stearic acid to oleic acid has been implicated in the regulation of cell growth and differentiation through effects on cell membrane fluidity and signal transduction.
In mammals Four SCD paralogs, Scd1 through Scd4, have been identified in mouse. In contrast, only 2 SCD paralogs, SCD1 and SCD5 (MIM 608370, Uniprot Q86SK9), have been identified in human. SCD1 shares about 85% amino acid identity with all 4 mouse SCD isoforms, as well as with rat Scd1 and Scd2. In contrast, SCD5 (also known as hSCD2) shares limited homology with the rodent SCDs and appears to be unique to primates. SCD-1 is an important metabolic control point. Inhibition of its expression may enhance the treatment of a host of metabolic diseases. One of the unanswered questions is that SCD remains a highly regulated enzyme, even though oleate is readily available, as it is an abundant monounsaturated fatty acid in dietary fat.
Structure
The enzyme's structure is key to its function. SCD-1 consists of four transmembrane domains. Both the amino and carboxyl terminus and eight catalytically important histidine regions, which collectively bind iron within the catalytic center of the enzyme, lie in the cytosol region. The five cysteines in SCD-1 are located within the lumen of the endoplasmic reticulum. The yeast version (OLE1) exists as a dimer in vivo. The two human versions exist as dimers and oligomers in vitro. The substrate binding site is long, thin and hydrophobic and kinks the substrate tail at the location where the di-iron catalytic centre introduces the double bond. The literature suggests that the enzyme accomplishes the desaturation reaction by removing the first hydrogen at C9 position and then the second hydrogen from the C-10 position. Because the C-9 and C-10 are positioned close to the iron-containing center of the enzyme, this mechanism is hypothesized to be specific for the position at which the double bond is formed.
… excerpt ends here. Continue reading the full article.
