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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 In biochemistry and nutrition, a monounsaturated fat is a fat that contains a monounsaturated fatty acid (MUFA), a subclass of fatty acid characterized by having a double bond in the fatty acid chain with all of the remaining carbon atoms being s ...
(MUFAs), specifically
oleate Oleic acid is a fatty acid that occurs naturally in various animal and vegetable fats and oils. It is an odorless, colorless oil, although commercial samples may be yellowish due to the presence of impurities. In chemical terms, oleic acid is cla ...
and
palmitoleate Palmitoleic acid, or (9''Z'')-hexadec-9-enoic acid, is an omega-7 fatty acid, omega-7 monounsaturated fat, monounsaturated fatty acid (16:1n-7) with the formula CH3(CH2)5CH=CH(CH2)7COOH. It is a rare component of fats. It is a common constituent ...
from
stearoyl-CoA Stearoyl-CoA is a coenzyme involved in the metabolism of fatty acids. Stearoyl-CoA is an 18-carbon long fatty acyl-CoA chain that participates in an unsaturation reaction. The reaction is catalyzed by the enzyme stearoyl-CoA desaturase, which is ...
and
palmitoyl-CoA Palmitoyl-CoA is an acyl-CoA thioester. It is an "activated" form of palmitic acid and can be transported into the mitochondrial matrix by the carnitine shuttle system (which transports fatty acyl-CoA molecules into the mitochondria), and once in ...
. 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-1 is a key
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
in
fatty acid metabolism Fatty acid metabolism consists of various metabolic processes involving or closely related to fatty acids, a family of molecules classified within the lipid macronutrient category. These processes can mainly be divided into (1) catabolic processe ...
. It is responsible for forming a
double bond In chemistry, a double bond is a covalent bond between two atoms involving four bonding electrons as opposed to two in a single bond. Double bonds occur most commonly between two carbon atoms, for example in alkenes. Many double bonds exist betw ...
in
stearoyl-CoA Stearoyl-CoA is a coenzyme involved in the metabolism of fatty acids. Stearoyl-CoA is an 18-carbon long fatty acyl-CoA chain that participates in an unsaturation reaction. The reaction is catalyzed by the enzyme stearoyl-CoA desaturase, which is ...
. This is how the
monounsaturated fatty acid In biochemistry and nutrition, a monounsaturated fat is a fat that contains a monounsaturated fatty acid (MUFA), a subclass of fatty acid characterized by having a double bond in the fatty acid chain with all of the remaining carbon atoms being s ...
oleic acid Oleic acid is a fatty acid that occurs naturally in various animal and vegetable fats and oils. It is an odorless, colorless oil, although commercial samples may be yellowish due to the presence of impurities. In chemical terms, oleic acid is cl ...
is produced from the
saturated fatty acid In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...
,
stearic acid Stearic acid ( , ) is a saturated fatty acid with an 18-carbon chain. The IUPAC name is octadecanoic acid. It is a soft waxy solid with the formula . The triglyceride derived from three molecules of stearic acid is called stearin. Stearic acid ...
. A series of
redox Redox ( , , reduction–oxidation or oxidation–reduction) is a type of chemical reaction in which the oxidation states of the reactants change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is t ...
reactions, during which two electrons flow from
NADH Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an ade ...
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
oxidoreductase In biochemistry, an oxidoreductase is an enzyme that catalyzes the transfer of electrons from one molecule, the reductant, also called the electron donor, to another, the oxidant, also called the electron acceptor. This group of enzymes usually ut ...
s, 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 A systematic name is a name given in a systematic way to one unique group, organism, object or chemical substance, out of a specific population or collection. Systematic names are usually part of a nomenclature. A semisystematic name or semitrivi ...
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 Iron is a chemical element; it has symbol Fe () and atomic number 26. It is a metal that belongs to the first transition series and group 8 of the periodic table. It is, by mass, the most common element on Earth, forming much of Earth's o ...
.


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 acid In chemistry, in particular in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...
s. The principal product of SCD is
oleic acid Oleic acid is a fatty acid that occurs naturally in various animal and vegetable fats and oils. It is an odorless, colorless oil, although commercial samples may be yellowish due to the presence of impurities. In chemical terms, oleic acid is cl ...
, which is formed by desaturation of stearic acid. 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. Four SCD
isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...
s, Scd1 through Scd4, have been identified in mouse. In contrast, only 2 SCD isoforms, SCD1 and SCD5 (MIM 608370, Unipro
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. It
catalyzes Catalysis () is the increase in rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recycles quick ...
the
chemical reaction A chemical reaction is a process that leads to the chemistry, chemical transformation of one set of chemical substances to another. When chemical reactions occur, the atoms are rearranged and the reaction is accompanied by an Gibbs free energy, ...
:stearoyl-CoA + 2 ferrocytochrome b5 + O2 + 2 H+ \rightleftharpoons oleoyl-CoA + 2 ferricytochrome b5 + 2 H2O The 4 substrates of this enzyme are
stearoyl-CoA Stearoyl-CoA is a coenzyme involved in the metabolism of fatty acids. Stearoyl-CoA is an 18-carbon long fatty acyl-CoA chain that participates in an unsaturation reaction. The reaction is catalyzed by the enzyme stearoyl-CoA desaturase, which is ...
,
ferrocytochrome b5 Cytochromes ''b''5 are ubiquitous electron transport hemoproteins found in animals, plants, fungi and purple phototrophic bacteria. The microsomal and mitochondrial variants are membrane-bound, while bacterial and those from erythrocytes and ot ...
, O2, and H+, whereas its 3
products Product may refer to: Business * Product (business), an item that can be offered to a market to satisfy the desire or need of a customer. * Product (project management), a deliverable or set of deliverables that contribute to a business solution ...
are oleoyl-CoA, ferricytochrome b5, and H2O.


Structure

The enzyme's structure is key to its function. SCD-1 consists of four transmembrane domains. Both the
amino In chemistry, amines (, ) are organic compounds that contain carbon-nitrogen bonds. Amines are formed when one or more hydrogen atoms in ammonia are replaced by alkyl or aryl groups. The nitrogen atom in an amine possesses a lone pair of elec ...
and carboxyl terminus and eight catalytically important
histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...
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 endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...
. The substrate binding site is long, thin and
hydrophobic In chemistry, hydrophobicity is the chemical property of a molecule (called a hydrophobe) that is seemingly repelled from a mass of water. In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, thu ...
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.


Role in human disease

Monounsaturated fatty acids, the products of SCD-1 catalyzed reactions, can serve as
substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (aquatic environment), the earthy material that exi ...
s for the synthesis of various kinds of lipids, including phospholipids, triglycerides, and can also be used as mediators in
signal transduction Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a biochemical cascade, series of molecular events. Proteins responsible for detecting stimuli are generally termed receptor (biology), rece ...
and differentiation. Because MUFAs are heavily utilized in cellular processes, variation in SCD activity in mammals is expected to influence physiological variables, including
cellular differentiation Cellular differentiation is the process in which a stem cell changes from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellula ...
, insulin sensitivity, metabolic syndrome, atherosclerosis,
cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
, and
obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...
. SCD-1 deficiency results in reduced
adiposity Adipose tissue (also known as body fat or simply fat) is a loose connective tissue composed mostly of adipocytes. It also contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular endothelial cells and ...
, increased insulin sensitivity, and resistance to diet-induced obesity. Under non-fasting conditions, SCD-1 mRNA is highly expressed in
white adipose tissue White adipose tissue or white fat is one of the two types of adipose tissue found in mammals. The other kind is brown adipose tissue. White adipose tissue is composed of monolocular Adipocyte, adipocytes. In humans, the healthy body fat percent ...
,
brown adipose tissue Brown adipose tissue (BAT) or brown fat makes up the adipose organ together with white adipose tissue (or white fat). Brown adipose tissue is found in almost all mammals. Classification of brown fat refers to two distinct cell populations with si ...
, and the
Harderian gland The Harderian gland is a gland found within the eye's orbit that occurs in tetrapods (reptiles, amphibians, birds and mammals) that possess a nictitating membrane. The gland can be compound tubular or compound tubuloalveolar, and the fluid it ...
. SCD-1 expression is significantly increased in liver tissue and heart in response to a high-carbohydrate diet, whereas SCD-2 expression is observed in brain tissue and induced during the neonatal myelination. Diets high in high-saturated as well as monounsaturated-fat can also increase SCD-1 expression, although not to the extent of the lipogenic effect of a high-carb diet. Elevated expression levels of SCD1 is found to be correlated with obesity and tumor malignancy. It is believed that tumor cells obtain most part of their requirement for fatty acids by de novo synthesis. This phenomenon depends on increased expression of fatty acid biosynthetic enzymes that produce required fatty acids in large quantities. Mice that were fed a high-carbohydrate diet had an induced expression of the liver SCD-1 gene and other lipogenic genes through an insulin-mediated SREBP-1c-dependent mechanism. Activation of SREBP-1c results in upregulated synthesis of MUFAs and liver
triglyceride A triglyceride (from '' tri-'' and '' glyceride''; also TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids. Triglycerides are the main constituents of body fat in humans and other vertebrates ...
s. SCD-1 knockout mice did not increase de novo
lipogenesis In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into Adipose tissue, fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in adipose, fat. Lipogenesis encompasses both fatty aci ...
but created an abundance of cholesterol esters. SCD1 function has also been shown to be involved in germ cell determination, adipose tissue specification, liver cell differentiation and cardiac development. The human SCD-1 gene structure and regulation is very similar to that of mouse SCD-1. Overexpression of SCD-1 in humans may be involved in the development of
hypertriglyceridemia Hypertriglyceridemia is the presence of high amounts of triglycerides in the blood. Triglycerides are the most abundant fatty molecule in most organisms. Hypertriglyceridemia occurs in various physiologic conditions and in various diseases, and ...
,
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis, characterized by development of abnormalities called lesions in walls of arteries. This is a chronic inflammatory disease involving many different cell types and is driven by eleva ...
, and
diabetes Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...
. One study showed that SCD-1 activity was associated with inherited
hyperlipidemia Hyperlipidemia is abnormally high levels of any or all lipids (e.g. fats, triglycerides, cholesterol, phospholipids) or lipoproteins in the blood. citing: and The term ''hyperlipidemia'' refers to the laboratory finding itself and is also use ...
. SCD-1 deficiency has also been shown to reduce ceramide synthesis by downregulating serine palmitoyltransferase. This consequently increases the rate of
beta-oxidation In biochemistry and metabolism, beta oxidation (also β-oxidation) is the Catabolism, catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA. Acetyl ...
in skeletal muscle. In carbohydrate metabolism studies, knockout SCD-1 mice show increased
insulin sensitivity Insulin resistance (IR) is a pathological response in which cells in insulin-sensitive tissues in the body fail to respond normally to the hormone insulin or downregulate insulin receptors in response to hyperinsulinemia. Insulin is a hormone ...
. Oleate is a major constituent of membrane phospholipids and membrane fluidity is influenced by the ratio of saturated to monounsaturated fatty acids. One proposed mechanism is that an increase in cell membrane fluidity, consisting largely of lipid, activates the
insulin receptor The insulin receptor (IR) is a transmembrane receptor that is activated by insulin, IGF-I, IGF-II and belongs to the large class of receptor tyrosine kinase. Metabolically, the insulin receptor plays a key role in the regulation of glucose h ...
. A decrease in MUFA content of the membrane phospholipids in the SCD-1−/− mice is offset by an increase in polyunsaturated fatty acids, effectively increasing membrane fluidity due to the introduction of more double bonds in the fatty acyl chain.


See also

*
Cyclopropene acid Cyclopropane fatty acids (CPA) are a subgroup of fatty acids that contain a cyclopropane group. Although they are usually rare, the seed oil from lychee contains nearly 40% CPAs in the form of triglycerides. Biosynthesis CPAs are derived from un ...
*
Fatty acid desaturase Fatty acid desaturases (also called unsaturases) are a family of enzymes that convert saturated fatty acids into unsaturated fatty acids and polyunsaturated fatty acids. For the common fatty acids of the C18 variety, desaturases convert stearic ...
*
Fatty acid synthesis In biochemistry, fatty acid synthesis is the creation of fatty acids from acetyl-CoA and NADPH through the action of enzymes. Two ''De novo synthesis, de novo'' fatty acid syntheses can be distinguished: cytosolic fatty acid synthesis (FAS/FASI) ...


References


Bibliography

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Further reading

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External links

* {{Portal bar, Biology, border=no EC 1.14.19 Iron enzymes Enzymes of unknown structure