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Stearoyl-CoA desaturase (Δ-9-desaturase) is an endoplasmic reticulum enzyme that catalyzes the rate-limiting step in the formation of
monounsaturated fatty acids In nutrition, biology, and chemistry, fat usually means any ester of fatty acids, or a mixture of such compounds, most commonly those that occur in living beings or in food. The term often refers specifically to triglycerides (triple est ...
(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. In chemical terms, oleic acid is classified as a monounsaturated omega ...
and palmitoleate 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 insi ...
. Oleate and palmitoleate are major components of membrane phospholipids, cholesterol esters and alkyl-diacylglycerol. In humans, the enzyme is encoded by the SCD
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
. Stearoyl-CoA desaturase-1 is a key
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
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 processes ...
. 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 Monounsaturated fats are fatty acids that have one double bond in the fatty acid chain with all of the remainder carbon atoms being single-bonded. By contrast, polyunsaturated fats have more than one double bond. Molecular description Fatty aci ...
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. In chemical terms, oleic acid is classified as a monounsaturated omega ...
is produced from the
saturated fatty acid A saturated fat is a type of fat in which the fatty acid chains have all single bonds. A fat known as a glyceride is made of two kinds of smaller molecules: a short glycerol backbone and fatty acids that each contain a long linear or branched ch ...
stearic acid Stearic acid ( , ) is a saturated fatty acid with an 18-carbon chain. The IUPAC name is octadecanoic acid. It is a waxy solid and its chemical formula is C17H35CO2H. Its name comes from the Greek word στέαρ "''stéar''", which means tallow. ...
. A series of
redox Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate (chemistry), substrate change. Oxidation is the loss of Electron, electrons or an increase in the oxidation state, while reduction ...
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 aden ...
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 semitrivial ...
of this enzyme class is stearoyl-CoA,ferrocytochrome-b5:oxygen oxidoreductase (9,10-dehydrogenating). Other names in common use include Delta9-desaturase, acyl-CoA desaturase,
fatty acid desaturase A fatty acid desaturase is an enzyme that removes two hydrogen atoms from a fatty acid, creating a carbon/carbon double bond. These desaturases are classified as: * Delta - indicating that the double bond is created at a fixed position from the ...
, and stearoyl-CoA, hydrogen-donor:oxygen oxidoreductase. This enzyme participates in
polyunsaturated fatty acid biosynthesis In nutrition, biology, and chemistry, fat usually means any ester of fatty acids, or a mixture of such compounds, most commonly those that occur in living beings or in food. The term often refers specifically to triglycerides (triple e ...
and
ppar signaling pathway In the field of molecular biology, the peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the reg ...
. It employs one cofactor,
iron Iron () is a chemical element with symbol Fe (from la, ferrum) 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, right in f ...
.


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, particularly 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, f ...
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. In chemical terms, oleic acid is classified as a monounsaturated omega ...
, 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 or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...
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 Inborn errors of metabolism form a large class of genetic diseases involving congenital disorders of enzyme activities. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrat ...
. 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 process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
the
chemical reaction A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical transformation of one set of chemical substances to another. Classically, chemical reactions encompass changes that only involve the pos ...
: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 o ...
, O2, and H+, whereas its 3
products Product may refer to: Business * Product (business), an item that serves as a solution to a specific consumer problem. * Product (project management), a deliverable or set of deliverables that contribute to a business solution Mathematics * Produ ...
are oleoyl-CoA,
ferricytochrome 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 ...
, 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 compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent s ...
and
carboxyl terminus The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
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 α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the de ...
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, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...
. The substrate binding site is long, thin and
hydrophobic In chemistry, hydrophobicity is the physical property of a molecule that is seemingly repelled from a mass of water (known as a hydrophobe). In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to be nonpolar and, th ...
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 substrates 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 series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
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 alters 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 multicellular ...
, insulin sensitivity, metabolic syndrome, atherosclerosis,
cancer Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
, and
obesity Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's we ...
. SCD-1 deficiency results in reduced
adiposity Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular en ...
, 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 adipocytes. In humans, the healthy amount of white adipose ti ...
,
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 s ...
. 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 (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''tri-'' and ''glyceride''). Triglycerides are the main constituents of body fat in humans and other vertebrates, as w ...
s. SCD-1 knockout mice did not increase de novo
lipogenesis In biochemistry, lipogenesis is the conversion of fatty acids and glycerol into fats, or a metabolic process through which acetyl-CoA is converted to triglyceride for storage in fat. Lipogenesis encompasses both fatty acid and triglyceride syn ...
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 h ...
,
atherosclerosis Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...
, and
diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
. One study showed that SCD-1 activity was associated with inherited
hyperlipidemia Hyperlipidemia is abnormally elevated levels of any or all lipids (fats, cholesterol, or triglycerides) or lipoproteins in the blood. citing: and The term ''hyperlipidemia'' refers to the laboratory finding itself and is also used as an umbre ...
. 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 is the 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, which enters the citric acid cycle, ...
in skeletal muscle. In carbohydrate metabolism studies, knockout SCD-1 mice show increased
insulin sensitivity Insulin resistance (IR) is a pathological condition in which cells fail to respond normally to the hormone insulin. Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood glucose (blood suga ...
. 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 homeo ...
. 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 *
Fatty acid desaturase A fatty acid desaturase is an enzyme that removes two hydrogen atoms from a fatty acid, creating a carbon/carbon double bond. These desaturases are classified as: * Delta - indicating that the double bond is created at a fixed position from the ...
*
Fatty acid synthesis In biochemistry, fatty acid synthesis is the creation of fatty acids from acetyl-CoA and NADPH through the action of enzymes called fatty acid synthases. This process takes place in the cytoplasm of the cell. Most of the acetyl-CoA which is conve ...


References


Bibliography

* * * *


Further reading

* * * * * * * * * *


External links

* EC 1.14.19 Iron enzymes Enzymes of unknown structure {{1.14-enzyme-stub