Stearoyl-CoA desaturase (Δ-9-desaturase) 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.[1] 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.[2][3][4]
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.[5] The complexed enzyme adds a single double bond between the C9 and C10 of long-chain
acyl-CoAs from de-novo synthesis.[1]
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.[citation needed] It employs one
cofactor,
iron.
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. 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.[citation needed]
Four SCD
isoforms, Scd1 through Scd4, have been identified in mouse. In contrast, only 2 SCD isoforms, 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.[2][6][7][8]
SCD-1 is an important metabolic control point. Inhibition of its expression may enhance the treatment of a host of
metabolic diseases.[9] 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.
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.[10]
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.[12] 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 and differentiation.[13] Because MUFAs are heavily utilized in cellular processes, variation in SCD activity in mammals is expected to influence physiological variables, including
cellular differentiation, insulin sensitivity, metabolic syndrome, atherosclerosis,
cancer, and
obesity. SCD-1 deficiency results in reduced
adiposity, increased insulin sensitivity, and resistance to diet-induced obesity.[14]
Under non-fasting conditions, SCD-1 mRNA is highly expressed in
white adipose tissue,
brown adipose tissue, and the
Harderian gland.[15] 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.[16] 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.[17]
Elevated expression levels of SCD1 is found to be correlated with obesity [18] and tumor malignancy.[19] 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.[20] 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
triglycerides. SCD-1 knockout mice did not increase de novo
lipogenesis but created an abundance of cholesterol esters.[21]
SCD1 function has also been shown to be involved in germ cell determination,[22] adipose tissue specification, liver cell differentiation[23] and cardiac development.[24]
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,
atherosclerosis, and
diabetes.[25] One study showed that SCD-1 activity was associated with inherited
hyperlipidemia. SCD-1 deficiency has also been shown to reduce ceramide synthesis by downregulating serine palmitoyltransferase. This consequently increases the rate of
beta-oxidation in skeletal muscle.[26]
In carbohydrate metabolism studies, knockout SCD-1 mice show increased
insulin sensitivity. Oleate is a major constituent of membrane phospholipids and membrane fluidity is influenced by the ratio of saturated to monounsaturated fatty acids.[27] One proposed mechanism is that an increase in cell membrane fluidity, consisting largely of lipid, activates the
insulin receptor. 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.[28]
^Wang J, Yu L, Schmidt RE, Su C, Huang X, Gould K, Cao G (Jul 2005). "Characterization of HSCD5, a novel human stearoyl-CoA desaturase unique to primates". Biochemical and Biophysical Research Communications. 332 (3): 735–42.
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^Wang H, Klein MG, Zou H, Lane W, Snell G, Levin I, Li K, Sang BC (22 June 2015). "Crystal structure of human stearoyl–coenzyme A desaturase in complex with substrate". Nature Structural & Molecular Biology. 22 (7): 581–585.
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^Miyazaki M, Ntambi JM (2003-02-01). "Role of stearoyl-coenzyme A desaturase in lipid metabolism". Prostaglandins, Leukotrienes, and Essential Fatty Acids. 68 (2): 113–121.
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^Hagen RM, Rodriguez-Cuenca S, Vidal-Puig A (2010-06-18). "An allostatic control of membrane lipid composition by SREBP1". FEBS Letters. Gothenburg Special Issue: Molecules of Life. 584 (12): 2689–2698.
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Oshino N, Imai Y, Sato R (1966). "Electron-transfer mechanism associated with fatty acid desaturation catalyzed by liver microsomes". Biochim. Biophys. Acta. 128 (1): 13–27.
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Oshino N, Imai Y, Sato R (January 1971). "A function of cytochrome b5 in fatty acid desaturation by rat liver microsomes". J. Biochem. 69 (1). Tokyo: 155–67.
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Choi Y, Park Y, Storkson JM, Pariza MW, Ntambi JM (Jun 2002). "Inhibition of stearoyl-CoA desaturase activity by the cis-9,trans-11 isomer and the trans-10,cis-12 isomer of conjugated linoleic acid in MDA-MB-231 and MCF-7 human breast cancer cells". Biochemical and Biophysical Research Communications. 294 (4): 785–90.
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Cohen P, Ntambi JM, Friedman JM (Dec 2003). "Stearoyl-CoA desaturase-1 and the metabolic syndrome". Current Drug Targets. Immune, Endocrine and Metabolic Disorders. 3 (4): 271–80.
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