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Information on EC 1.14.19.17 - sphingolipid 4-desaturase and Organism(s) Mus musculus and UniProt Accession O09005
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1.14.19.17 sphingolipid 4-desaturaseIUBMB Comments
The enzyme, which has been characterized from plants, fungi, and mammals, generates a trans double bond at position 4 of sphinganine bases in sphingolipids . The preferred substrate is dihydroceramide, but the enzyme is also active with dihydroglucosylceramide . Unlike EC 1.14.19.29, sphingolipid 8-desaturase, this enzyme does not contain an integral cytochrome b5 domain and requires an external cytochrome b5 . The product serves as an important signalling molecules in mammals and is required for spermatide differentiation .
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The taxonomic range for the selected organisms is: Mus musculus
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
Synonyms
degs1, dihydroceramide desaturase, des-1, degs2, dihydroceramide desaturase 1, dihydroceramide delta4-desaturase, sphingolipid delta4-desaturase, dihydroceramide desaturase-1, delta4 desaturase, dihydroceramide delta4-desaturase 1, 
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topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
dehydroceramide desaturase
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-
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-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
a dihydroceramide + 2 ferrocytochrome b5 + O2 + 2 H+ = a (4E)-sphing-4-enine ceramide + 2 ferricytochrome b5 + 2 H2O
the desaturation reaction catalyzed by Des1 is presumably initiated by an enzyme-bound iron-oxo species that abstracts specifically the C-4 pro (R)-hydrogen atom from the substrate. FAD takes electrons from NADH and delivers them to ferrocytochrome b5 with bound Fe3+, which is converted to ferricytochrome b5 with Fe2+. Cytochrome b5-Fe2+ passes the electrons to another enzyme-bound Fe3+ to reduce O2 and form ceramide from dihydroceramide
SYSTEMATIC NAME
IUBMB Comments
dihydroceramide,ferrocytochrome b5:oxygen oxidoreductase (4,5-dehydrogenating)
The enzyme, which has been characterized from plants, fungi, and mammals, generates a trans double bond at position 4 of sphinganine bases in sphingolipids [1]. The preferred substrate is dihydroceramide, but the enzyme is also active with dihydroglucosylceramide [2]. Unlike EC 1.14.19.29, sphingolipid 8-desaturase, this enzyme does not contain an integral cytochrome b5 domain [4] and requires an external cytochrome b5 [3]. The product serves as an important signalling molecules in mammals and is required for spermatide differentiation [5].
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
a dihydroceramide + 2 ferrocytochrome b5 + O2 + 2 H+
a (4E)-sphing-4-enine ceramide + 2 ferricytochrome b5 + 2 H2O
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-
-
?
dihydroceramide + ferrocytochrome b5 + O2 + H+
(4E)-sphing-4-enine ceramide + ferricytochrome b5 + H2O
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-
-
?
additional information
?
-
the electron provided by NAD(P)H is sequentially transported from the cofactor to NADH-cytochrome b5 reductase, cytochrome b5, and the terminal desaturase, which reduces oxygen to water and oxidizes dihydroceramide to ceramide. Desaturation of the D-erythro-isomer by Des1 is much faster than that of the L or D-threo-isomers
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-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
a dihydroceramide + 2 ferrocytochrome b5 + O2 + 2 H+
a (4E)-sphing-4-enine ceramide + 2 ferricytochrome b5 + 2 H2O
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-
-
?
dihydroceramide + ferrocytochrome b5 + O2 + H+
(4E)-sphing-4-enine ceramide + ferricytochrome b5 + H2O
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-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
NAD(P)H
Des1 requires NADPH or NADH as electron donor and oxygen as electron acceptor
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Fe2+
required for the catalytic reaction, oscillates from Fe2+ to Fe3+, bound to the enzyme and to cofactor cytochrome b5
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
4-oxo-N-(4-hydroxyphenyl)retinamide
leads to an increase in C16 and C18 dihydroceramide substrate accumulation
celecoxib
i.e. 4-[5-(4-methylphenyl)-3-(trifluoromethyl)pyrazol-1-yl]benzenesulfonamide
DELTA9-tetrahydrocannabinol
i.e. (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6 H-benzo[c]chromen-1-ol or THC
additional information
no inhibition of the enzyme by N-[4-methoxyphenyl]retinamide and by non-retinoid RBP4 ligand A1120, RBP4 is a serum retinol-binding protein. The presence of fenretinide or 4-oxo-N-(4-hydroxyphenyl)retinamide leads to 2.7 and 3fold increases in ratio for C16 and C18 ceramides ratio respectively
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fenretinide
i.e. N-(4-hydroxyphenyl) retinamide or 4-HPR, a synthetic derivate of all-trans-retinoic acid, 4-HPR inhibition of Des1 might occur indirectly through increased oxidative species in vivo, but Des1 is a direct in vitro target for 4-HPR, which provokes an irreversible inhibition upon long incubation times. Inhibition mechanism, overview
fenretinide
i.e. N-(4-hydroxyphenyl)retinamide, a synthetic retinoid, leads to an increase in C16 and C18 dihydroceramide substrate accumulation
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
myristoylation of Des1 increases the enzyme activity and alters its subcellular localization, targeting the enzyme from the endoplasmic reticulum to the mitochondrial outer membrane
myristoylation of Des1 increases the enzyme activity and alters its subcellular localization, targeting the enzyme from the endoplasmic reticulum to the mitochondrial outer membrane
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
physiological function
malfunction
DEGS1 inhibition enhances insulin sensitivity, DEGS1 ablation induces autophagy and blocks cellular proliferation, and provides protection from chemotherapeutic agents through the activation of prosurvival pathways. Homozygous DEGS1 knockout mouse exhibits a severe phenotype characterised by low survival rate and multiple abnormalities. The heterozygous mice are viable with normal birth Mendelian rates, superficial biochemical phenotypical analysis reveals that mutant degs1 hets mice show higher DhCer/Cer ratios in multiple organs. This is associated with enhanced insulin sensitivity, normal glucose tolerance and resistance to dexamethasone induced insulin resistance. Embryonic fibroblasts from DEGS1knockout mice show enhanced AKT signalling, likely due to the absence of ceramides and not a result of the direct effect of dihydroceramide accumulation. DEGS1 heterozygotes gain more weight over time in comparison to wild-type mice
malfunction
homozygous DES1-null mice are viable, they fail to thrive and have numerous health abnormalities, dying within the first 8-weeks of age. In contrast, the heterozygous mice are viable with normal Mendelian birth rates. Lipid analysis reveal that DES1 heterozygous mice show higher dhCer/Cer ratios in multiple organs. Importantly, these mice are protected from glucocorticoid-, saturated fat- and obesity-induced insulin resistance, as well as from diet-induced hypertension. Cells from DES1 null mice are resistant to apoptosis, and, although they exhibit a remarkably strong activation of protein kinase B, they show high levels of autophagy. The latter results from activation of AMP-activated protein kinase. Therefore, ablation of DES1 simultaneously stimulates anabolic and catabolic signaling through activation of protein kinase B and AMP-activated protein kinase pathways, respectively. Activation of pro-survival and anabolic signaling intermediates provided protection from apoptosis caused by etoposide. Heterozygous deletion of DES1 prevented vascular dysfunction and hypertension in mice after high-fat feeding
metabolism
the enzyme catalyses the final step in the de novo biosynthesis of ceramides controlling the step from dihydroceramides to ceramides
metabolism
the enzyme catalyzes the oxidation of dhCer to ceramide (Cer) by dihydroceramide desaturase 1 (Des1), the last step of the de novo sphingolipids biosynthetic pathway. Ceramides, and, to a lesser extent, dihydroceramides are further metabolized to complex sphingolipids, such as (dihydro) sphingomyelins and (dihydro) glycosphingolipids by other enzymes
physiological function
DELTA4-desaturated sphingolipids provide an early signal necessary to trigger the entry into both meiotic and spermatid differentiation pathways during spermatogenesis
physiological function
dihydroceramide desaturase (Des1) is the last enzyme in the de novo synthesis of ceramides (Cer). It catalyzes the insertion of a double bond into dihydroceramides (dhCer) to convert them to Cer, both of which are further metabolized to more complex (dihydro) sphingolipids. Dihydroceramides are implicated in a wide spectrum of biological processes. Des1 is regulated by fatty acids, myristoylation of Des1 increases the enzyme activity and alters its subcellular localization, targeting the enzyme from the endoplasmic reticulum to the mitochondrial outer membrane, where it causes an increase in ceramide levels that in turn leads to apoptosis
physiological function
enzyme dihydroceramide desaturase 1 is the gatekeeper of ceramide induced lipotoxicity. The enzyme is dysregulated by factors such as oxidative stress, hypoxia and inflammation. Dihydroceramides constitute a biologically active molecule from the sphingolipid family with certain differential characteristics with respect to its delta-4 unsaturated counterparts, the ceramides. DEGS1 mediates the adaptation to chronic hypoxia and is involved in the induction of insulin resistance mediated by palmitate. Role of fatty acids as modulators of DEGS1 activity and ceramide synthesis. DEGS1 may have a part in fatty acid induced insulin resistance and apoptosis. Biological role of dihydroceramides, e.g. in apoptosis and autophagy, in the cell cycle, or as regulators of lipid homeostasis, detailed overview
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). DEGS1_MOUSE
323
6
38241
Swiss-Prot
other Location (Reliability: 3)
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
lipoprotein
myristoylation of Des1 increases the enzyme activity and alters its subcellular localization, targeting the enzyme from the endoplasmic reticulum to the mitochondrial outer membrane, where it causes an increase in ceramide levels that in turn leads to apoptosis
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
palmitate induces the expression of DEGS1 leading to an associated increase in ceramide levels. Increased levels of palmitate may enhance the synthesis of ceramides by increasing the flux of palmitate substrate and expression rates of DEGS1. Monounsaturated fatty acids, including oleate, are able to attenuate the induction elicited by palmitate and prevent ceramide production
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Ternes, P.; Franke, S.; Zaehringer, U.; Sperling, P.; Heinz, E.
Identification and characterization of a sphingolipid delta 4-desaturase family
J. Biol. Chem.
277
25512-25518
2002
Caenorhabditis elegans (G5EC63), Mus musculus (O09005), Mus musculus, Homo sapiens (O15121), Homo sapiens, Candida albicans (Q5AJX2), Candida albicans, Drosophila melanogaster (Q94515), Drosophila melanogaster
Rodriguez-Cuenca, S.; Barbarroja, N.; Vidal-Puig, A.
Dihydroceramide desaturase 1, the gatekeeper of ceramide induced lipotoxicity
Biochim. Biophys. Acta
1851
40-50
2015
Chlorocebus aethiops, Mus musculus (O09005), Homo sapiens (O15121), Drosophila melanogaster (Q94515)
Casasampere, M.; Ordonez, Y.F.; Pou, A.; Casas, J.
Inhibitors of dihydroceramide desaturase 1 Therapeutic agents and pharmacological tools to decipher the role of dihydroceramides in cell biology
Chem. Phys. Lipids
197
33-44
2016
Drosophila melanogaster, Drosophila melanogaster (Q94515), Mus musculus (O09005), Homo sapiens (O15121), Rattus norvegicus (Q5XIF5)
Poliakov, E.; Samuel, W.; Duncan, T.; Gutierrez, D.B.; Mata, N.L.; Redmond, T.M.
Inhibitory effects of fenretinide metabolites N-[4-methoxyphenyl]retinamide (MPR) and 4-oxo-N-(4-hydroxyphenyl)retinamide (3-keto-HPR) on fenretinide molecular targets beta-carotene oxygenase 1, stearoyl-CoA desaturase 1 and dihydroceramide DELTA4-desaturase 1
PLoS ONE
12
e0176487
2017
Mus musculus (O09005), Homo sapiens (O15121), Mus musculus C57BL/6 (O09005)
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