DEGS1

Official Full Name

delta 4-desaturase, sphingolipid 1

Organism

Homo sapiens

GeneID

8560

Background

This gene encodes a member of the membrane fatty acid desaturase family which is responsible for inserting double bonds into specific positions in fatty acids. This protein contains three His-containing consensus motifs that are characteristic of a group of membrane fatty acid desaturases. It is predicted to be a multiple membrane-spanning protein localized to the endoplasmic reticulum. Overexpression of this gene inhibited biosynthesis of the EGF receptor, suggesting a possible role of a fatty acid desaturase in regulating biosynthetic processing of the EGF receptor. [provided by RefSeq, Mar 2010]

Synonyms

MLD; DEGS; DES1; Des-1; FADS7; HLD18; MIG15; DEGS-1;

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Detailed Information

Sphingolipids play a critical role in human diseases ranging from neurodevelopmental disorders to cancer, and the enzyme dihydroceramide desaturase Δ4-dihydroceramide desaturase 1 (DEGS1) functions in the final step of the neoceramide biosynthesis, a link in the sphingolipid pathway. Defects in DEGS1 lead to the recently described myelodysplastic leukodystrophy-18 (HLD18).

Function of DEGS1

DEGS1 is a mitochondria-associated endoplasmic reticulum membrane-resident (MAM-resident) enzyme, completing previous reports that DEGS1 is located exclusively in the endoplasmic reticulum. 1 (dynamin-related protein 1) activation is reduced; (b) cholesterol metabolism, with impaired sterol O-acyltransferase activity and a reduction in cholesteryl esters; (c) phospholipid metabolism, with an increase in phosphatidic acid and phosphatidylserine and a decrease in phosphatidylethanolamine; and (d) lipid droplet biogenesis, with an increase in size and number of lipid droplets.

Impact on Sphingolipid Synthesis of DEGS1

The introduction of a double bond at the delta 4 position of the sphingolipid backbone by DEGS1 is a critical step in the synthesis of various sphingolipid species. Ceramides, for example, are synthesized from palmitoyl-CoA and sphingosine, and the desaturation reaction catalyzed by DEGS1 is necessary for the production of ceramides with a delta 4 double bond. Similarly, sphingomyelins are synthesized from ceramides, and the presence of a delta 4 double bond in the ceramide backbone is essential for the formation of sphingomyelins. Gangliosides, which are abundant in the brain and involved in cell signaling, are also synthesized from sphingolipids containing a delta 4 double bond. Therefore, DEGS1 plays a pivotal role in the production of these complex sphingolipids, which are crucial for cell function and membrane integrity.

Potential Impact of DEGS1 on Neurodegenerative Diseases

Neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease are associated with altered sphingolipid metabolism. For example, reduced ceramide levels have been observed in the brains of patients with Alzheimer's disease, suggesting that defects in ceramide synthesis may be part of the pathogenesis of this disease. Similarly, elevated levels of sphingolipids have been found in the brains of patients with Parkinson's disease, suggesting that altered sphingolipid metabolism may be involved in the pathogenesis of this disease. In addition, gangliosides have been implicated in the regulation of cell signaling pathways that are altered in various neurodegenerative diseases. Thus, DEGS1 may be a potential therapeutic target for the treatment of neurodegenerative diseases.

References:

Ternes P, Franke S, Zähringer U, Sperling P, Heinz E. Identification and characterization of a sphingolipid delta 4-desaturase family. J Biol Chem. 2002;277(28):25512-25518. doi:10.1074/jbc.M202947200
Blackburn NB, Michael LF, Meikle PJ, et al. Rare DEGS1 variant significantly alters de novo ceramide synthesis pathway. J Lipid Res. 2019;60(9):1630-1639. doi:10.1194/jlr.P094433

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