Sphingolipid delta-4 desaturase DES1 (DEGS1) (DEGS1)

Sphingolipid delta-4 desaturase DES1 (DEGS1) is a membrane-bound enzyme that catalyzes the final step in the de novo biosynthesis of ceramide by introducing a trans-4,5 double bond into the sphingoid base of dihydroceramide (UniProt, 2024). It is primarily localized to the endoplasmic reticulum and mitochondria-associated membranes (MAMs), where it plays a critical role in maintaining lipid homeostasis and membrane integrity (NIH, 2023). Beyond its metabolic function, DEGS1 is involved in signaling pathways regulating cell proliferation, apoptosis, and autophagy (PubMed, 2024). Mutations in the DEGS1 gene are linked to hypomyelinating leukodystrophy-18, a severe neurological disorder characterized by impaired myelination (GeneCards, 2024). In the context of drug development, DEGS1 is a target for cancer therapy and metabolic diseases, as its inhibition leads to the accumulation of dihydroceramides, which can trigger cell death or improve insulin sensitivity (Guide to Pharmacology, 2024). Several small molecules, including fenretinide and opaganib, have been shown to inhibit DEGS1 activity, making it a significant focus for therapeutic intervention in oncology and metabolic health (PubMed, 2026).

Other names

Delta 4-desaturase, sphingolipid 1Dihydroceramide desaturase 1DES1Membrane lipid desaturase (MLD)DEGS-1FADS7Cell migration-inducing gene 15 proteinDegenerative spermatocyte homolog 1Retinol isomerase

DEGS1 inhibitors block the conversion of dihydroceramide to ceramide, leading to an increase in intracellular dihydroceramide levels and a decrease in ceramide levels. This shift in the sphingolipid profile can induce autophagy, cell cycle arrest, and apoptosis in cancer cells, and may also improve insulin sensitivity in metabolic disorders (PubMed, 2016; Guide to Pharmacology, 2024).