Sphingolipid delta-4-desaturase (DEGS1)

Sphingolipid delta-4-desaturase, primarily represented by the DEGS1 isoform in humans, is a critical enzyme in the de novo sphingolipid biosynthetic pathway that catalyzes the final step of ceramide synthesis by introducing a trans-double bond at the C4-C5 position of dihydroceramide [1, 6]. This enzyme is predominantly localized to the endoplasmic reticulum and mitochondria-associated membranes (MAMs), where it plays a vital role in maintaining membrane integrity, mitochondrial dynamics, and lipid homeostasis [1, 18]. Mutations in the DEGS1 gene are associated with hypomyelinating leukodystrophy-18 (HLD18), a severe neurological disorder characterized by myelin deficiency and neurodegeneration [1, 6, 18]. Pharmacological modulation of DEGS1 is of significant therapeutic interest, as its inhibition leads to the accumulation of dihydroceramides and depletion of ceramides, which can influence cell survival, insulin sensitivity, and inflammatory responses [8, 11, 15]. Consequently, DEGS1 is being investigated as a potential target for treating various conditions, including cancer, type 2 diabetes, and cardiovascular diseases [6, 8, 11]. Several compounds, including curcumin, THC, and the drug tezacaftor, have been identified as inhibitors of this enzyme [7, 10].

Other names

Dihydroceramide desaturase 1DES1MLDDegs1Degs2Sphingolipid delta(4)-desaturaseCell migration-inducing gene 15 proteinDegenerative spermatocyte homolog 1

Inhibition of the conversion of dihydroceramide to ceramide, leading to dihydroceramide accumulation and ceramide depletion [6, 10, 18]