CDP-diacylglycerol synthase (CDS)

CDP-diacylglycerol synthase (CDS) is an essential integral membrane enzyme that catalyzes the formation of CDP-diacylglycerol (CDP-DAG) from phosphatidic acid (PA) and cytidine triphosphate (CTP) [4, 11]. This reaction represents the rate-limiting step in the biosynthesis of phosphatidylinositol (PI), a precursor for key signaling lipids such as PI(4,5)P2 and PI(3,4,5)P3 [1, 4]. In humans, two isoforms, CDS1 and CDS2, are primarily localized in the endoplasmic reticulum where they maintain the availability of phosphoinositides for signal transduction pathways, including the phospholipase C (PLC) and PI3K/Akt pathways [14, 15]. Beyond its role in signaling, CDP-DAG is also a precursor for cardiolipin synthesis in mitochondria, although this activity is largely mediated by the distinct enzyme TAMM41 [11, 12]. In the context of disease, CDS has emerged as a novel therapeutic target through the identification of a synthetic lethal vulnerability in cancer [5, 8]. Studies have shown that cancer cells with low expression of CDS1, such as uveal melanoma and certain mesenchymal-like tumors, become critically dependent on CDS2 for lipid homeostasis and survival [7, 10]. Targeted inhibition or ablation of CDS2 in these cells disrupts the phosphatidylinositol cycle, leads to the accumulation of toxic lipid droplets, and induces apoptosis [8, 10]. While no FDA-approved drugs currently target CDS, experimental small-molecule inhibitors and genetic targeting strategies are under investigation as potential treatments for cancers harboring specific genomic or transcriptional profiles of CDS isoforms [1, 5, 9].

Other names

Cytidine-5'-diphosphate-1,2-diacyl-sn-glycerol synthetasePhosphatidate cytidylyltransferaseCDP-diglyceride synthaseCDP-diacylglycerol synthetaseCTP:phosphatidate cytidylyltransferaseCDS1CDS2