GK5

Glycerol kinase 5, tissue-specialized glycerol kinase enzyme predominantly expressed in skin sebaceous glands. Member of FGGY carbohydrate kinase family. Catalyzes ATP-dependent phosphorylation of glycerol to produce sn-glycerol-3-phosphate, the first step of glycerol utilization pathway. ~60 kDa protein with catalytic aspartate residues (Asp-280, Asp-443) essential for enzymatic activity. Cytosolic enzyme with distinct dual role: (1) Metabolic function - provides glycerol-3-phosphate for triglyceride synthesis in sebaceous glands; (2) Regulatory function - negatively regulates SREBP (sterol regulatory element-binding protein) processing and activation. Binds C-terminal regulatory domain of SREBP-1 and SREBP-2, inhibiting their cleavage and nuclear translocation, thereby limiting expression of lipid biosynthetic genes in skin. Skin-specific negative regulator of cholesterol and fatty acid synthesis - loss causes excessive lipid accumulation (cholesterol, triglycerides, ceramides) in sebaceous glands and pronounced alopecia in mice. GK5-deficient Gk5^toku mouse exhibits ~80% lethality due to hair growth defects, rescuable by simvastatin (HMG-CoA reductase inhibitor). Kinase activity essential for SREBP regulatory function - catalytically-dead mutants fail to suppress SREBP activation. Distinguishable from X-linked glycerol kinase (GK) which cannot compensate for GK5's regulatory role. Expression widespread at mRNA level but protein predominantly in skin; enriched in sebaceous glands. In cancer, GK5 upregulated in gefitinib-resistant NSCLC cells where it promotes cell survival through SREBP1/SCD1 pathway, conferring drug resistance. GK5 enables cancer cells to maintain lipogenesis and resist apoptosis under EGFR inhibition. Potential therapeutic target in oncology and dermatology.