A new pathway for synthesis of phosphatidylinositol-4,5-bisphosphate

• Published in: Nature (London) Vol. 390; no. 6656; pp. 192 - 196
• Main Authors: Rameh, Lucia E, Tolias, Kimberley F, Duckworth, Brian C, Cantley, Lewis C
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 13-11-1997
• Subjects: 3T3 Cells; Animals; Cellular biology; Enzymes; Mice; Phosphatidylinositol 4,5-Diphosphate - biosynthesis; Phosphatidylinositol Phosphates - metabolism; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; Phosphatidylinositols - metabolism; Phosphoric Monoester Hydrolases - chemistry; Phosphoric Monoester Hydrolases - metabolism; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor) - classification; Phosphotransferases (Alcohol Group Acceptor) - metabolism; Substrate Specificity
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/36621

Phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2), a key molecule in the phosphoinositide signalling pathway, was thought to be synthesized exclusively by phosphorylation of PtdIns-4-P at the D-5 position of the inositol ring. The enzymes that produce PtdIns-4,5-P2 in vitro fall into two related subfamilies (type I and type II PtdInsP-5-OH kinases, or PIP(5)Ks) based on their enzymatic properties and sequence similarities. Here we have reinvestigated the substrate specificities of these enzymes. As expected, the type I enzyme phosphorylates PtdIns-4-P at the D-5 position of the inositol ring. Surprisingly, the type II enzyme, which is abundant in some tissues, phosphorylates PtdIns-5-P at the D-4 position, and thus should be considered as a 4-OH kinase, or PIP(4)K. The earlier error in characterizing the activity of the type II enzyme is due to the presence of contaminating PtdIns-5-P in commercial preparations of PtdIns-4-P. Although PtdIns-5-P was previously thought not to exist in vivo, we find evidence for the presence of this lipid in mammalian fibroblasts, establishing a new pathway for PtdIns-4,5-P2 synthesis.