3.3 Lipid-modifying enzymes

The internal surface of the plasma membrane provides a useful environment for spreading signals received by surface receptors around the cell. Several specialist enzymes are activated by membrane-bound receptors, creating large numbers of small lipid-soluble second messenger molecules, which can diffuse easily through the membrane. These enzymes all use phosphatidylinositol (PI) and its derivatives as their substrates. PI itself is a derivative of glycerol: the OH group on carbon atom 1 has been replaced with an inositol ring linked via a phosphate group, and the OH groups on carbon atoms 2 and 3 have been replaced by two fatty acyl chains, one saturated and one unsaturated (Figure 30a).

Figure 30 The generation of second messengers from phosphatidylinositol (PI). (a) The structure of phosphatidylinositol (PI), which is the parent molecule for several key second messengers. Arrows indicate modifications by PLC and PI 3-kinase (denoted as PI 3K on figure). (b) PI (shown in green) can be phosphorylated on its inositol ring by lipid kinases including phosphatidylinositol kinase and phosphatidylinositol phosphate kinase (denoted as PIK and PIPK on figure). (c) Each of these intermediate products can be further phosphorylated by PI 3-kinase to produce the second messengers PI(3)P, PI(3,4)P₂ and PI(3,4,5)P₃ (shown in purple). It is the phosphorylation of the 3 position which is critical for the second messenger function, as will be seen later. (d) Alternatively, the intermediate product PI(4,5)P₂ can be cleaved by phospholipase C (PLC) at the position indicated by the blue arrow in part (a) to produce the second messengers diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP₃, blue). (Note that IP₃ is the only second messenger product of this system that does not remain membrane bound.)

The fatty acyl chains are embedded in the cytosolic leaflet of the plasma membrane, leaving the inositol ring projecting into the cytosol. Carbon atoms 3, 4 and 5 of the inositol ring can be phosphorylated by lipid kinases (Figure 30). The best-studied enzymes employing these substrates are the phospholipase C family, which cleave the fatty acyl chains from the inositol ring, and phosphatidylinositol 3-kinase (PI 3-kinase), which phosphorylates carbon atom 3 of the inositol ring. These products then serve as second messengers. We shall now briefly explain the action of these enzymes, and then go on to describe the roles of the second messengers they generate.