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Phosphatidylinositol (PtdIns) is a membrane phospholipid which can be phosphorylated at the 3, 4 and 5 positions of the inositol ring to generate seven phosphoinositides (PIs): PtdIns3P, PtdIns4P, PtdIns5P, PtdIns(3,4)P2, PtdIns(4,5)P2, PtdIns(3,5)P2 and PtdIns(3,4,5)P3 (Figure 1A). Phosphorylation and dephosphorylation by lipid kinases and phosphatases can rapidly interconvert PI species resulting in their dynamic production.
The phosphorylated head groups of PIs bind with variable affinity and specificity to various protein modules or to unique protein surfaces (Figure 1B). Specific membrane compartments are characterized by the presence of specific PI species, and PI binding often functions together with other membrane proteins, such as small GTPases of the Ras superfamily, to recruit cytosolic proteins to these compartments. In some instances, the interaction of the protein with the lipid regulates the activity of the protein, as occurs in the activation of 3-phosphoinositide-dependent protein kinase 1 (PDK1) by PtdIns(3,4,5)P3. Through these interactions, PIs play a major role in recruiting and regulating proteins at the membrane interface and so control a wide range of processes, including the assembly and activity of signaling scaffolds, actin and microtubule dynamics, membrane budding and fusion, and the transport of ions and metabolites across the membrane.
Figure 1. The phosphoinositide metabolic cycle and target proteins.
Given the importance of PI metabolism for cellular signaling and trafficking events, it is obvious that a number of intracellular bacterial pathogens modulate and exploit PIs to ensure survival and efficient intracellular replication. Pathogenic bacteria employ different strategies to interfere with the host PI metabolism, including the production of (i) PI-binding (effector) proteins that use PIs as a membrane anchor, (ii) PI-metabolizing enzymes that directly modulate the host cell PI levels, and (iii) lipid and protein factors that activate, inactivate or recruit host cell PI-metabolizing enzymes. Altering the PI levels on a pathogen vacuole might cause the organelle identity to change, a process called ‘identity theft’. Consequently, the pathogen-containing vacuole might mimic a nonendosomal compartment, or shed its early endosomal identity to avoid the acquisition of proteins or vesicles targeted to this organelle and, thereby prevent phagosome maturation along the ‘default’ bactericidal pathway.
It may be an exaggeration, but with some efforts, every human disease can be linked to altered inositol lipid metabolism. Although PIs are probably to be important in multifactorial diseases, it is easier to define the role of these lipids in disorders caused by a clearly identifiable single defect in inositol lipid metabolizing enzymes or effector proteins. Some of these are profoundly apparent, such as the combined immunodeficiency seen in Bruton’s tyrosine kinase patients, because of a single mutation within the PH domain of the Btk tyrosine kinase that prevents its interaction with PtdIns(3,4,5)P3. Others cause more subtle aberrations such as the activating mutations of PLCγ2 in patients with spontaneous inflammations, cold urticaria, and autoimmunity. A lot more human diseases are caused by excess PIs than the lack of them as exemplified by the cancer-causing elevations of PtdIns(3,4,5)P3. There is general agreement that PtdIns(3,4,5)P3 is an oncogenic lipid, and enormous information is available on how PtdIns(3,4,5)P3 can help tumor cells to survive and metastasize.
Progress in molecular biology techniques and the sequencing of the various genomes gave an enormous boost to these efforts and helped identify many of the inositide converting enzymes known today. Advances in genetics and positional cloning identified enzyme defects in inositide metabolism in several human diseases, and gene knockout and transgenic technologies allowed the creation of animal models for better understanding the physiological and pathological roles of these lipids and their selected metabolic enzymes. Creative Biogene is able to offer a variety of phosphoinositide metabolism related products including stable cell lines, viral particles and clones for your drug discovery projects.
Phosphoinositide Metabolism Product Panel
| ARF1 | MTMR14 | PIK3R1 | PIP5K1C | INPPL1 | OCRL |
| FIG4 | MTMR3 | PIK3R2 | PITPNB | PIP4K2A | PIP4K2B |
| INPP5E | MTMR4 | PIK3R3 | SYNJ1 | MTM1 | PI4K2A |
| INPP5J | MTMR6 | PIK3R6 | SYNJ2 | MTMR1 | PI4K2B |
| INPP5K | MTMR7 | PIKFYVE | VAC14 | PIP5K1A |
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