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Phosphatidylinositol

Phosphatidylinositol or inositol phospholipid is a biomolecule. It was initially called "inosite" when it was discovered by Léon Maquenne and Johann Joseph von Scherer in the late 19th century. It was discovered in bacteria but later also found in eukaryotes, and was found to be a signaling molecule.

Phosphatidylinositol

Depicting the Phosphatidylinisitol molecule with an overview of different segregated components; Inositol, Phosphate, Glycerol-backbone, sn-1 acyl chain, sn-2 acyl chain. Made by Mathias Sollie Sandsdalen in BioRender.com, modified from N.J. Blunsom and S. Cockcroft.[1]
Names
IUPAC name
[(2R)-3-[hydroxy-[(5R)-2,3,4,5,6-pentahydroxycyclohexyl]oxyphosphoryl]oxy-2-octadecanoyloxypropyl] (8Z,11Z,14Z,17Z)-icosa-8,11,14,17-tetraenoate
Other names
  • PI
  • PtdIns
Identifiers
ChEBI
DrugBank
Properties
C47H83O13P
Molar mass 887,104 g/mol, neutral with fatty acid composition - 18:0, 20:4
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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The biomolecule can exist in 9 different isomers. It is a lipid which contains a phosphate group, two fatty acid chains, and one inositol sugar molecule. Typically, the phosphate group has a negative charge (at physiological pH values). As a result, the molecule is amphiphilic.

The production of the molecule is limited to the endoplasmic reticulum.

History of phospatidylinositol

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Phosphatidylinositol (PI) and its derivatives have a rich history dating back to their discovery by Johann Joseph von Scherer[2] and Léon Maquenne[3][4][5] in the late 19th century. Initially known as "inosite" based on its sweet taste, the isolation and characterization of inositol laid the groundwork for understanding its cyclohexanol structure. Théodore Posternak's work further elucidated the configuration of myo-inositol,[6][7][8] the principal form found in eukaryotic tissues. The study of inositol isomers and their physiological functions has revealed a complex interplay in various organisms.

The esterified presence of inositol in lipids, particularly PI, was first observed in bacteria and later confirmed in eukaryotic organisms by researchers like Clinton Ballou[9][10] and Dan Brown.[11] Their pioneering work established the structure of PI and its phosphorylated forms, shedding light on their roles as signaling molecules. Despite the complexity of inositol nomenclature and isomerism, modern research has greatly advanced the understanding of their diverse functions in cellular physiology and signaling pathways.

The discovery of PI and its derivatives, along with their intricate roles in cellular signaling, marks a significant chapter in the field of biochemistry. From early investigations into inositol's structure to the identification of its various isomers and their physiological functions, the study of inositol compounds continues to uncover new insights into cellular processes. [12]

Structure and chemistry

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Phosphatidylinositol (PI), also known as inositol phospholipid, is a lipid composed of a phosphate group, two fatty acid chains, and one inositol molecule. It belongs to the class of phosphatidylglycerides and is typically found as a minor component on the cytosolic side of eukaryotic cell membranes. The phosphate group imparts a negative charge to the molecules at physiological pH.[13]

PI can exist in nine different forms, myo-, scyllo-, muco-, epi-, neo-, allo-, D-chiro-, L-chiro-, and cis-inositol. These isomers are common in biology and have many functions, for example taste sensory, regulating phosphate levels, metabolic flux, transcription, mRNA export and translation, insulin signaling, embryonic development and stress response. Cis-inositol is the only isomer not found naturally in nature.[14]

PI exhibits an amphiphilic nature, with both polar and non-polar regions, due to its glycerophospholipid structure containing a glycerol backbone, two non-polar fatty acid tails, and a phosphate group substituted with an inositol polar head group.[15]

Phosphoinositides

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Phosphorylated forms of phosphatidylinositol (PI) are called phosphoinositides and play important roles in lipid signaling, cell signaling and membrane trafficking. The inositol ring can be phosphorylated by a variety of kinases on the three, four and five hydroxyl groups in seven different combinations. However, the two and six hydroxyl groups are typically not phosphorylated due to steric hindrance.[16]

All seven variations of the following phosphoinositides have been found in animals:

Phosphatidylinositol monophosphates:

Phosphatidylinositol bisphosphates:

Phosphatidylinositol trisphosphate:

These phosphoinositides are also found in plant cells, with the exception of PIP3.[17][18][19]

Hydrolysis

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The significance of phosphatidylinositol (PI) metabolism lies in its role as a potential transducing mechanism, evident from studies showing hormone and neurotransmitter-induced hydrolysis of PI. The hydrolysis starts with the enzyme PI 4-kinase alpha (PI4Kα) converting PI into PI 4-phosphate (PI4P), which is then converted into PI (4,5) biphosphate (PI(4,5)P2) by the enzyme PI 4-phosphate-5-kinase (PI4P5K). PI(4,5)P2 is then hydrolysed by phospholipase C (PLC) and forms the second messengers, inositol (1,4,5) triphosphate (IP3) and diacylglycerol (DG). DG is then phosphyrylated to phosphatidic acid (PA) by DG kinase (DGK). PA is also directly produced from phosphatidylcholine (PC) by phospholipase D (PLD). Lipid transfer proteins facilitate the exchange of PI and PA between membranes, ensuring its availability for receptor mechanisms on the plasma membrane, even in organelles like mitochondria incapable of PI synthesis.[20][21][22]

 
Depicting the process of hydrolysis and biosynthesis at the plasma membrane and Endoplasmic Reticulum (ER). Describing the cycle of PI, with respective enzymatic processes and reactions. Made by Mathias Sollie Sandsdalen in BioRender.com, modified from N.J. Blunsom and S. Cockcroft.[20]

Biosynthesis

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The synthesis of Phosphatidylinositol (PI) is limited to the Endoplasmatic Reticulum (ER), which is the largest membrane component of the cell.[23] This site also contributes the synthesis to the majority of phospholipids, namely phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS) and triacylglycerol (TG).[24] The synthesis involves a series of enzymatic reactions.

The biosynthesis and phosphorylation of PI is mainly confined to the cytosolic facing surface of organelles by already residential kinases, but not at the ER spesifically. De novo PI synthesis of PI starts with an acylated process of Glyceraldehyde-3-phosphate (G-3-P) by GPAT enzymes at the sn-1 acyl chain position.[25] The process is then followed by a second acylation with LPAAT1, LPAAT2 and LPAAT3, LPAAT enzymes, at the sn-2 acyl chain position.[26] This double step process acylates G-3-P to phosphatidic acid (PA).

PA is converted into the intermediate CDP- diacylglycerol (CDP-DG) by a process called CDP-diaglycerol synthase. This synthesis is catalyzed by the use of CDS1 and CDS2, CDS- enzymes. In the final enzymatic process, CDP-DG and inositol are catalyzed by the enzyme PI synthase (PIS) and synthesised into PI.[27][28]

References

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  1. ^ Blunsom, Nicholas J.; Cockcroft, Shamshad (2020). "Phosphatidylinositol synthesis at the endoplasmic reticulum". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1865 (1). doi:10.1016/j.bbalip.2019.05.015. PMID 31173893. S2CID 182948709.
  2. ^ Scherer, Johann J. (1850). "Uber eine neue aus dem Muskelfleisch gewonnene Zuckerart". Liebigs Ann. Chem. 73 (3): 322. doi:10.1002/jlac.18500730303.
  3. ^ Maquenne, Léon (1887). "Préparation, proprietés et constitution se l'inosite". Comptes rendus hebdomadaires des séances de l'Académie des Sciences. 104: 225-227.
  4. ^ Maquenne, Léon (1887). "Sur les propriétés de l'inosite". Comptes rendus hebdomadaires des séances de l'Académie des Sciences. 104: 297-299.
  5. ^ Maquenne, Léon (1887). "Sur quelques dérivés de l'inosite". Comptes rendus hebdomadaires des séances de l'Académie des Sciences. 104: 1719-1722.
  6. ^ Posternak, Théodore (1942). "Recherches dans la série des cyclites VI. Sut la configuration de la méso-inosite, de la scyllite et d'un inosose obtenu par voie biochimique (scyllo-ms-inosose)". Helv. Chim. Acta. 25 (4): 746-752. doi:10.1002/hlca.19420250410.
  7. ^ Dangschat, Gerda (1942). "Acetonierung und Konfiguration des Meso-inosits". Die Naturwissenschaften (in German). 30 (9–10): 146–147. Bibcode:1942NW.....30..146D. doi:10.1007/BF01475387. ISSN 0028-1042. S2CID 38695213.
  8. ^ Falkenburger, Björn H.; Jensen, Jill B.; Dickson, Eamonn J.; Suh, Byung-Chang; Hille, Bertil (2010). "SYMPOSIUM REVIEW: Phosphoinositides: lipid regulators of membrane proteins: Phosphoinositides instruct membrane proteins". The Journal of Physiology. 588 (17): 3179–3185. doi:10.1113/jphysiol.2010.192153. PMC 2976013. PMID 20519312.
  9. ^ Pizer, Frances Lane; Ballou, Clinton E. (1959). "Studies on myo-Inositol Phosphates of Natural Origin". Journal of the American Chemical Society. 81 (4): 915–921. doi:10.1021/ja01513a040. ISSN 0002-7863.
  10. ^ Ballou, Clinton E.; Pizer, Lewis I. (1959). "SYNTHESIS OF AN OPTICALLY ACTIVE myo-INOSITOL 1-PHOSPHATE". Journal of the American Chemical Society. 81 (17): 4745. doi:10.1021/ja01526a074. ISSN 0002-7863.
  11. ^ Brown, D. M.; Clark, B. F. C.; Letters, R. (1961). "732. Phospholipids. Part VII. The structure of a monophosphoinositide". Journal of the Chemical Society (Resumed): 3774–3779. doi:10.1039/jr9610003774. ISSN 0368-1769.
  12. ^ Irvine, Robin F. (2016). "A short history of inositol lipids". Journal of Lipid Research. 57 (11): 1987–1994. doi:10.1194/jlr.R071712. PMC 5087877. PMID 27623846.
  13. ^ Kooijman, Edgar E.; King, Katrice E.; Gangoda, Mahinda; Gericke, Arne (2009-10-13). "Ionization Properties of Phosphatidylinositol Polyphosphates in Mixed Model Membranes". Biochemistry. 48 (40): 9360–9371. doi:10.1021/bi9008616. ISSN 0006-2960. PMID 19725516.
  14. ^ Thomas, Mark P.; Mills, Stephen J.; Potter, Barry V. L. (2016-01-26). "The "Other" Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances in myo -Inositol Chemistry)". Angewandte Chemie International Edition. 55 (5): 1614–1650. doi:10.1002/anie.201502227. ISSN 1433-7851. PMC 5156312. PMID 26694856.
  15. ^ Hoener, Marius C.; Brodbeck, Urs (1992). "Phosphatidylinositol-glycan-specific phospholipase D is an amphiphilic glycoprotein that in serum is associated with high-density lipoproteins". European Journal of Biochemistry. 206 (3): 747–757. doi:10.1111/j.1432-1033.1992.tb16981.x. ISSN 0014-2956. PMID 1606959.
  16. ^ Falkenburger, Björn H.; Jensen, Jill B.; Dickson, Eamonn J.; Suh, Byung-Chang; Hille, Bertil (2010-09-01). "SYMPOSIUM REVIEW: Phosphoinositides: lipid regulators of membrane proteins: Phosphoinositides instruct membrane proteins". The Journal of Physiology. 588 (17): 3179–3185. doi:10.1113/jphysiol.2010.192153. PMC 2976013. PMID 20519312.
  17. ^ Muller-Roeber B, Pical C (2002). Inositol Phospholipid Metabolism in Arabidopsis. Characterized and Putative Isoforms of Inositol Phospholipid Kinase and Phosphoinositide-Specific Phospholipase C.
  18. ^ Falkenburger, Björn H.; Jensen, Jill B.; Dickson, Eamonn J.; Suh, Byung-Chang; Hille, Bertil (2010-09-01). "SYMPOSIUM REVIEW: Phosphoinositides: lipid regulators of membrane proteins: Phosphoinositides instruct membrane proteins". The Journal of Physiology. 588 (17): 3179–3185. doi:10.1113/jphysiol.2010.192153. PMC 2976013. PMID 20519312.
  19. ^ Tabaei, Seyed R.; Guo, Feng; Rutaganira, Florentine U.; Vafaei, Setareh; Choong, Ingrid; Shokat, Kevan M.; Glenn, Jeffrey S.; Cho, Nam-Joon (2016-05-17). "Multistep Compositional Remodeling of Supported Lipid Membranes by Interfacially Active Phosphatidylinositol Kinases". Analytical Chemistry. 88 (10): 5042–5045. doi:10.1021/acs.analchem.6b01293. ISSN 0003-2700. PMC 5291064. PMID 27118725.
  20. ^ a b Blunsom, Nicholas J.; Cockcroft, Shamshad (2020). "Phosphatidylinositol synthesis at the endoplasmic reticulum". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1865 (1): 158471. doi:10.1016/j.bbalip.2019.05.015. PMID 31173893. S2CID 182948709.
  21. ^ Berridge, Michael J. (1981). "Phosphatidyldmositol hydrolysis: A multifunctional transducing mechanism". Molecular and Cellular Endocrinology. 24 (2): 115–140. doi:10.1016/0303-7207(81)90055-1. PMID 6117490. S2CID 27566538.
  22. ^ Ivanova, Adelina; Atakpa-Adaji, Peace (2023). "Phosphatidylinositol 4,5-bisphosphate and calcium at ER-PM junctions — Complex interplay of simple messengers". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1870 (6): 119475. doi:10.1016/j.bbamcr.2023.119475. PMID 37098393.
  23. ^ Schink, Kay O.; Tan, Kia-Wee; Stenmark, Harald (2016). "Phosphoinositides in Control of Membrane Dynamics". Annual Review of Cell and Developmental Biology. 32 (1): 143–171. doi:10.1146/annurev-cellbio-111315-125349. ISSN 1081-0706. PMID 27576122.
  24. ^ Choy, Christopher H.; Han, Bong-Kwan; Botelho, Roberto J. (2017). "Phosphoinositide Diversity, Distribution, and Effector Function: Stepping Out of the Box". BioEssays. 39 (12). doi:10.1002/bies.201700121. ISSN 0265-9247. PMID 28977683. S2CID 22778474.
  25. ^ Ridgway, Neale D. (2016), "Phospholipid Synthesis in Mammalian Cells", Biochemistry of Lipids, Lipoproteins and Membranes, Elsevier, pp. 209–236, doi:10.1016/b978-0-444-63438-2.00007-9, ISBN 978-0-444-63438-2, S2CID 89265741, retrieved 2024-02-15
  26. ^ Chatterjee, Soumya Deep; Zhou, Juan; Dasgupta, Rubin; Cramer-Blok, Anneloes; Timmer, Monika; van der Stelt, Mario; Ubbink, Marcellus (2021). "Protein Dynamics Influence the Enzymatic Activity of Phospholipase A/Acyltransferases 3 and 4". Biochemistry. 60 (15): 1178–1190. doi:10.1021/acs.biochem.0c00974. ISSN 0006-2960. PMC 8154263. PMID 33749246.
  27. ^ Bunney, Tom D.; Katan, Matilda (2011). "PLC regulation: emerging pictures for molecular mechanisms". Trends in Biochemical Sciences. 36 (2): 88–96. doi:10.1016/j.tibs.2010.08.003. PMID 20870410.
  28. ^ Ivanova, Adelina; Atakpa-Adaji, Peace (2023). "Phosphatidylinositol 4,5-bisphosphate and calcium at ER-PM junctions — Complex interplay of simple messengers". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1870 (6): 119475. doi:10.1016/j.bbamcr.2023.119475. PMID 37098393.
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