{{Short description|Signaling molecule}} {{Too technical|date=February 2024}} {{Chembox | verifiedrevid = 409517204 | Name = Phosphatidylinositol | ImageFile = Phosphatidylinositol structure with components.jpg | ImageSize = 350 | ImageCaption = Depicting the phosphatidylinositol molecule with an overview of different segregated components; Inositol, Phosphate, Glycerol-backbone, sn-1 acyl chain, sn-2 acyl chain.<ref>{{cite journal |last1=Blunsom |first1=Nicholas J. |last2=Cockcroft |first2=Shamshad |date=2020 |title=Phosphatidylinositol synthesis at the endoplasmic reticulum |journal=Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids |volume=1865 |issue=1 |article-number=158471 |doi=10.1016/j.bbalip.2019.05.015|pmid=31173893 |s2cid=182948709 |url=https://discovery.ucl.ac.uk/id/eprint/10075844/ }}</ref> | ImageName1 = Components of phosphatidylinositol | IUPACName = [(2R)-3-[hydroxy-[(5R)-2,3,4,5,6-pentahydroxycyclohexyl]oxyphosphoryl]oxy-2-octadecanoyloxypropyl] (8Z,11Z,14Z,17Z)-icosa-8,11,14,17-tetraenoate | OtherNames = {{Unbulleted list|PI|PtdIns}} | Section1 = {{Chembox Identifiers | CASNo = | ChEBI = 28874 | DrugBank = DB02144 | PubChem = }} | Section2 = {{Chembox Properties | Formula = C<sub>47</sub>H<sub>83</sub>O<sub>13</sub>P | MolarMass = 887,104 g/mol, neutral with fatty acid composition - 18:0, 20:4 | Appearance = | Density = | MeltingPt = | BoilingPt = | Solubility = }} | Section3 = {{Chembox Hazards | MainHazards = | FlashPt = | AutoignitionPt = }} }} '''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.
The biomolecule can exist in nine 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==
Phosphatidylinositol (PI) and its derivatives have a rich history dating back to their discovery by Johann Joseph von Scherer<ref>{{cite journal |last1=Scherer |first1=Johann J. |date=1850 |title=Uber eine neue aus dem Muskelfleisch gewonnene Zuckerart |journal=Liebigs Ann. Chem. |volume=73 |issue=3 |page=322|doi=10.1002/jlac.18500730303|lang=de}}</ref> and Léon Maquenne<ref>{{cite journal |last1=Maquenne |first1=Léon |date=1887 |title=Préparation, proprietés et constitution se l'inosite |journal=Comptes rendus hebdomadaires des séances de l'Académie des Sciences |volume=104 |page=225-227|lang=fr}}</ref><ref>{{cite journal |last1=Maquenne |first1=Léon |date=1887 |title=Sur les propriétés de l'inosite |journal=Comptes rendus hebdomadaires des séances de l'Académie des Sciences |volume=104 |page=297-299|lang=fr}}</ref><ref>{{cite journal |last1=Maquenne |first1=Léon |date=1887 |title=Sur quelques dérivés de l'inosite |journal=Comptes rendus hebdomadaires des séances de l'Académie des Sciences |volume=104 |page=1719-1722|lang=fr}}</ref> 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,<ref>{{cite journal |last1=Posternak |first1=Théodore |date=1942 |title=Recherches dans la série des cyclites VI. Sur la configuration de la méso-inosite, de la scyllite et d'un inosose obtenu par voie biochimique (scyllo-ms-inosose)|lang=fr|journal=Helv. Chim. Acta |volume=25 |issue=4 |page=746-752|doi=10.1002/hlca.19420250410 }}</ref><ref>{{Cite journal |last=Dangschat |first=Gerda |date=1942 |title=Acetonierung und Konfiguration des Meso-inosits |url=https://link.springer.com/10.1007/BF01475387 |journal=Die Naturwissenschaften |language=de |volume=30 |issue=9–10 |pages=146–147 |doi=10.1007/BF01475387 |bibcode=1942NW.....30..146D |s2cid=38695213 |issn=0028-1042|url-access=subscription }}</ref><ref>{{Cite journal |last1=Falkenburger |first1=Björn H. |last2=Jensen |first2=Jill B. |last3=Dickson |first3=Eamonn J. |last4=Suh |first4=Byung-Chang |last5=Hille |first5=Bertil |date=2010 |title=SYMPOSIUM REVIEW: Phosphoinositides: lipid regulators of membrane proteins: Phosphoinositides instruct membrane proteins |journal=The Journal of Physiology |language=en |volume=588 |issue=17 |pages=3179–3185 |doi=10.1113/jphysiol.2010.192153 |pmc=2976013 |pmid=20519312}}</ref> 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<ref>{{Cite journal |last1=Pizer |first1=Frances Lane |last2=Ballou |first2=Clinton E. |date=1959 |title=Studies on myo-Inositol Phosphates of Natural Origin |journal=Journal of the American Chemical Society |language=en |volume=81 |issue=4 |pages=915–921 |doi=10.1021/ja01513a040 |bibcode=1959JAChS..81..915P |issn=0002-7863}}</ref><ref>{{Cite journal |last1=Ballou |first1=Clinton E. |last2=Pizer |first2=Lewis I. |date=1959 |title=SYNTHESIS OF AN OPTICALLY ACTIVE myo-INOSITOL 1-PHOSPHATE |journal=Journal of the American Chemical Society |language=en |volume=81 |issue=17 |page=4745 |doi=10.1021/ja01526a074 |bibcode=1959JAChS..81.4745B |issn=0002-7863}}</ref> and Dan Brown.<ref>{{Cite journal |last1=Brown |first1=D. M. |last2=Clark |first2=B. F. C. |last3=Letters |first3=R. |date=1961 |title=732. Phospholipids. Part VII. The structure of a monophosphoinositide |url=https://xlink.rsc.org/?DOI=jr9610003774 |journal=Journal of the Chemical Society (Resumed) |language=en |pages=3774–3779 |doi=10.1039/jr9610003774 |issn=0368-1769|url-access=subscription }}</ref> 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.<ref>{{Cite journal |last=Irvine |first=Robin F. |date=2016 |title=A short history of inositol lipids |journal=Journal of Lipid Research |language=en |volume=57 |issue=11 |pages=1987–1994 |doi=10.1194/jlr.R071712 |doi-access=free |pmc=5087877 |pmid=27623846}}</ref>
==Structure and chemistry==
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.<ref>{{Cite journal |last1=Kooijman |first1=Edgar E. |last2=King |first2=Katrice E. |last3=Gangoda |first3=Mahinda |last4=Gericke |first4=Arne |date=2009-10-13 |title=Ionization Properties of Phosphatidylinositol Polyphosphates in Mixed Model Membranes |url=https://pubs.acs.org/doi/10.1021/bi9008616 |journal=Biochemistry |language=en |volume=48 |issue=40 |pages=9360–9371 |doi=10.1021/bi9008616 |pmid=19725516 |issn=0006-2960|url-access=subscription }}</ref>
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.{{citation needed|date=January 2026}} Cis-inositol is the only isomer not found naturally in nature.<ref>{{Cite journal |last1=Thomas |first1=Mark P. |last2=Mills |first2=Stephen J. |last3=Potter |first3=Barry V. L. |date=2016-01-26 |title=The "Other" Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances in myo -Inositol Chemistry) |journal=Angewandte Chemie International Edition |language=en |volume=55 |issue=5 |pages=1614–1650 |doi=10.1002/anie.201502227 |issn=1433-7851 |pmc=5156312 |pmid=26694856 |bibcode=2016ACIE...55.1614T }}</ref>
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.<ref>{{Cite journal |last1=Hoener |first1=Marius C. |last2=Brodbeck |first2=Urs |date=1992 |title=Phosphatidylinositol-glycan-specific phospholipase D is an amphiphilic glycoprotein that in serum is associated with high-density lipoproteins |url=https://febs.onlinelibrary.wiley.com/doi/10.1111/j.1432-1033.1992.tb16981.x |journal=European Journal of Biochemistry |language=en |volume=206 |issue=3 |pages=747–757 |doi=10.1111/j.1432-1033.1992.tb16981.x |pmid=1606959 |issn=0014-2956}}</ref>
==Phosphoinositides== 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.<ref>{{Cite journal |last1=Falkenburger |first1=Björn H. |last2=Jensen |first2=Jill B. |last3=Dickson |first3=Eamonn J. |last4=Suh |first4=Byung-Chang |last5=Hille |first5=Bertil |date=2010-09-01 |title=SYMPOSIUM REVIEW: Phosphoinositides: lipid regulators of membrane proteins: Phosphoinositides instruct membrane proteins |journal=The Journal of Physiology |language=en |volume=588 |issue=17 |pages=3179–3185 |doi=10.1113/jphysiol.2010.192153 |pmc=2976013 |pmid=20519312}}</ref>
All seven variations of the following phosphoinositides have been found in animals:
Phosphatidylinositol monophosphates: * Phosphatidylinositol 3-phosphate, also known as PtdIns3''P'' or PI(3)P * Phosphatidylinositol 4-phosphate, also known as PtdIns4''P'' or PI(4)P * Phosphatidylinositol 5-phosphate, also known as PtdIns5''P'' or PI(5)P
Phosphatidylinositol bisphosphates: * Phosphatidylinositol 3,4-bisphosphate, also known as PtdIns(3,4)''P''<sub>2</sub> or PI(3,4)P<sub>2</sub> * Phosphatidylinositol 3,5-bisphosphate, also known as PtdIns(3,5)''P''<sub>2</sub> or PI(3,5)P<sub>2</sub> * Phosphatidylinositol 4,5-bisphosphate, also known as PtdIns(4,5)''P''<sub>2</sub>, PI(4,5)P<sub>2</sub> or often simply referred to as PIP<sub>2</sub>
Phosphatidylinositol trisphosphate: * Phosphatidylinositol 3,4,5-trisphosphate, also known as PtdIns(3,4,5)''P''<sub>3</sub> or PI(3,4,5)P<sub>3</sub>
These phosphoinositides are also found in plant cells, with the exception of PIP<sub>3</sub>.<ref name="Muller-Roeber B">{{cite journal|last1=Muller-Roeber|first1=B|last2=Pical|first2=C|title=Inositol Phospholipid Metabolism in Arabidopsis. Characterized and Putative Isoforms of Inositol Phospholipid Kinase and Phosphoinositide-Specific Phospholipase C|year=2002|journal=Plant Physiology|volume=130|issue=1|doi=10.1104/pp.004770|doi-access=free|pages=22-46|pmid=12226484|pmc=166537}}</ref><ref>{{Cite journal |last1=Falkenburger |first1=Björn H. |last2=Jensen |first2=Jill B. |last3=Dickson |first3=Eamonn J. |last4=Suh |first4=Byung-Chang |last5=Hille |first5=Bertil |date=2010-09-01 |title=SYMPOSIUM REVIEW: Phosphoinositides: lipid regulators of membrane proteins: Phosphoinositides instruct membrane proteins |journal=The Journal of Physiology |language=en |volume=588 |issue=17 |pages=3179–3185 |doi=10.1113/jphysiol.2010.192153 |pmc=2976013 |pmid=20519312}}</ref><ref>{{Cite journal |last1=Tabaei |first1=Seyed R. |last2=Guo |first2=Feng |last3=Rutaganira |first3=Florentine U. |last4=Vafaei |first4=Setareh |last5=Choong |first5=Ingrid |last6=Shokat |first6=Kevan M. |last7=Glenn |first7=Jeffrey S. |last8=Cho |first8=Nam-Joon |date=2016-05-17 |title=Multistep Compositional Remodeling of Supported Lipid Membranes by Interfacially Active Phosphatidylinositol Kinases |journal=Analytical Chemistry |language=en |volume=88 |issue=10 |pages=5042–5045 |doi=10.1021/acs.analchem.6b01293 |issn=0003-2700 |pmc=5291064 |pmid=27118725}}</ref>
==Biosynthesis== The synthesis of phosphatidylinositol (PI) is limited to the endoplasmic reticulum (ER), which is the largest membrane component of the cell.<ref>{{Cite journal |last1=Schink |first1=Kay O. |last2=Tan |first2=Kia-Wee |last3=Stenmark |first3=Harald |date=2016 |title=Phosphoinositides in Control of Membrane Dynamics |url=https://www.annualreviews.org/doi/10.1146/annurev-cellbio-111315-125349 |journal=Annual Review of Cell and Developmental Biology |language=en |volume=32 |issue=1 |pages=143–171 |doi=10.1146/annurev-cellbio-111315-125349 |pmid=27576122 |issn=1081-0706|url-access=subscription }}</ref> This site also contributes the synthesis to the majority of phospholipids, namely phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS) and triacylglycerol (TG).<ref>{{Cite journal |last1=Choy |first1=Christopher H. |last2=Han |first2=Bong-Kwan |last3=Botelho |first3=Roberto J. |date=2017 |title=Phosphoinositide Diversity, Distribution, and Effector Function: Stepping Out of the Box |url=https://onlinelibrary.wiley.com/doi/10.1002/bies.201700121 |journal=BioEssays |language=en |volume=39 |issue=12 |article-number=1700121 |doi=10.1002/bies.201700121 |pmid=28977683 |s2cid=22778474 |issn=0265-9247|url-access=subscription }}</ref> The synthesis involves a series of enzymatic reactions.
''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.<ref>{{Citation |last=Ridgway |first=Neale D. |title=Phospholipid Synthesis in Mammalian Cells |date=2016 |work=Biochemistry of Lipids, Lipoproteins and Membranes |pages=209–236 |url=https://linkinghub.elsevier.com/retrieve/pii/B9780444634382000079 |access-date=2024-02-15 |publisher=Elsevier |language=en |doi=10.1016/b978-0-444-63438-2.00007-9 |isbn=978-0-444-63438-2|s2cid=89265741 |url-access=subscription }}</ref> The process is then followed by a second acylation with LPAAT1, LPAAT2 and LPAAT3, LPAAT enzymes, at the ''sn-2'' acyl chain position.<ref>{{Cite journal |last1=Chatterjee |first1=Soumya Deep |last2=Zhou |first2=Juan |last3=Dasgupta |first3=Rubin |last4=Cramer-Blok |first4=Anneloes |last5=Timmer |first5=Monika |last6=van der Stelt |first6=Mario |last7=Ubbink |first7=Marcellus |date=2021 |title=Protein Dynamics Influence the Enzymatic Activity of Phospholipase A/Acyltransferases 3 and 4 |journal=Biochemistry |language=en |volume=60 |issue=15 |pages=1178–1190 |doi=10.1021/acs.biochem.0c00974 |issn=0006-2960 |pmc=8154263 |pmid=33749246}}</ref> This double step process acylates G-3-P to phosphatidic acid (PA).
PA is converted into the intermediate CDP-diacylglycerol (CDP-DAG) by an enzyme called CDP-diacylglycerol synthase. Two genes, ''CDS1'' and ''CDS2'', encode different isoforms of CDP-diacylglycerol synthase. In the final enzymatic process, CDP-DAG and inositol are used as substrates by the enzyme phosphatidylinositol synthase and converted into PI and cytidine monophosphate (CMP).<ref>{{Cite journal |last1=Bunney |first1=Tom D. |last2=Katan |first2=Matilda |date=2011 |title=PLC regulation: emerging pictures for molecular mechanisms |url=https://linkinghub.elsevier.com/retrieve/pii/S0968000410001660 |journal=Trends in Biochemical Sciences |language=en |volume=36 |issue=2 |pages=88–96 |doi=10.1016/j.tibs.2010.08.003|pmid=20870410 |url-access=subscription }}</ref><ref name=ivanovaatakpa2023>{{Cite journal |last1=Ivanova |first1=Adelina |last2=Atakpa-Adaji |first2=Peace |date=2023 |title=Phosphatidylinositol 4,5-bisphosphate and calcium at ER-PM junctions — Complex interplay of simple messengers |journal=Biochimica et Biophysica Acta (BBA) - Molecular Cell Research |language=en |volume=1870 |issue=6 |article-number=119475 |doi=10.1016/j.bbamcr.2023.119475|pmid=37098393 |doi-access=free }}</ref>
==Metabolism== Important reactions involving phosphatidylinositol include the hydrolysis of PIP<sub>2</sub> into inositol triphosphate and diacylglycerol by phospholipase C and phosphorylation of PIP<sub>2</sub> into PIP<sub>3</sub> by class I phosphotidylinositol-3-kinases. However, the metabolism of phosphatidylinositol is complex, with a multitude of lipid kinases, phosphatases and phospholipases potentially involved<ref name=dicksonhille2019>{{cite journal|last1=Dickson|first1=Eamonn J.|last2=Hille|first2=Bertil|title=Understanding phosphoinositides: rare, dynamic, and essential membrane phospholipids|journal=Biochemical Journal|volume=476|issue=1|year=2019|pages=1-23|doi=10.1042/BCJ20180022|pmid=30617162|pmc=6342281}}</ref>—for example, PIP<sub>3</sub> can also be generated from phosphotidylinositol(3,4)-bisphosphate by type 1α phosphatidylinositol-4-phosphate 5-kinase under conditions of oxidative stress.<ref>{{cite journal|last=Hinchliffe|first=Katherine A.|title=Cellular signalling: Stressing the importance of PIP3|journal=Current Biology|year=2001|volume=11|issue=9|pages=371-373|doi=10.1016/S0960-9822(01)00197-X|pmid= 11369251|doi-access=free}}</ref><ref>{{cite journal|last1=Halstead|first1=J.R.|last2=Roefs|first2=M.|last3=Ellson|first3=C.D.|last4=D'Andrea|first4=S.|last5=Chen|first5=C.-S.|last6=D'Santos|first6=C.S.|last7=Divecha|first7=N.|title=A novel pathway of cellular phosphatidylinositol(3,4,5)-trisphosphate synthesis is regulated by oxidative stress|journal=Current Biology|year=2001|volume=11|pages=386-395|doi=10.1016/s0960-9822(01)00121-x|issue=6|doi-access=free|pmid=11301249}}</ref>
=== Hydrolysis === thumb|alt=Diagram|The process of hydrolysis and biosynthesis of PI separated between the plasma membrane and endoplasmic reticulum (ER), depicting respective enzymatic processes and reactions.<ref name=":0">{{Cite journal |last1=Blunsom |first1=Nicholas J. |last2=Cockcroft |first2=Shamshad |date=2020 |title=Phosphatidylinositol synthesis at the endoplasmic reticulum |url=https://linkinghub.elsevier.com/retrieve/pii/S1388198119300897 |journal=Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids |language=en |volume=1865 |issue=1 |page=158471 |doi=10.1016/j.bbalip.2019.05.015|pmid=31173893 |s2cid=182948709 |url-access=subscription }}</ref>
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)P<sub>2</sub> or PIP<sub>2</sub>) by the enzyme PI 4-phosphate-5-kinase (PI4P5K). PI(4,5)P<sub>2</sub> is then hydrolysed by phospholipase C (PLC) to form the second messengers inositol (1,4,5) triphosphate (IP<sub>3</sub>) and diacylglycerol (DG). DG is then phosphorylated 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.<ref name=":0"/><ref name=ivanovaatakpa2023/><ref>{{Cite journal |last=Berridge |first=Michael J. |date=1981 |title=Phosphatidylinositol hydrolysis: A multifunctional transducing mechanism |url=https://linkinghub.elsevier.com/retrieve/pii/0303720781900551 |journal=Molecular and Cellular Endocrinology |language=en |volume=24 |issue=2 |pages=115–140 |doi=10.1016/0303-7207(81)90055-1|pmid=6117490 |s2cid=27566538 |url-access=subscription }}</ref>
===Phosphorylation=== The phosphorylation of PI mainly occurs on the cytosolic-facing surface of cellular membranes by cytoplasmic or peripheral membrane<ref>{{cite journal|last1=Rao|first1=Vibha D.|last2=Misra|first2=Saurav|last3=Boronenkov|first3=Igor V.|last4=Anderson|first4=Richard A.|last5=Hurley|first5=James H.|title=Structure of Type IIβ Phosphatidylinositol Phosphate Kinase|year=1998|journal=Cell|volume=94|issue=6|pages=829-839|doi=10.1016/S0092-8674(00)81741-9|doi-access=free|pmid=9753329}}</ref> kinases. These phosphate groups can be removed by specific lipid phosphatases.<ref name=dicksonhille2019/> Rare PI derivatives, such as PI(3,4,5)P<sub>3</sub> or PIP<sub>3</sub>, are produced transiently in response to growth factor signaling and play important roles in cancer biology when they are dysregulated. Diseases that can be caused by congenital defects in the phosphorylation of phosphotidylinositol include Charcot-Marie-Tooth disease, Lowe's syndrome and certain ciliopathies.<ref name=dicksonhille2019/>
==References== <references />
==External links== * {{MeshName|Phosphatidylinositols}} * [https://web.archive.org/web/20070126091146/http://www.lipidlibrary.co.uk/Lipids/pi/index.htm Phosphatidylinositol at Lipid Library]
Category:Phospholipids Category:Membrane biology