Depicting the phosphatidylinositol molecule with an overview of different segregated components; Inositol, Phosphate, Glycerol-backbone, sn-1 acyl chain, sn-2 acyl chain.[1]
The biomolecule can exist in nine different isomers. It is alipid which contains aphosphate group, twofatty acid chains, and oneinositol sugar molecule. Typically, the phosphate group has a negative charge (at physiologicalpH values). As a result, the molecule isamphiphilic.
Phosphatidylinositol (PI) and its derivatives have a rich history dating back to their discovery by Johann Joseph von Scherer[2] andLéon 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 itscyclohexanol 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 inositolisomers and their physiological functions has revealed a complex interplay in various organisms.
The esterified presence ofinositol inlipids, particularly PI, was first observed inbacteria and later confirmed ineukaryotic organisms by researchers likeClinton Ballou[9][10] and Dan Brown.[11] Their pioneering work established the structure of PI and itsphosphorylated forms, shedding light on their roles assignaling molecules. Despite the complexity of inositol nomenclature and isomerism, modern research has greatly advanced the understanding of their diverse functions in cellular physiology andsignaling pathways.
The discovery of PI and its derivatives, along with their intricate roles in cellular signaling, marks a significant chapter in the field ofbiochemistry. 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 intocellular processes.[12]
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 ofeukaryotic 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. Theseisomers 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] Cis-inositol is the only isomer not found naturally in nature.[14]
PI exhibits anamphiphilic 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]
Phosphorylated forms of phosphatidylinositol (PI) are called phosphoinositides and play important roles inlipid signaling,cell signaling andmembrane trafficking. The inositol ring can bephosphorylated by a variety ofkinases on the three, four and five hydroxyl groups in seven different combinations. However, the two and six hydroxyl groups are typically not phosphorylated due tosteric hindrance.[16]
All seven variations of the following phosphoinositides have been found in animals:
De novo PI synthesis of PI starts with anacylated process ofglyceraldehyde 3-phosphate (G-3-P) by GPAT enzymes at thesn-1 acyl chain position.[22] The process is then followed by a second acylation with LPAAT1, LPAAT2 and LPAAT3, LPAAT enzymes, at thesn-2 acyl chain position.[23] This double step process acylates G-3-P tophosphatidic acid (PA).
PA is converted into the intermediate CDP-diacylglycerol (CDP-DAG) by an enzyme called CDP-diacylglycerol synthase. Two genes,CDS1 andCDS2, encode different isoforms of CDP-diacylglycerol synthase. In the final enzymatic process, CDP-DAG and inositol are used as substrates by the enzymephosphatidylinositol synthase and converted into PI andcytidine monophosphate (CMP).[24][25]
Important reactions involving phosphatidylinositol include the hydrolysis of PIP2 into inositol triphosphate and diacylglycerol byphospholipase C and phosphorylation of PIP2 into PIP3 byclass I phosphotidylinositol-3-kinases. However, the metabolism of phosphatidylinositol is complex, with a multitude of lipidkinases,phosphatases andphospholipases potentially involved[26]—for example, PIP3 can also be generated from phosphotidylinositol(3,4)-bisphosphate by type 1αphosphatidylinositol-4-phosphate 5-kinase under conditions of oxidative stress.[27][28]
The process of hydrolysis and biosynthesis of PI separated between the plasma membrane and endoplasmic reticulum (ER), depicting respective enzymatic processes and reactions.[29]
The significance of phosphatidylinositol (PI) metabolism lies in its role as a potentialtransducing 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 or PIP2) by the enzyme PI 4-phosphate-5-kinase (PI4P5K). PI(4,5)P2 is then hydrolysed by phospholipase C (PLC) to form the second messengers inositol (1,4,5) triphosphate (IP3) 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 likemitochondria incapable of PI synthesis.[29][25][30]
The phosphorylation of PI mainly occurs on thecytosolic-facing surface of cellular membranes by cytoplasmic orperipheral membrane[31] kinases. These phosphate groups can be removed by specific lipid phosphatases.[26] Rare PI derivatives, such as PI(3,4,5)P3 or PIP3, are produced transiently in response togrowth factor signaling and play important roles incancer biology when they are dysregulated. Diseases that can be caused bycongenital defects in the phosphorylation of phosphotidylinositol includeCharcot-Marie-Tooth disease,Lowe's syndrome and certainciliopathies.[26]
^Scherer, Johann J. (1850). "Uber eine neue aus dem Muskelfleisch gewonnene Zuckerart".Liebigs Ann. Chem. (in German).73 (3): 322.doi:10.1002/jlac.18500730303.
^Maquenne, Léon (1887). "Préparation, proprietés et constitution se l'inosite".Comptes rendus hebdomadaires des séances de l'Académie des Sciences (in French).104: 225-227.
^Maquenne, Léon (1887). "Sur les propriétés de l'inosite".Comptes rendus hebdomadaires des séances de l'Académie des Sciences (in French).104: 297-299.
^Maquenne, Léon (1887). "Sur quelques dérivés de l'inosite".Comptes rendus hebdomadaires des séances de l'Académie des Sciences (in French).104: 1719-1722.
^Posternak, Théodore (1942). "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)".Helv. Chim. Acta (in French).25 (4): 746-752.doi:10.1002/hlca.19420250410.
