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]
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.
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
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
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:
These phosphoinositides are also found in plant cells, with the exception of PIP3.[17][18][19]
Hydrolysis
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]
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]
^Scherer, Johann J. (1850). "Uber eine neue aus dem Muskelfleisch gewonnene Zuckerart". Liebigs Ann. Chem. 73 (3): 322.
doi:
10.1002/jlac.18500730303.
^Maquenne, Léon (1887). "Préparation, proprietés et constitution se l'inosite". C.R. Hebd. Séance, Acad. Sci. Paris. 104: 225-227.
^Maquenne, Léon (1887). "Sur les propriétés de l'inosite". C.R. Hebd. Séance, Acad. Sci. Paris. 104: 297-299.
^Maquenne, Léon (1887). "Sur quelques dérivés de l'inosite". C.R. Hebd. Séance, Acad. Sci. Paris. 104: 1719-1722.
^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.
^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.
ISSN0002-7863.
^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.
ISSN0002-7863.
^Muller-Roeber B, Pical C (2002). Inositol Phospholipid Metabolism in Arabidopsis. Characterized and Putative Isoforms of Inositol Phospholipid Kinase and Phosphoinositide-Specific Phospholipase C.