Phosphatidylinositol or inositol phospholipid is a

biomolecule A biomolecule or biological molecule is loosely defined as a molecule produced by a living organism and essential to one or more typically biological processes. Biomolecules include large macromolecules such as proteins, carbohydrates, lipids ...

. 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 Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...

but later also found in

eukaryotes The eukaryotes ( ) constitute the domain of Eukaryota or Eukarya, organisms whose cells have a membrane-bound nucleus. All animals, plants, fungi, seaweeds, and many unicellular organisms are eukaryotes. They constitute a major group of ...

, and was found to be a

signaling molecule In biology, cell signaling (cell signalling in British English) is the Biological process, process by which a Cell (biology), cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all Cell (biol ...

. The biomolecule can exist in 9 different isomers. It is a

lipid Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...

which contains a

phosphate group Phosphates are the naturally occurring form of the element phosphorus. In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosp ...

, two fatty acid chains, and one

inositol In biochemistry, medicine, and related sciences, inositol generally refers to ''myo''-inositol (formerly ''meso''-inositol), the most important stereoisomer of the chemical compound cyclohexane-1,2,3,4,5,6-hexol. Its elemental formula, formula is ...

sugar molecule. Typically, the phosphate group has a negative charge (at physiological pH values). As a result, the molecule is

amphiphilic In chemistry, an amphiphile (), or amphipath, is a chemical compound possessing both hydrophilic (''water-loving'', polar) and lipophilic (''fat-loving'', nonpolar) properties. Such a compound is called amphiphilic or amphipathic. Amphiphilic c ...

. The production of the molecule is limited to the

endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...

History of phospatidylinositol

Phosphatidylinositol (PI) and its derivatives have a rich history dating back to their discovery by Johann Joseph von Scherer and Léon Maquenne in the late 19th century. Initially known as "

inosite In biochemistry, medicine, and related sciences, inositol generally refers to ''myo''-inositol (formerly ''meso''-inositol), the most important stereoisomer of the chemical compound cyclohexane-1,2,3,4,5,6-hexol. Its formula is ; the molecule has ...

" based on its sweet taste, the isolation and characterization of inositol laid the groundwork for understanding its

cyclohexanol Cyclohexanol is the organic compound with the formula HOCH(CH2)5. The molecule is related to cyclohexane by replacement of one hydrogen atom by a hydroxyl group. This compound exists as a deliquescent colorless solid with a camphor-like odor, whi ...

structure. Théodore Posternak's work further elucidated the configuration of myo-inositol, the principal form found in eukaryotic tissues. The study of inositol

isomers In chemistry, isomers are molecules or polyatomic ions with identical molecular formula – that is, the same number of atoms of each element – but distinct arrangements of atoms in space. ''Isomerism'' refers to the existence or possibili ...

and their physiological functions has revealed a complex interplay in various organisms. The esterified presence of

lipids Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins Vitamin A, A, Vitamin D, D, Vitamin E, E and Vitamin K, K), monoglycerides, diglycerides, phospholipids, and others. The fu ...

, particularly PI, was first observed in

and later confirmed in

eukaryotic The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...

organisms by researchers like

Clinton Ballou Clinton Edward Ballou (June 18, 1923 – March 8, 2021) was an American academic who was a professor of biochemistry at the University of California, Berkeley. His research focused on the metabolism of carbohydrates and the structures of microbial ...

and Dan Brown. Their pioneering work established the structure of PI and its

phosphorylated In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writt ...

forms, shedding light on their roles as

signaling molecules In biology, cell signaling (cell signalling in British English) is the process by which a cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all cellular life in both prokaryotes and eukary ...

. 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 Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events. Proteins responsible for detecting stimuli are generally termed receptors, although in some cases the term ...

. The discovery of PI and its derivatives, along with their intricate roles in cellular signaling, marks a significant chapter in the field of

biochemistry Biochemistry, or biological chemistry, is the study of chemical processes within and relating to living organisms. A sub-discipline of both chemistry and biology, biochemistry may be divided into three fields: structural biology, enzymology, a ...

. 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 The cell is the basic structural and functional unit of all life, forms of life. Every cell consists of cytoplasm enclosed within a Cell membrane, membrane; many cells contain organelles, each with a specific function. The term comes from the ...

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

cell membranes. The phosphate group imparts a negative charge to the molecules at physiological pH. PI can exist in nine different forms, myo-, scyllo-, muco-, epi-, neo-, allo-, D-chiro-, L-chiro-, and cis-inositol. These

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. PI exhibits an

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.

Phosphoinositides

Phosphorylated forms of phosphatidylinositol (PI) are called phosphoinositides and play important roles in

lipid signaling Lipid signaling, broadly defined, refers to any biological cell signaling event involving a lipid messenger that binds a protein target, such as a receptor (biochemistry), receptor, kinase or phosphatase, which in turn mediate the effects of these ...

cell signaling In biology, cell signaling (cell signalling in British English) is the Biological process, process by which a Cell (biology), cell interacts with itself, other cells, and the environment. Cell signaling is a fundamental property of all Cell (biol ...

and

membrane trafficking Membrane vesicle trafficking in eukaryotic animal cells involves movement of biochemical signal molecules from synthesis-and-packaging locations in the Golgi body to specific release locations on the inside of the plasma membrane of the secretory c ...

. The inositol ring can be

by a variety of

kinases In biochemistry, a kinase () is an enzyme that catalysis, catalyzes the transfer of phosphate groups from High-energy phosphate, high-energy, phosphate-donating molecules to specific Substrate (biochemistry), substrates. This process is known as ...

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 Steric effects arise from the spatial arrangement of atoms. When atoms come close together there is generally a rise in the energy of the molecule. Steric effects are nonbonding interactions that influence the shape ( conformation) and reactivi ...

. All seven variations of the following phosphoinositides have been found in animals: Phosphatidylinositol monophosphates: *

Phosphatidylinositol 3-phosphate Phosphatidylinositol 3-phosphate (PI3P) is a phospholipid found in cell membranes that helps to recruit a range of proteins, many of which are involved in protein trafficking, to the membranes. It is the product of both the class II and III phosph ...

, also known as PtdIns3''P'' or PI(3)P *

Phosphatidylinositol 4-phosphate Phosphatidylinositol-4-phosphate (PtdIns4''P'', PI-4-P, PI4P, or PIP) is a precursor of phosphatidylinositol (4,5)-bisphosphate. PtdIns4''P'' is prevalent in the membrane of the Golgi apparatus. In the Golgi apparatus, PtdIns4''P'' binds to the G ...

, also known as PtdIns4''P'' or PI(4)P *

Phosphatidylinositol 5-phosphate Phosphatidylinositol 5-phosphate (PtdIns5P) is a phosphoinositide, one of the phosphorylated derivatives of phosphatidylinositol (PtdIns), that are well-established membrane-anchored regulatory molecules. Phosphoinositides participate in signaling ...

, also known as PtdIns5''P'' or PI(5)P Phosphatidylinositol bisphosphates: * Phosphatidylinositol 3,4-bisphosphate, also known as PtdIns(3,4)''P''₂ or PI(3,4)P₂ *

Phosphatidylinositol 3,5-bisphosphate Phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) is one of the seven phosphoinositides found in eukaryotic cell membranes. In quiescent cells, the PtdIns(3,5)P2 levels, typically quantified by HPLC, are the lowest amongst the constitutively ...

, also known as PtdIns(3,5)''P''₂ or PI(3,5)P₂ *

Phosphatidylinositol 4,5-bisphosphate Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)''P''2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)''P''2 is enriched at the plasma membrane where it is a substrate for a number of ...

, also known as PtdIns(4,5)''P''₂, PI(4,5)P₂ or often simply referred to as PIP₂ Phosphatidylinositol trisphosphate: * Phosphatidylinositol 3,4,5-trisphosphate, also known as PtdIns(3,4,5)''P''₃ or PI(3,4,5)P₃ These phosphoinositides are also found in plant cells, with the exception of PIP₃.

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 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 A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

incapable of PI synthesis. Phosphatidylinositol hydrolysis and synthesis

Biosynthesis

The

synthesis Synthesis or synthesize may refer to: Science Chemistry and biochemistry *Chemical synthesis, the execution of chemical reactions to form a more complex molecule from chemical precursors **Organic synthesis, the chemical synthesis of organi ...

of Phosphatidylinositol (PI) is limited to the

Endoplasmatic Reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for "little ne ...

(ER), which is the largest membrane component of the cell. This site also contributes the synthesis to the majority of phospholipids, namely

phosphatidylcholine Phosphatidylcholines (PC) are a class of phospholipids that incorporate choline as a headgroup. They are a major component of biological membranes and can easily be obtained from a variety of readily available sources, such as egg yolk or soyb ...

(PC),

phosphatidylethanolamine Phosphatidylethanolamine (PE) is a class of phospholipids found in biological membranes. They are synthesized by the addition of cytidine diphosphate-ethanolamine to diglycerides, releasing cytidine monophosphate. S-Adenosyl methionine, ''S''-Ade ...

(PE),

phosphatidylserine Phosphatidylserine (abbreviated Ptd-L-Ser or PS) is a phospholipid and is a component of the cell membrane. It plays a key role in cell cycle signaling, specifically in relation to apoptosis. It is a key pathway for viruses to enter cells via a ...

(PS) and

triacylglycerol A triglyceride (from ''tri-'' and '' glyceride''; also TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids. Triglycerides are the main constituents of body fat in humans and other vertebrates as ...

(TG). The synthesis involves a series of enzymatic reactions. The biosynthesis and phosphorylation of PI is mainly confined to the

cytosolic The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

facing surface of organelles by already residential

, but not at the ER specifically. ''

De novo De novo (Latin, , used in English to mean 'from the beginning', 'anew') may refer to: Science and computers * ''De novo'' mutation, a new germline mutation not inherited from either parent * ''De novo'' protein design, the creation of a protei ...

'' PI synthesis of PI starts with an

acylated In chemistry, acylation is a broad class of chemical reactions in which an acyl group () is added to a substrate. The compound providing the acyl group is called the acylating agent. The substrate to be acylated and the product include the follo ...

process of

Glyceraldehyde-3-phosphate Glyceraldehyde 3-phosphate, also known as triose phosphate or 3-phosphoglyceraldehyde and abbreviated as G3P, GA3P, GADP, GAP, TP, GALP or PGAL, is a metabolite that occurs as an intermediate in several central pathways of all organisms.Nelson, D ...

(G-3-P) by GPAT enzymes at the ''sn-1'' acyl chain position. The process is then followed by a second acylation with LPAAT1, LPAAT2 and LPAAT3, LPAAT enzymes, at the ''sn-2'' acyl chain position. This double step process acylates G-3-P to

phosphatidic acid Phosphatidic acids are anionic phospholipids important to cell signaling and direct activation of lipid-gated ion channels. Hydrolysis of phosphatidic acid gives rise to one molecule each of glycerol and phosphoric acid and two molecules of fatty a ...

(PA). PA is converted into the intermediate CDP-diacylglycerol (CDP-DAG) by an enzyme called CDP-diacylglycerol synthase. Two genes,

CDS1 Phosphatidate cytidylyltransferase 1 is an enzyme that in humans is encoded by the ''CDS1'' gene. Function Breakdown products of phosphoinositides are ubiquitous second messengers that function downstream of many G protein-coupled receptors and ...

and

CDS2 Phosphatidate cytidylyltransferase 2 is an enzyme that in humans is encoded by the ''CDS2'' gene. Breakdown products of Phosphatidylinositol#Phosphoinositides, phosphoinositides are ubiquitous second messenger system, second messengers that fun ...

, 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 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 ...

and converted into PI and

cytidine monophosphate Cytidine monophosphate, also known as 5'-cytidylic acid or simply cytidylate, and abbreviated CMP, is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid with the nucleoside cytidine. CMP consists of the phosphate grou ...

(CMP).

References

External links

* {{MeshName, Phosphatidylinositols
Phosphatidylinositol at Lipid Library
Phospholipids Membrane biology