Phosphatidylcholine (PC): Phosphatidylcholineis a quaternary amine (2-hydroxyethyl-N, N, N-trimethylammonium) present infood as well as milk in both free and esterified forms. The main forms presentin foods are phosphatidylcholine, lecithin, These are also present as animaltissues, free choline, phosphocholine (PChol), glycerophosphocholine (GPC) andsphingomyelin (SPM), and minor amounts of cytidine-5-diphosphate-choline(CDP-choline) and acetylcholine. 1,2Choline, PChol and GPC are water-soluble cholinecompounds, while PC and SPM are soluble in lipids. Choline can also besynthesised de novo by the human body but this synthesis may becomeinsufficient, making choline an important part of human diet.
Choline ispredominantly provided via the diet. The human body can also use de novosynthesis like methylation of phosphatidylethanolamine (PE) from the hepaticphosphatidylethanolamine N-methyltransferase (PEMT) pathway, or by hydrolysisof PC formed in the CDP-choline pathway in all cells of the body to formcholine. The PC formed in the PEMT pathway contains substantial amounts oflong-chain polyunsaturated fatty acids, like docosahexaenoic acid andarachidonic acid. These fatty acids are very important to the development ofthe human brain. 3 Phosphatidylethanolamine (PE): Phosphatidylethanolamine contributes to about 20-30% of total phospholipid content and is thesecond most abundant phospholipid in membranes of mammals. PE has two importantcharacteristics that include 1. PEconsists of a relatively small head group, thus it can accommodate theinsertion of proteins within the membrane while still maintaining the integrityof membrane. 2.
PE has a propensity to form a non-bilayer structure, which helpsin formation of new membranes and vesicles, and also membrane fusion andbudding process. 4, 5 PE is also highly present in the membranes of mitochondria, being anessential molecule for growth and stability of these energy-producingorganelles. PE is used in the production of glycosylphosphatidylinositol, whichfacilitates the anchoring of proteins to the membrane. 6 Further consists twotypes of lipids majorly, 1. Phosphatidylethanolamine or cephalin is one type ofa lipid which is found organic and natural membranes. Phosphatidylethanolaminealso occurs in play tissues and even mammals however in fewer amounts. It isactually synthesized by the inclusion of diglyceride to CDP-ethanolamine whichreleases CMP. Cephalin is a lipid derivative and normally originates in livingcells even though human physiology it originates especially in the nervoustissues like neural tissue, nerves, white matter in brain and in the spinalcord.
7 2. Lecithin is one type of phosphatidylethanolamine whichcontains a mixture of glycerol etherified along with phosphoric acid and twofatty acids. However, the group of phosphate is combined with choline in thephosphatidylethanolamine called Lecithin. Phosphatidylinositol (PI): PIconstitutes to around 10% of phospholipids in a cell or tissue. Inositol is a cyclohexane derivative wherein all 6 carbonsare substituted by hydroxyl groups. The most common isoform of Phosphatidylinositol is myo-inositol. Their lipid composition inthe mammalian (inositol phospholipids) PIPn carry stearic and arachidonic acidesters at the glycerol sn-1 and sn-2-positions, respectively.
8 Phosphatidylserine (PS): Phosphatidylserine (PS) is the major anionicphospholipid class that is enriched in the inner leaflet of the plasma membraneof the neural tissues. PS is synthesized from phosphatidylcholine orphosphatidylethanolamine by exchanging the base head group with serine inreactions are catalyzed by phosphatidylserine synthase 1 and phosphatidylserinesynthase 2 located in the endoplasmic reticulum. Activation of, mitocondrialRaf-1 and protein kinase C signaling, This supports neuronal survival anddifferentiation, necessiating interaction of these proteins with PS localizedin the cytoplasmic leaflet of the plasma membrane.9 Bioavailability (ADME) / Pharmacokinetics: Phosphatidylcholine (PC): SincePhosphatidylcholine is a charged hydrophilic cation, it needs transportmechanisms to cross biological membranes. Three transport mechanisms are known1. Sodium and chloride dependent high affinity mechanism 2.
A sodium-independentlow-affinity carrier-mediated saturable mechanism in all tissues 3.Asodium–independent saturable uptake mechanism Free choline is transported in the aqueous phase of plasma, whereasphosphorylated choline compounds i.e. PC, PChol, GPC, SPM are associated withor are part of lipoproteins.
10 In new-born’s, serum free cholineconcentrations were significantly higher i.e. > twice maternal values andphospholipid-bound choline concentrations were significantly lower by about 40%than in their mothers 11. Phospholipid-bound choline plasma concentrations inthe infants are observed to increase by 893 by 40% starting from day 5–15 afterbirth to reaching age of about ten years.
Plasma free choline concentration of new-bornsremained high for two weeks after birth, was observed to be slightly higherthan adult levels at the age of two years and remained stable at around10µmol/L at the age 3-12 years. This high new-born’s plasma concentrationpossibly reflects the increase of choline. But there was no correlation betweenmaternal and new-borns plasma phospholipid-bound choline 12, 13 Phosphatidylethanolamine(PE): Studiesindicate that Erythrocytephosphatidylethanolamine and phosphatidylcholine in infants fed human milk have20 to 22 carbon polyunsaturated fatty acids that are higher than infants consuming onlyvegetable fat. 14 Phosphatidylinositol (PI): Innew-borns which are considered to be healthy there is a negative correlationbetween lung effluent phosphatidylglycerol and serum myoinositol, wherein r = -0.968, and a positive linear correlation between myoinositol and lung effluentphosphatidylinositol, r = 0.849. 15 Phosphatidylserine (PS): Phosphatidylserine is obtained by uptake from the cerebral circulationor by glucose synthesis.
The serine concentration in normal human plasma is 11.2mg/L, these accounts for 3% of the total plasma free amino acid content 16. Three Na+dependent neutral amino acid transporters that are present on the abluminalsurface of the capillary endothelium are used to transport Phosphatidylserine across the blood brain barrier by 17. Factors that influence and modulatedigestion, absorption and metabolism: Phosphatidylcholine (PC): Sodiumand chloride dependent high-affinity carrier-mediated saturable uptake systemin presynaptic cholinergic nerve terminals are linked to acetylcholinesynthesis 18. The transporter is the high-affinity choline transporter whichis a solute carrier that needs adenosine triphosphate hydrolysis. Further,disturbing the cell membrane can reduce choline availability for acetylcholinesynthesis and eliminate cholinergic transmission in the body. These areimportant for metabolism and transportation of Phosphatidylcholine 19. Sodium independent low-affinity carriermediated saturable mechanism in all tissues.
This mechanism is based on hydrolysis,with an average affinity for choline to be > 20–200 µM. 20. This mechanismcan take place in enterocytes, hepatocytes, kidneys, placental tissue,mitochondria, and synaptosomes, and supplies choline for the synthesis of PCand SPM as well as of betaine. This type of uptake for Phosphatidylcholine isstereospecific and can be inhibited by similar nitrogen-methyl compounds. Sodium–independent saturable uptakemechanism for Phosphatidylcholine is for choline to cross the blood-brain barrierand erythrocyte membranes by facilitated diffusion. This is a high affinitymechanism 21 Phosphatidylethanolamine (PE): The CDP-ethanolamine pathway consists of three enzymatic steps.
ATP-dependent phosphorylation of ethanolamine by ethanolamine kinase to formphosphoethanolamine with Adenosine diphosphate (ADP) released as a byproduct is the first step 14. The second step of the CDP-ethanolamine pathway, which is considered tobe rate-limiting, is catalyzed by the protein, and CTP:phosphoethanolaminecytidylyltransferase 22 .Final step of PE synthesis by the CDP-ethanolaminepathway, 1,2-diacylglycerol ethanolamine phosphotransferase utilizes the energyprovided by CDP-ethanolamine to attach ethanolamine to the membrane-embeddeddiacylglycerol (DAG) thus forming PE 14, 23, 24. Further in another research conducted by Riekhofand Voelker wherein acylation of Lyso- Phosphatidylethanolamine and head Group Exchange these two forms of Phosphatidylethanolamine synthesis are considered minor pathwaysof Phosphatidylethanolamine production.Lyso- Phosphatidylethanolamine is brought in through the exogenouslysophospholipid metabolism pathway. This pathway can utilize dietary lyso- Phosphatidylethanolamine that is first translocated across the plasmamembrane and then acylated 25. Phosphatidylinositol (PI): Investigation of Phosphoinositide metabolism inSynaptojanin 1–deficient mice correlated with increased steady-state levels ofspecific phosphoinositides in living cells.
cortical neurons in primary culture after 10days in vitro were metabolically labeled with 3Hinositol for 48hr. Lipid extraction followed by HPLC analysis revealed a selective increase of1.6-fold, p < 0.
001 of PI(4,5)P2 in neurons 26 Phosphatidylserine (PS): Studies with rat brain cortical mitochondriaindicate that the most effective Phosphatidylserine substrate for the Phosphatidylserinedecarboxylation reaction is the18:0, 22:6 molecular species 27. Therefore, the Phosphatidylethanolamine formed by Phosphatidylserine decarboxylation is expected to contain anabundance of DHA in the sn-2 position. However, the mitochondrialPhosphatidylethanolamine molecularspecies profile does not reflect this substrate preference, presumably due tothe contribution of other mechanisms such as the cytidinediphosphate-ethanolamine pathway which preferentially produces mono- anddi-unsaturated PE molecular species 28. Phosphatidylethanolamine synthesized from Phosphatidylserine by the Phosphatidylserinedecarboxylation reaction accumulatesin the inner mitochondrial membrane, whereas PE produced by the mitochondrialcytidine diphosphate-ethanolamine pathway is mainly localized to the outermembrane 29. Furtherfrom research studies it can be observed that Phosphatidylserine is not hydrolyzed by the Ca2+-dependentsynaptosomal phospholipase activated by K+ depolarization thathydrolyzes Phosphatidylcholine,while it is converted to lysophosphatidylserine by a Ca2+-independent phospholipase in brain 30, 31.
De novo synthesisof those nutrients and the effect of age: Phosphatidylcholine (PC): Studieshave claimed that apart from dietery intake Phosphatidylcholine in the body canbe generated de novo via the hepatic PEMT pathway. Both dietary and endogenous choline sourcesare incorporated into Phosphatidylcholine. Phosphatidylcholine is synthesisedin all cells from choline 32. Phosphatidylethanolamine (PE): The PhosphatidylserineDecarboxylases enzyme is localizedat the inner mitochondrial membrane and produces Phosphatidylethanolamine as an alternative to the de novo Phosphatidylethanolamine synthesis via cytidine diphosphate-ethanolaminepathway 33, 34, 35. A role of the PhosphatidylserineDecarboxylases reaction in neurite development also is suggested by thefinding that nerve growth factor increases the decarboxylation of Phosphatidylserine while stimulating neurite outgrowth inPC12 cells. Another function of the Phosphatidylserine Decarboxylases reaction is to supply Phosphatidylethanolamine in coordination with cardiolipin formitochondrial biogenesis and protein import into the inner mitochondrialmembrane 36, 37.
