Glycerophosphocholines (GP01)

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Contents

Basics

Phosphatidylcholine (PC) is a phospholipid that is a major constituent of cell membranes. Phosphatidylcholine is also known as PtdCho, 1,2-diacyl-:ussn:ue-glycero-3-phosphocholine or lecithin. It has a role in the maintenance of cell-membrane integrity and is vital to all of the basic biological processes. These are information flow that occurs within cells from DNA to RNA to proteins, the formation of cellular energy and intracellular communication or signal transduction. Phosphatidylcholine, particularly phosphatidylcholine rich in polyunsaturated fatty acids, has a marked fluidizing effect on cellular membranes. Decreased cell-membrane fluidization and breakdown of cell-membrane integrity, as well as impairment of cell-membrane repair mechanisms, are associated with a number of disorders, including liver disease, neurological diseases, various cancers and cell death.

Structure

Chemically, Phosphatidylcholine is a glycerophospholipid, built on glycerol and substituted at all three carbons. Carbons 1 and 2 are substituted by fatty acids and carbon 3 by phosphorylcholine.

Phosphatidylcholine
Phosphatidylcholine

Formula: C10H18NO8PR2

LIPID MAPS Phosphatidylcholine generic structure

Natural sources

Phosphatidylcholine

Nomenclature

Trivial - non systematic - names:

  • Phosphatidylcholine
  • Lecithin
  • 1,2-Diacyl-sn-glycero-3-phosphocholine

IUPAC

Glycerophospholipids and subclasses

Biophysical properties

Biology / biochemistry

Biochemical synthesis

Mammalian cells derive the bulk of their PC from the “Kennedy pathway” described in the work of Kennedy and coworkers almost 40 years ago that is located at the cytosolic side of the endoplasmatic reticulum. Here the first step is the phosphorylation of choline by the enzyme choline kinase (Fig. 24_2).

Figure 24_2. Kennedy Pathway
Figure 24_2. Kennedy Pathway


The formed phosphocholine is subsequently activated by a phosphate cytidylyltransferase that generates CDP-choline. Finally the enzyme choline phosphotransferase transfers the choline group of CDP-choline to diacylglycerol (DAG) which leads to the formation of PC. Alternatively, phosphatidylethanolamine (PE) is generated via the “Kennedy pathway” employing similar biochemical reaction steps. The PE thus formed can be sequentially methylated on its primary amine using S-adenosylmethionine as the methyl donor by the enzyme PE-N-Methyl-Transferase (PEMT) to form PC after the sequential transfer of 3 methyl groups. These sequential reactions are termed the PEMT pathway.

Both the phosphatidylserine and “Kennedy pathway” are found in mammalian cells but there are some tight restrictions on specific elements of the pathways. In contrast to yeast, the methylation reaction in mammalian cells is not sufficient for supplying all of the PC needed for cell growth.

Summed up, in vivo, phosphatidylcholine is produced via two major pathways. In the predominant pathway, two fatty acids are added to glycerol phosphate to generate phosphatidic acid. Next, phosphatidic acid is converted to diacylglycerol, after which phosphocholine is added on from CDPcholine. The second, minor pathway is phosphatidylethanolamine methylation, in which the phosphatidylethanolamine has three methyl groups added to its ethanolamine head-group, thereby converting it into phosphatidylcholine.

Metabolism

Enzymes/gene lists

  • Choline kinase

Dietary choline is absorbed by the intestine in the form of lysophosphatidylcholine or choline, and uptake of the latter is mediated by choline transporters. Upon entry into the cell, choline is immediately phosphorylated to phosphocholine or oxidized to betaine in some cell types such as hepatocytes. The phosphorylation of choline is catalyzed by choline kinase. The choline kinases can exist as either homodimers or heterodimers.

  • CTP:phosphocholine cytidylyltransferase

Although choline kinase catalyzes the initial and committed step in the conversion of choline to PC, choline kinase is usually not considered to be rate-limiting or to regulate the rate of PC biosynthesis. Rather, the second reaction in the pathway, catalyzed by CTP:phosphocholine cytidylyltransferase (CT), is usually rate-limiting. CT in the mouse is also encoded by two genes. Pcyt1a encodes CT 2 and the splice variant CT 3 and is located on chromosome 16 .

  • CDP-choline:1,2-diacylglycerol cholinephosphotransferase

The final reaction in the choline pathway for PC biosynthesis is catalyzed by CDP-choline:1,2-diacylglycerol cholinephosphotransferase (CPT). This enzyme has never been purified from any source, probably because it is an intrinsic membrane protein found primarily on the ER. With new molecular tools, such as the use of a tagged protein in an expression system, CPT purification can now be undertaken with a higher probability of success. Also, the gene(s) in mice that encodes CPT has not been characterized. However, two human CPT cDNAs have been cloned and expressed . Most studies indicate that there is an excess of CPT activity in cells; hence, the amount of enzyme does not limit the rate of PC biosynthesis. However, in vivo, it seems clear that the CPT reaction is governed by the supply of both CDP-choline and diacylglycerol.

Source: Zhaoyu Li and Dennis E. Vance, Journal of Lipid Research, Vol. 49, 1187-1194, June 2008

Associated biological processes

Technology

Analysis methods

Chemical synthesis

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