PE-methyltransferases

FIGURE 6.2 Phosphatidylcholine (PC) synthesis by the CDP-ethanolamine pathway. Structures of ethanolamine and choline. The nucleotide moiety S-adenosyl methionine (SAM) is required to transfer the methyl group of methionine to phosphatidylethanolamine (PE) to form PC. In the process, SAM is converted to S-adenosyl homocysteine (SAH). The nitrogen atom of PC has four covalent bonds and is called a quaternary amine. It bears a positive charge that is not influenced by changes in the pH of the surroimding fluids. The PE methyltransferase pathway of PC synthesis occurs only in the liver. 

All nucleated cells contain PC and utilize the CDP-choline pathway. Thus, it was not obvious why the alternative pathway for PC synthesis, the PE methylation pathway (Fig. 4), survived during evolution. Nor was it obvious why PE methyltransferase (PEMT) activity is essentially a liver-specific enzyme whereas 2% or less of the hepatic PEMT activity is found in other tissues. In addition to producing PC, PEMT generates three... 

Fig. 10. Genetic analysis of aminoglycerophospholipid transport in eukaryotes. The transport of PS synthesized in the ER is regulated by PSTA and PSTB genes. The acronym stands for PS transport (either A or B pathways). Likewise, the transport of PE synthesized in the mitochondria or Golgi/vacuole is proposed to be regulated by PEEA and PEEB genes. The acronyms stand for PE export (either A or B pathways). Both known and proposed mutations along the metabolic and transport pathways appear in lower case italics. The table summarizes the mutants, genes, and proteins that have been identified in Chinese hamster ovary (CHO) cells and yeast. Other abbreviations pss, PS synthase psd, PS decarboxylase pern, PE methyltransferase Cho, choline Etn, ethanolamine Ser, serine.

Figure 1. Pathways for the synthesis of phosphatidylcholine, phosphatidylethanolamine and sphingomyelin. Abbreviations CK, choline kinase CPT, cholinephosphotransferase CT, CTP phosphooholine cytidylyltransferase DAG, diacylglycerol PC, phosphatidylcholine PE, phosphatidylethanolamine PEMT, phosphatidylethanolamine-N-methyltransferase SM, sphingomyelin SMase, sphingomyelinase SMsyn, sphingomyelin synthase.

A minor pathway to synthesize PC, which is mainly active in liver cells, utilizes the enzyme phosphatidylethanolamine-A-methyltransferase (PEMT), which converts phosphatidylethanolamine (PE) to PC by the subsequent transfer of three methyl groups from S-adenosylmethionine (Vance et al, 1997). The PEMT pathway, which links PE synthesis to PC, was found to be critical for PC homeostasis in the Uver dining choline deficiency (Walkey et al, 1997). 

Fig. 1. Phospholipid biosynthetic pathways in animal cells. The abbreviations are DHAP, dihydroxyacetone phosphate G-3-P, glycerol-3-phosphate PA, phosphatidic acid DG, diacylglycerol CDP-DG, cytidine diphosphodiacylglycerol PI, phosphatidylinositol PG, phosphatidylglycerol PG-P, phosphatidylglycerol phosphate DPG, diphosphatidylglycerol PP, phosphatidic acid phosphatase PE, phosphatidylethanolamine PC phosphatidylcholine PEMT, phosphatidylethanolamine A-methyltransferase CT, CTP phosphocholine cytidylyltransferase PS, phosphatidylserine CK/EK, choline/ethanolamine kinase CPT, CDP-choline 1,...

Fig. 3. Regulation of PC biosynthesis via the CDP-choline pathway by modulation of the binding of CTP phosphocholine cytidylyltransferase (CT) to membranes. Three different modes of regulation of CT activity are indicated. The abbreviations are CK, choline kinase CPT, CDP-choline 1,2-diacylglycerol cholinephos-photransferase PEMT, phosphatidylethanolamine Af-methyltransferase PC, phosphatidylcholine PE, phos-phatidylethanolamine DG, diacylglycerol.

Bacteria generally do not contain PC but Rhodobacter sphaeroides and some other bacteria make PC by the methylation of PE. Interestingly, this methyltransferase is a soluble protein that has virtually no homology to PEMT or the yeast enzymes (V. Arondel, 1993). Also, in some bacteria, such as Sinorhizobium meliloti, a novel choline-dependent pathway was discovered in which choline reacts with CDP-DG to form PC (O. Geiger, 2003). 

Both Kennedy pathway through CDP-choline and successive methylation from PE to PC catalyzed by A-methyltransferases [2, 3] play equal roles in... 

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