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Download Chem*3560 Lecture 23: Phospholipid Biosynthesis
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Chem*3560 Lecture 23: Phospholipid Biosynthesis Fats and phospholipids share the same initial synthesis pathway Fats and phospholipids both contain fatty acids linked by ester bonds to a glycerol backbone , and are described as glycerolipids . The synthesis pathway starts by reducing dihydroxyacetone phosphate to glycerol phosphate, with NADH as the reductant (Lehninger p789). NAD+ dependent glycerol phosphate dehydrogenase dihydroxyacetone phosphate + NADH + H+ → L-glycerol-3-phosphate + NAD + (Compare this with FAD dependent glycerol phosphate dehydrogenase, which runs in the opposite direction because FAD is a stronger oxidant than NAD+) FAD dependent glycerol phosphate dehydrogenase L-glycerol-3-phosphate + FAD → dihydroxyacetone phosphate + FADH2 Alternatively, existing glycerol molecules may be phosphorylated by glycerol kinase. glycerol kinase glycerol + ATP → L-glycerol-3-phosphate + ADP Note that glycerol is symmetrical, but becomes chiral after the phosphate is added at one end. This is followed by two successive additions of acyl ester. Fatty acid (typically 16-18 C atoms) is first converted to the active CoA thioester by acyl CoA synthetase: acyl CoA synthetase stearate (18:0) + HSCoA + ATP → stearoyl-CoA + 5'-AMP + PPi pyrophosphatase ↓ 2 Pi PPi is the abbreviation for HP2 O7 3– , inorganic pyrophosphate. Pyrophosphatase helps provide driving force for the synthetase reaction by immediately breaking down PPi and keeping its cellular concentration very low. When ATP is broken down to 5'-AMP, this is equivalent in energy terms to 2 × ATP to ADP. Acyl-CoA is then used to donate acyl ester groups to the glycerol backbone: acyltransferase L-glycerol-3-phosphate + acyl-CoA → 1-acylglycerol-3-phosphate + HSCoA acyltransferase 1-acylglycerol-3-phosphate + stearoyl-CoA → 1,2-diacylglycerol-3-phosphate + HSCoA 1. glycerol phosphate dehydrogenase 2. glycerol kinase 3. acyl transferase The last product, 1,2-diacylglycerol-3-phosphate, is also known as phosphatidic acid, and its phospholipid derivatives are phosphatidyl-X. Phospholipids also tend to have a saturated fatty acid in position 1 and an unsaturated fatty acid in position 2. The fat synthesis pathway branches here Phosphate is first removed by phosphatidic acid phosphatase, then acyl transferase can add the third acyl ester group to make triacylglycerol or fat (Lehninger p. 790). Phospholipids are derived by adding a head group to phosphatidic acid Phospholipids are major components of membrane bilayers, so are structural components of the cell, whereas triacylglycerols are stored as the bodies main energy reserve. Phosphatidic acid itself tends to disrupt bilayer structure, and must be modified by adding a polar headgroup. The head group is a hydroxyl or alcohol compound that forms an ester bond with the phosphate of phospahtidic acid. The makes the product a phosphodiester, phosphate with two ester groups. Phospholipid precursors are activated by forming a cytidine diphosphate derivative The activation process and activated product is exactly analogous to the formation of UDP-glucose as an activated glucose donor. The substrate phosphate ester displaces pyrophosphate (PPi). PPi concentration is kept very low because it is immediately broken down by pyrophosphatase, and this low product concentration provides the driving force for the reaction. The enzyme CTP:phosphatidate cytidylyl transferase is systematically named based on the idea that the cytidylyl radical (radical of 5'-CMP) is transferred from CTP to phosphatidic acid. The product, CDP-diacylglycerol contains a high energy bond between the two phosphates, so can act as a donor of diacylglycerol (bond breaks between glycerol and phosphate) or as a donor of the phosphatidyl radical (bond breaks between the phosphates) (Lehninger p. 792-3). Head groups: phosphatidyl serine and phosphatidyl ethanolamine Microorganisms use the head group hydroxyl compound to displace CMP and then link up to the phosphatidyl radical. The amino acid serine , which has a hydroxyl group side chain provides the head group for the negative phospholipid, phosphatidyl serine . Phosphatidyl serine can then be decarboxylated to produce the important neutral phospholipid, phosphatidyl ethanolamine. In animals, phosphatidyl ethanolamine and phosphatidyl choline are made by a different strategy, in which ethanolamine and choline are activated as CDP ethanolamine and CDP choline (Lehninger p.794-5). Diacylglycerol then displaces CMP to bond to the phosphate attached to the headgroup, as shown for the synthesis of phosphatidyl choline, a major animal phospholipid. The strategy used in animals is optimized for what is called salvage synthesis, in which existing molecules of ethanolamine, choline and diacylglyerol are reused. The bacterial strategy is better for de novo synthesis, in which molecules are created from simple starting compounds such as aminoacids or dihydroxyacetone. Animals produce phosphatidyl serine by a process called headgroup exchange: phosphatidyl ethanolamine serine transferase Phosphatidyl ethanolamine + serine → phosphatidyl serine + ethanolamine phosphatidyl serine CO2 decarboxylase Decarboxylation of phosphatidyl serine produces new molecules of ethanolamine. phosphatidyl ethanolamine New molecules of choline are made on the phospholipid structure of phophatidyl ethanolamine. The methyl donor is a compound of methionine and adenosine called S-adenosyl methionine or SAM for short, leaving behind S-adenosylhomocysteine, SAHC (Lehninger p.795). This is an expensive process, because it consumes a three molecules of methionine, which animals can't synthesize, and can only obtain in the diet. The dietary content of methionine is quite low, so animals conserve choline as much as possible.