Glycerolipid Biosynthesis

A common pathway operates in nearly all organisms for the synthesis of phos-phatidic acid, the precursor to other glycerolipids. Glycerokinase catalyzes the phosphorylation of glycerol to form glycerol-3-phosphate, which is then acyl-ated at both the 1- and 2-positions to yield phosphatidic acid (Figure 25.18). The first acylation, at position 1, is catalyzed by glycerol-3-phosphate acyl-transferase, an enzyme that in most organisms is specific for saturated fatty acyl groups. Eukaryotic systems can also utilize dihydroxyacetone phosphate as a starting point for synthesis of phosphatidic acid (Figure 25.18). Again a specific acyltransferase adds the first acyl chain, followed by reduction of the backbone keto group by acyldihydroxyacetone phosphate reductase, using NADPH as the reductant. Alternatively, dihydroxyacetone phosphate can be reduced to glycerol-3-phosphate by glycerol-3-phosphate dehydrogenase.

Eukaryotes Synthesize Glycerolipids from CDP-Diacylglycerol or Diacylglycerol

In eukaryotes, phosphatidic acid is converted directly either to diacylglycerol or to cytidine diphosphodiacylglycerol (or simply CDP-diacylglycerol; Figure 25.19). From these two precursors, all other glycerophospholipids in eukaryotes are derived. Diacylglycerol is a precursor for synthesis of triacylglycerol, phos-phatidylethanolamine, and phosphatidylcholine. Triacylglycerol is synthesized mainly in adipose tissue, liver, and intestines and serves as the principal energy storage molecule in eukaryotes. Triacylglycerol biosynthesis in liver and adipose tissue occurs via diacylglycerol acyltransferase, an enzyme bound to the cytoplasmic face of the endoplasmic reticulum. A different route is used, however, in intestines. Recall (Figure 24.3) that triacylglycerols from the diet are broken down to 2-monoacylglycerols by specific lipases. Acyltransferases then acylate 2-monoacylglycerol to produce new triacylglycerols (Figure 25.20).

Phosphatidylethanolamine Is Synthesized from Diacylglycerol and CDP-Ethanolamine

Phosphatidylethanolamine synthesis begins with phosphorylation of ethanol-amine to form phosphoethanolamine (Figure 25.19). The next reaction involves transfer of a cytidylyl group from CTP to form CDP-ethanolamine and pyrophosphate. As always, PPi hydrolysis drives this reaction forward. A specific phosphoethanolamine transferase then links phosphoethanolamine to the di-acylglycerol backbone. Biosynthesis of phosphatidylcholine is entirely analogous because animals synthesize it directly. All of the choline utilized in this pathway must be acquired from the diet. Yeast, certain bacteria, and animal livers, however, can convert phosphatidylethanolamine to phosphatidylcholine by methylation reactions involving S-adenosylmethionine (see Chapter 26).

Exchange of Ethanolamine for Serine Converts Phosphatidylethanolamine to Phosphatidylserine

Mammals synthesize phosphatidylserine (PS) in a calcium ion-dependent reaction involving aminoalcohol exchange (Figure 25.21). The enzyme catalyzing this reaction is associated with the endoplasmic reticulum and will accept phos-phatidylethanolamine (PE) and other phospholipid substrates. A mitochon-drial PS decarboxylase can subsequently convert PS to PE. No other pathway converting serine to ethanolamine has been found.

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