Lipid Synthesis Prof S. Kajuna Triacylglycerols Synthesis of triacylglycerols occurs primarily in liver and in adipose tissue from CoA derivative of fatty acids via phosphatidic acid. Free fatty acids are converted to acyl CoA derivatives by one of several chain-length dependent fatty acid CoA ligases in microsomes.

Fatty acid + CoA + ATP = Fatty acyl CoA + AMP +ppi 1-acylglycerol -3-phosphate is then formed from acyl CoA and L-glycerol-3-phosphate to give 1-acylglycerol-3-phosphate in a reaction catalysed by glycerol-3-phosphate acyltransferase. 1-acylglycerol-3-phosphate reacts with a second acyl CoA in a reaction catalysed by lysophosphatidic acid acyltransferase to give phosphatidic acid.

Phosphatidates Formation of phosphatidylethanolamine: Initially, ethanolamine is phosphorylated by an ethanolamine kinase to form phosphoethanolamine Ethanolamine + ATP = -HO3-P-OCH2CH2NH3+ + ADP A cytidyl transferase then catalyses reaction of phosphoethanolamine with CTP to yield cytidine diphosphoethanolamine. CDP-ethanolamine is then converted to the phosphatidate by a phosphotransferase-catalysed reaction.

CDP-ethanolamine + L-1,2-diacylglycerol = phosphatidylethanolamine The 1,2-diacylglycerol may arise from triacylglycerol or by the action of a phosphatase on phosphatidic acid. Formation of phosphatidylcholine: This occurs in stages by successive transfer of three methyl groups from S-adenosylmethionine to phosphatidylethanolamine. The methylations are catalysed by N-methyltransferase.

Phosphatidic acid is a precursor of both the triacylglycerols and some phosphoglycerides. Glycerol-3-phosphate is derived from free glycerol which is phosphorylated by glycerokinase and ATP, or by reduction of dihydroxyacetone phosphate. Hydrolysis of phosphatidic acid by a phosphatidic acid phosphatase yields a 1,2-diacylglycerol, which in turn reacts with another mole of acyl CoA in a reaction catalysed by diacylglycerol acyltransferase to form a neutral triacylglycerol.

In addition to the above pathway for formation of phosphatidic acid, there is acylation of dihydroxyacetone phosphate by dihydroxyacetone phosphate acyltransferase. Reduction to lysophosphatidic acid is accomplished by a microsomal oxidoreductase.

Cytidine triphosphate + phosphocholine =cytidine diphosphocholine +ppi The ppi is derived from CTP. A cholinephosphotransferase catalyses reactions of cytidine diphosphocholine (CDP-choline) with 1,2-diacylglycerol to yield phosphatidylcholine and cytidine monophosphate (CMP). Formation of Phosphatidylserine: In mammals phosphatidylserine is formed by an exchange reaction, catalysed by phosphatidylethanolamine:serine transferase. Phosphatidylserine is decarboxylated by phosphatidylserine decarboxylase, an enzyme containing pyridoxal phosphate. The net result of the exchange reaction and the decarboxylation is the conversion of serine to ethanolamine. This provides additional ethanolamine for the de novo synthesis of phosphatidylcholine, as described earlier.

Formation of Phosphatidylinositides and Phosphatidylglycerols These nitrogen-free derivatives of glycerol phosphate are synthesised by transferases. CDP-diacylglycerol + myoinositol = phosphatidylinositol + CMP 3-phosphatidyl-1-glycerophosphate = 3-phosphatidyl-1-glycerol + pi Diphosphatidylglycerol (cardiolipin) is formed from two molecules of phosphatidylglycerol. CDP-diglyceride is required as a cofactor.

2 Phospatidylglycerol + cardiolipin + glycerol Plasmalogens (Ether lipids): The acyl group of monoacyl dihydroxyphosphate is exchanged for a fatty alcohol (formed by reduction of fatty acid) with retention of the α-hydrogen atoms and the oxygen of the alcohol. The O-alkyl dihydroxyacetone phosphate is then reduced to O-alkylglyceryl phosphate with NADPH or NADH as hydrogen donor. This is followed by acylation via a fatty acyl CoA. The 1-alkyl-2-acylglycerol phosphate is dephosphorylated and converted to an alkyl analog of the phosphoglycerides containing choline, ethanolamine, or serine by the reactions previously described. The 1-alkyl-2-acylglyceryl phosphoethanolamine is converted to the plasmalogen by a specific desaturase in the presence of O2 and NADH or NADPH.

Sphingolipids Formation of sphingosines: The long chain aliphatic bases sphinganine – (dihydrosphingosine-) and sphingenine- (sphingosine) are synthesised by many animal tissues. PalmitoylCoa + L-serine = 3-dehydrosphinganine 3-dehydrosphinganine is in turn acted upon by a reductase enzyme in the presence of NADPH to form D-sphinganine. Subsequently the carboxyl group of serine is lost as CO2 .

Formation of Ceramides: The ceramides, fatty acid amides of sphingosine, are formed by a ceramide: N-acyl transferase from fatty acyl CoA derivatives. Formation of sphingomyelins: There are several routes for the synthesis of sphingomyelins. One accounts for most of the synthesis and is catalysed by a CDP-choline:ceramide –choline phosphotransferases, found in liver mitochondria and homogenates of brain and spleen.

Glycolipids The cerebrosides, ceramide oligosaccharides, cerebroside sulfatides, globosides and gangliosides are present in small amounts in the membranes of a wide variety of tissues. Nervous tissues are particularly rich in gangliosides. The biological functions of the glycosphingolipids are not completely understood, but certain viruses, such as influenza, adhere to cell surfaces through viral receptors that bind specific sialic acid groups in gangliosides. Cholera and diphtheria toxins also bind to host cells through sialic acid groups in gangliosides. The specificity of the ABO and the Lewis blood group antigens on cells such as erythrocytes are determined by the carbohydrate groups of ceramide oligosaccharides.

Glycolipids are synthesised by the sequential actions of a series of glycosyltransferases. The simplest glycolipids, gluco- or galactocerebrosides (ceramide monosaccharides), are synthesized by the transfer of a monosaccharide from the appropriate nucleotide sugar (i.e UDP-Gal, UDP-Glc, or CMP-Sia) to the C-1 hydroxyl group of a ceramide, the lipid component of all glycosphingolipids. Further addition of monosaccharides from nucleotide sugars produces the more complex glycolipids with two, three, or more sugars in glycosidic linkage. The synthetic pathways are similar to those for the synthesis of the O-linked oligosaccharides in glycoproteins. Synthesis of the sulphatides also requires the transfer of sulphate from 31-phosphoadenosine-51-phosphosulphate to specific hydroxyl groups on the carbohydrate. The main feature that distinguishes gangliosides from other types of glycolipids is the presence of sialic acid, which is often N-acetylneuraminic acid.