Lipids play a variety of cellular roles, some only recently recognized. They are the principal form of stored energy in most organisms and major constituents of cellular membranes. Specialized lipids serve as pigments (retinal, carotene), cofactors (vitamin K), detergents (bile salts), transporters (dolichols), hormones (vitamin D derivatives, sex hormones), extracellular and intracellular messengers (eicosanoids, phosphatidylinositol derivatives), and anchors for membrane proteins (covalently attached fatty acids, prenyl groups, phosphatidylinositol).

The ability to synthesize a variety of lipids is essential to all organisms. This topic describes the biosynthetic pathways for some of the most common cellular lipids, illustrating the strategies employed in assembling these water-insoluble products from water-soluble precursors such as acetate. Like other biosynthetic pathways, these reaction sequences are endergonic and reductive. They use ATP as a source of metabolic energy and a reduced electron carrier (usually NADPH) as a reductant.

In eukaryotic cells, phospholipid synthesis occurs primarily on the surfaces of the smooth ER and the inner mitochondrial membrane. Some newly formed phospholipids remain at the site of synthesis, but most are destined for other cellular locations. The process by which water-insoluble phospholipids move from the site of synthesis to the point of their eventual function is not fully understood, but we discuss some mechanisms that have emerged in recent years.


Fatty acid synthesis in animal and yeast cell occur in cytosol whereas in plant it occur in chloroplast stroma. Biosynthesis of fatty acid involves step wise addition of carbon units. The 2 carbon units are supplied from acetyl coA, which in turn derived from oxidation of glucose. Acetyl coA formed in matrix of mitrochondria cannot cross the inner mitochondrial membrane and the acetyl coA shuttle system is require to transport the 2 carbon units out of the mitochondria into the cytosol. The acetyl group passes out of mitochondria as citrate.

Within mitochondria acetyl coA reacts with oxaloacetate to form citrate in a reaction catalyse by citrate synthase. Under condition where acetyl coA and ATP are in high concentration the citrate leaves the mitochondria and in cytosol reacts with cytosolic coA and ATP to form acetyl coA and oxaloacetate in a reaction catalysed by citrate cleavage enzyme, citrate lyase.

Oxaloacetate cannot directly return to mitochondria matrix by crossing the mitochondrial membrane so it is first reduce into malate by malate dehydrogenase. Malate is oxidatively decarboxylated to pyruvate by malic enzyme and return in this form, into mitochondria. In mitochondria pyruvate is carboxylated into oxaloacetate by enzyme pyruvate caboxylase.

FIGURE DEPICTING :- Shuttle system for acetyl coA

Synthesis of palmitic acid

Palmitic acid is 16 carbon saturated fatty acid. A sequence of seven enzyme catalyzed reaction convert two carbon unit to four carbon unit.

The first committed and reversible step in fatty acid synthesis is the ATP dependent carboxylation of acetyl coA to form malonyl coA. The reaction is catalyzed by acetyl coA carboxylase which has biotin as prosthetic group. This enzyme is an allosteric enzyme. Palmitoyl coA , the final product of fatty acid synthesis act as a negative modulator where as citrate act as allosteric activator of this enzyme. Regulatory effect of citrate and palmitoyl coA are dependent on the phosphorylation state of the enzyme. Phosphorylation of regulatory sites decreases the affinity of the enzyme for citrate and in this case high level of citrate is required for activation.

The next step in biosynthetic pathway is formation of acetyl ACP and malonyl ACP by the enzyme acetyl transferase and malonyl  transferase  respectively

The activated intermediates of fatty acid biosynthesis are bound to sulfhydryl group of phosphopantetheine  molecule.

The four enzyme of fatty acid biosynthesis constitute elongation step. It includes condensation, reduction, dehydration and reduction. Repetition of elongation step increase chain length by 2 carbon atoms. In this way seven elongation cycle produces palmitic acid. Finally palmitoyl thioesterse catalyze the hydrolysis of the thioester  that binds the acyl chain to pantothiene enzyme releasing free palmitate. Palmitic acid carbon 16 and 15 are donated by acetyl coA and rest by malonyl coA.

We can consider the overall reaction for the synthesis of palmitate from acetyl-CoA in two parts. First, the formation of seven malonyl-CoA molecules:


Then, seven cycles of condensation and reduction


The enzyme that catalyze the reaction 2-7 forms multienzyme complex known as fatty acid synthase. There are two major variants of fatty acid synthase – fatty acid synthase 1 (FAS1) found in vertebrate and fungi (FAS2) found in plants and bacteria.

Elongation of fatty acid

The normal product of cytosolic fatty acid synthase complex  is palmitic acid longer than 16 carbon can be formed through the addition of two carbon units by elongation eukaryotes fatty acid elongation occur in ER and mitochondria.

The most active elongation system is found in ER. It adds malonyl coA onto palmitate in manner similar to action of fatty acid synthase except that coA is involve rather than ACP. Stearic acid is common product of elongation system (18 carbon).

A mitochondria elongation system uses acetyl coA rather then malonyl coA.

FIGURE DEPICTING Addition of two carbons to a growing fatty acyl chain: a four-step sequence
FIGURE DEPICTING :- Addition of two carbons to a growing fatty acyl chain: a four-step sequence


Cholesterol is a major constituent of the plasma membrane of animal cells. Most of the cholesterol derives from endogenous biosynthesis, which takes place mainly in liver ( about 50%). The rest is taken up from the food. Most of the cholesterol is incorporated into the lipid layer of plasma membrane. All 27 carbon atom in cholesterol are provided by acetate moiety (acetyl coA)

Four basic steps are involved in cholesterol synthesis

Formation of mevalonate from acetate

The first step in biosynthesis leads to intermediate mevalonate. The molecule of acetyl coA condense to form acetoacetyl coA, which condense with third molecule of acetyl coA to yield 6 carbon compound beta –hydroxyl-beta-methylglutary-coA  (HMG coA), the reaction is committed and rate determining step.

Conversion of mevalonate to isopentenyl pyrophosphate

After phosphorylation, mevalonate is decarboxylatedto isopentenyl pyrophosphate, activated C5 isoprenoid compound, with consumption of AT P.        

Polymerization of six isopentenyl pyrophosphate to form linear structure called squalene

Isopentenyl pyrophosphate undergo isomerisation to form dimethylallyl diphophate. The two C5 molecules condense to yield geranyl pyrophosphate, and the addition of another pyrophosphate produce fernasyl pyrophosphate. This can then undergo dimerization, in a head to head reaction, to yield squalene.

Cyclization of squalene form steroid nucleus.

Squalene, a linear isoprenoid, is cyclised with o2 being consumed to form lenosterol, a c30 sterol. Three methyl groups are cleaved from this in a subsequent reaction steps, to yield the end product cholesterol.

FIGURE DEPICTING Biosynthesis of cholesterol
FIGURE DEPICTING :- Biosynthesis of cholesterol


Synthesis of phosphatidylserine, phosphatidylethanolamine, and phosphatidylglycerol

The first strategy for head-group attachment is illustrated by the synthesis of phosphatidylserine, phosphatidylethanolamine, and phosphatidylglycerol in E. coli. The diacylglycerol is activated by condensation of phosphatidic acid with CTP to form CDP-diacylglycerol, with the elimination of pyrophosphate. Displacement of CMP through nucleophilic attack by the hydroxyl group of serine or by the C-1 hydroxyl of glycerol 3-phosphate yields phosphatidylserine or phosphatidylglycerol 3-phosphate, respectively. The latter is processed further by cleavage of the phosphate monoester (with release of Pi ) to yield phosphatidylglycerol.

Phosphatidylserine and phosphatidylglycerol can serve as precursors of other membrane lipids in bacteria. Decarboxylation of the serine moiety in phosphatidylserine, catalyzed by phosphatidylserine decarboxylase, yields phosphatidylethanolamine. In E. coli, condensation of two molecules of phosphatidylglycerol, with elimination of one glycerol, yields cardiolipin, in which two diacylglycerols are joined through a common head group.

In eukaryotes, phosphatidylglycerol, cardiolipin, and phosphatidylinositol  are synthesized by the same strategy used for phospholipid synthesis in bacteria. Phosphatidylglycerol is made exactly as in bacteria. Cardiolipin synthesis in eukaryotes differs slightly: phosphatidylglycerol condenses with CDP-diacylglycerol , not with another molecule of phosphatidylglycerol as in E. coli. Phosphatidylinositol is synthesized by condensation of CDP diacylglycerol with inositol . Specific phosphatidylinositol kinases then convert phosphatidylinositol to its phosphorylated derivatives.

Yeast, like bacteria, can produce phosphatidylserine by condensation of CDP-diacylglycerol and serine, and can synthesize phosphatidylethanolamine from phosphatidylserine in the reaction catalyzed by phosphatidylserine decarboxylase. Phosphatidylethanolamine may be converted to phosphatidylcholine (lecithin) by the addition of three methyl groups to its amino group; S-adenosylmethionine is the methyl group donor  for all three methylation reactions. These pathways are the major sources of phosphatidylethanolamine and phosphatidylcholine in all eukaryotic cells.

 In mammals, phosphatidylserine is not synthesized from CDP-diacylglycerol; instead, it is derived from phosphatidylethanolamine or phosphatidylcholine via one of two head-group exchange reactions carried out in the endoplasmic reticulum. Synthesis of phosphatidylethanolamine and phosphatidylcholine in mammals occurs by phosphorylation and activation of the head group, followed by condensation with diacylglycerol. For example, choline is reused (“salvaged”) by being phosphorylated then converted to CDP-choline by condensation with CTP. A diacylglycerol displaces CMP from CDP-choline, producing phosphatidylcholine.

An analogous salvage pathway converts ethanolamine obtained in the diet to phosphatidylethanolamine. In the liver, phosphatidylcholine is also produced by methylation of phosphatidylethanolamine (with S-adenosylmethionine, as described above), but in all other tissues phosphatidylcholine is produced only by condensation of diacylglycerol and CDP-choline.

FIGURE DEPICTING The major path from phosphatidylserine to phosphatidylethanolamine and phosphatidylcholine in all eukaryotes.
FIGURE DEPICTING :- The major path from phosphatidylserine to phosphatidylethanolamine and phosphatidylcholine in all eukaryotes

The biosynthesis of sphingolipids  and glycerophospholipids

The biosynthesis of sphingolipids takes place in four stages:

  1.  synthesis of the 18-carbon amine sphinganine from palmitoyl-CoA and serine
  2.  attachment of a fatty acid in amide linkage to yield N-acylsphinganine
  3.  desaturation of the sphinganine moiety to form N-acylsphingosine (ceramide)
  4.  attachment of a head group to produce a sphingolipid such as a cerebroside or sphingomyelin.

The first few steps of this pathway occur in the endoplasmic reticulum; the attachment of head groups in stage 4 occurs in the Golgi complex. The pathway shares several features with the pathways leading to glycerophospholipids: NADPH provides reducing power, and fatty acids enter as their activated CoA derivatives. In cerebroside formation, sugars enter as their activated nucleotide derivatives. Head-group attachment in sphingolipid synthesis has several novel aspects. Phosphatidylcholine, rather than CDP-choline, serves as the donor of phosphocholine in the synthesis of sphingomyelin. In glycolipids—the cerebrosides and gangliosides —the head-group sugar is attached directly to the C-1 hydroxyl of sphingosine in glycosidic linkage rather than through a phosphodiester bond. The sugar donor is a UDP-sugar (UDP-glucose or UDP-galactose).


  • Long-chain saturated fatty acids are synthesized from acetyl-CoA by a cytosolic system of six enzymatic activities plus acyl carrier protein (ACP). There are two types of fatty acid synthase. FAS I, found in vertebrates and fungi, consists of multifunctional polypeptides. FAS II is a dissociated system found in bacteria and plants. Both contain two types of —SH groups (one furnished by the phosphopantetheine of ACP, the other by a Cys residue of β-ketoacyl-ACP synthase) that function as carriers of the fatty acyl intermediates.
  •  Malonyl-ACP, formed from acetyl-CoA (shuttled out of mitochondria) and CO2 , condenses with an acetyl bound to the Cys —SH to yield acetoacetylACP, with release of CO2 . This is followed by reduction to the D-β-hydroxy derivative, dehydration to the trans-Δ 2 -unsaturated acyl-ACP, and reduction to butyryl-ACP. NADPH is the electron donor for both reductions. Fatty acid synthesis is regulated at the level of malonyl-CoA formation.
  • Six more molecules of malonyl-ACP react successively at the carboxyl end of the growing fatty acid chain to form palmitoyl-ACP—the end product of the fatty acid synthase reaction. Free palmitate is released by hydrolysis.
  • Palmitate may be elongated to the 18-carbon stearate. Palmitate and stearate can be desaturated to yield palmitoleate and oleate, respectively, by the action of mixed-function oxidases.
  •  Mammals cannot make linoleate and must obtain it from plant sources; they convert exogenous linoleate to arachidonate, the parent compound of eicosanoids (prostaglandins, thromboxanes, leukotrienes, and specialized proresolving mediators), a family of very potent signaling molecules. The synthesis of prostaglandins and thromboxanes is inhibited by NSAIDs that act on the cyclooxygenase activity of prostaglandin H2 synthase.
  • Cholesterol is formed from acetyl-CoA in a complex series of reactions, through the intermediates β-hydroxy-β-methylglutaryl-CoA, mevalonate, and two activated isoprenes, dimethylallyl pyrophosphate and isopentenyl pyrophosphate. Condensation of isoprene units produces the noncyclic squalene, which is cyclized to yield the steroid ring system and side chain.
  • ­­­­­Diacylglycerols are the principal precursors of glycerophospholipids.
  • In bacteria, phosphatidylserine is formed by the condensation of serine with CDP-diacylglycerol; decarboxylation of phosphatidylserine produces phosphatidylethanolamine. Phosphatidylglycerol is formed by condensation of CDP-diacylglycerol with glycerol 3-phosphate, followed by removal of the phosphate in monoester linkage.
  • Yeast pathways for the synthesis of phosphatidylserine, phosphatidylethanolamine, and phosphatidylglycerol are similar to those in bacteria; phosphatidylcholine is formed by methylation of phosphatidylethanolamine.
  •  Mammalian cells have some pathways similar to those in bacteria, but somewhat different routes for synthesizing phosphatidylcholine and phosphatidylethanolamine. The head-group alcohol (choline or ethanolamine) is activated as the CDP derivative, then condensed with diacylglycerol. Phosphatidylserine is derived only from phosphatidylethanolamine.
  • The characteristic double bond in plasmalogens is introduced by a mixed function oxidase. The head groups of sphingolipids are attached by unique mechanisms.
  • Phospholipids travel to their intracellular destinations via transport vesicles or specific proteins, Chromosomes.


  • Lehninger  principles of biochemistry seventh edition By  David L. Nelson and Michael M. Cox
  • voets and voets biochemistry 4th edition
  • Life sciences  fundamental and practices sixth edition, pathfinder publication By Pranav Kumar and Usha Mina
  • Essential cell biology (fourth edition) by ALBERTS, BRAY, HOPKIN, JOHNSON, LEWIS, RAFF, ROBERTS, WALTER

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