Lipid Classification and Fatty Acid Structure
Lipids are divided into three major groups: triacylglycerols (TAGs, true fats), phospholipids, and steroids. TAGs are composed of a glycerol backbone and three fatty acid residues. Phospholipids share the same glycerol backbone and two fatty acid residues, but the third position contains a phosphoric acid residue linked to a positively charged polar head group (choline, ethanolamine, serine, inositol). Steroids are represented by cholesterol and its derivatives, such as bile acids, steroid hormones, and vitamin D.
Functionally, TAGs serve as the primary energy storage form, also providing thermal insulation and mechanical protection. Due to their amphiphilic nature (a hydrophilic head and two hydrophobic tails), phospholipids form the bilayer of biological membranes.
Fatty acids are subdivided into saturated (lacking double bonds) and unsaturated—monounsaturated (one double bond) and polyunsaturated (several double bonds). Fatty acid notation includes the number of carbon atoms followed by a colon and the number of double bonds; the bond position is indicated using the Δ symbol (counted from the carboxyl group) or the ω symbol (counted from the methyl end). It is essential to know palmitic, stearic, linoleic, linolenic, arachidonic, and eicosapentaenoic acids.
Acetyl-CoA and Acyl-CoA
These compounds are frequently confused. Acetyl-CoA contains a two-carbon acetyl group (CH₃–CO–) and is formed during the oxidative decarboxylation of pyruvate, entering the Krebs cycle. Acyl-CoA (R–CO–S-CoA) is an activated fatty acid with a long hydrocarbon radical R; acyl-CoA acts specifically as the acyl group donor in the synthesis of fats and phospholipids.
It is also important to distinguish between "fats" (triacylglycerols, composed of glycerol and three fatty acids) and "fatty acids" as independent molecules.
Formation of Glycerol-3-Phosphate
TAG synthesis requires two types of substrates: acyl-CoA and glycerol-3-phosphate. The latter can be obtained via two pathways.
- From free glycerol: the enzyme glycerol kinase transfers a phosphate group from ATP to the third carbon atom of glycerol, yielding ADP and glycerol-3-phosphate.
- From glucose: the glycolysis intermediate dihydroxyacetone phosphate is reduced to glycerol-3-phosphate by the enzyme glycerol-3-phosphate dehydrogenase using NADH (NADH → NAD⁺).
Both pathways operate in the liver because both enzymes are present. Adipose tissue lacks glycerol kinase, making glucose the exclusive source of glycerol-3-phosphate.
Assembly of Triacylglycerol
Acyl groups from two molecules of acyl-CoA are sequentially attached to glycerol-3-phosphate (with the release of HS-CoA). These reactions are catalyzed by acyl-CoA transferases. Following the addition of two fatty acids, phosphatidic acid (phosphatidate) is formed—a key intermediate metabolite common to both TAG and phospholipid synthesis.
- Hydrolytic cleavage of the phosphate group of phosphatidate by the enzyme phosphatidate phosphatase yields diacylglycerol.
- Addition of the third fatty acid residue from acyl-CoA, mediated by acyl-CoA transferase, to form triacylglycerol.
The pathway from glycerol-3-phosphate to TAG is identical in the liver and adipose tissue; only the source of glycerol-3-phosphate differs.
Glycerophospholipid Synthesis Strategies
Glycerophospholipids (phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol) differ in their polar head groups. Eukaryotes utilize two strategies for component activation involving CTP (cytidine triphosphate).
- First strategy: CTP activates core phosphatidic acid to form CDP-diacylglycerol, to which a free head group is subsequently attached. Phosphatidylinositol is synthesized via this pathway (enzyme: inositol synthase), with the release of CMP.
- Second strategy: CTP activates the head group, forming CDP-choline or CDP-ethanolamine, which then attach to free diacylglycerol to yield phosphatidylcholine or phosphatidylethanolamine, respectively.
Interconversions of Phospholipids
Phosphatidylserine is not synthesized de novo by either of the two strategies in eukaryotes. It is formed from phosphatidylethanolamine or phosphatidylcholine by substituting the head group with free serine (a reversible reaction).
A direct link exists between phosphatidylethanolamine and phosphatidylcholine: methyltransferase transfers three methyl groups from S-adenosylmethionine (SAM) to the amino group of ethanolamine, converting phosphatidylethanolamine into phosphatidylcholine.
Phosphatidylethanolamine can be generated from phosphatidylserine via a decarboxylation reaction (catalyzed by a decarboxylase): the carboxyl group of serine is cleaved, leaving an ethanolamine residue. Thus, these three phospholipids are linked through a network of interconversions.
Key points
- Triacylglycerols and phospholipids share a common glycerol backbone and a common intermediate metabolite—phosphatidic acid.
- Acetyl-CoA is a two-carbon substrate of the Krebs cycle; acyl-CoA is an activated long-chain fatty acid.
- Glycerol-3-phosphate is formed from glycerol (glycerol kinase, ATP) or from DHAP (glycerol-3-phosphate dehydrogenase, NADH).
- Adipose tissue lacks glycerol kinase, meaning TAGs are synthesized exclusively from glucose.
- Acyl-CoA transferases transfer fatty acid residues to glycerol-3-phosphate and diacylglycerol.
- Phosphatidylinositol is synthesized via CDP-diacylglycerol; phosphatidylcholine and phosphatidylethanolamine are synthesized via CDP-activated head groups.
- Phosphatidylserine is formed through head group exchange from phosphatidylethanolamine or phosphatidylcholine.
- Methylation of phosphatidylethanolamine using SAM yields phosphatidylcholine; decarboxylation of phosphatidylserine yields phosphatidylethanolamine.