Review of lipids:

Membrane lipids come in three categories:

a. glycerophospholipids, made up of glycerol, fatty acids, phosphate, and another alcohol

b. sphingolipids, which contain a long-chain amino alcohol

c. cholesterol, a tetracyclic alcohol

Together they form the membranous structures found in biological systems.

Synthesis of glycerophospholipids:

Fatty acid synthesis has been described (see Topic 809). Activated fatty acids and glycerol phosphate are required in order to begin the synthesis glycerophospholipids. Glycerol phosphate is derived from dihydroxyacetone phosphate, which is formed in glycolysis.

dihydroxyacetone phosphate (DHAP) + NADH ----> glycerol-3-phosphate + NAD+

Fatty acids are converted to CoA derivatives, which are the activated forms of fatty acids. The fatty acids are joined to the glycerol phosphate by the enzyme glycerol-3-phosphate acyltransferase.

glycerol-3-phosphate + 2 Acyl-CoA ----> phosphatidic acid

The phosphatidic acid is activated in turn to CDP-diacylglycerol:

phosphatidic acid + CTP ----> CDP-diacylglycerol + PPi

CDP-diacylglycerol + serine ---> phosphatidyl serine + CMP

phosphatidyl serine ----> CO2 + phosphatidyl ethanolamine

phosphatidyl ethanolamine + 3 AdoMet ----> phosphatidyl choline + 3 Ado-homoCys

It is important to salvage choline groups since the amino acid methionine (Met) is often limiting in animal diets.

Source of methyl groups for phosphatidylcholine:

Vitamin B12 has been demonstrated to provide two functions in humans: it is involved in the conversion of branched chain amino acids into succinyl-CoA and in the production of S-adenosyl methionine (Ado Met).

Synthesis of sphingosine:

Sphingolipids (which derive their name from the Sphinx) are mysterious, yet important lipids that are found in highly differentiated tissues, such as brain and nerves. Their functions still not fully understood. The synthesis of sphingosine takes place by the following route:

fatty acyl-CoA + serine ----> 3-keto dihydrosphingosine

3-keto dihydrosphingosine + NADPH ----> dihydrosphingosine

dihydrosphingosine + FAD ----> sphingosine

Plasmalogens and related alkyl ethers:

In plasmalogens, the C-1 substituent of glycerol is converted to an a,b-unsaturated ether (not ester).

Platelet activating factor is one of the most potent small molecule known; it is active at 10-11 M (compared to 10-13 for antibody-antigen binding).

Tay-Sachs disease

Gangliosides make up about 6% of lipids of gray matter of the brain. Like other biological molecules gangliosides undergo turnover; breakdown, which occurs in lysosomes, begins with the removal of sugars.

In Tay-Sachs disease a b-N-aceylhexosaminidase is missing or deficient, and as a consequence the ganglioside GM2 can not be broken down:

ganglioside GM2 --x-->

Levels of this ganglioside in the brain become elevated to many times the normal level; the result is weakness, retardation of development, death of the individual by the age of three.