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Fatty Acid and Lipid Synthesis

©2000 Timothy Paustian, University of Wisconsin-Madison

The structure of lipids is described in the cell membrane page in the bacterial structure chapter. Lipid synthesis consists of two phases

1. Fatty acid synthesis where the long alkyl chains are assembled using acetyl-CoA as substrate.

2. Assembly of the lipid by combining, sn-glycerol-3-phosphate, the finished fatty acid and the polar head group.

Fatty acid synthesis

Synthesis of fatty acids takes place in the cytoplasm and involves initiation of synthesis by the formation of acetoacetyl-ACP and then an elongation cycle where 2 carbon units are successively added to the growing chain.

ACP

Acyl carrier protein (ACP) serves as a chaperone for the synthesis of fatty acids. The growing fatty acid chain is covalently bound to ACP during the entire synthesis of the fatty acid and only leaves the protein when it is attached to the glycerol backbone of the forming lipid. ACP is one of the most abundant proteins in the bacterial cell (60,000 molecules per E. coli cell) which makes sense given the amount of lipid that must be synthesized to make an entire cell membrane. The formation of acetoacetyl-ACP can be catalyzed by a number of enzymes, but in all cases the starting substrate is acetyl-CoA.

Figure 1 - Synthesis of acetoacetyl-ACP from CoA.

Once formed, acetoacetyl-ACP enters the elongation cycle for fatty acid synthesis. This cycle is the reverse of the b-oxidation of fatty acids discussed earlier. The first step in the elongation cycle is condensation of malonyl-CoA with a growing acetoacetyl-ACP chain. This adds two carbons to the chain. The next three reactions use 2 NADPH to reduce the b-ketone (red in figure) and generate an acyl-ACP molecule two carbons longer than the original substrate. The acyl-ACP molecule continues through the cycle until the appropriate chain length is reached. In E. coli fatty acid chains in lipids are 12-20 carbons long. The length of the fatty acid chains and the number of double bonds (unsaturation) is dependent upon the temperature the bacteria is growing at. The membrane must remain fluid. Using short chain fatty acids with higher degrees of unsaturation increases the fluidity of the membrane. As the temperature increases, longer fatty acid chains with fewer double bonds will be more prevalent in the membrane.

Figure 2 - The elongation cycle of fatty acid biosynthesis.

Assembly of the Lipid

The enzymes of phospholipid synthesis are bound to the inside of the cytoplasmic membrane. The glycerol backbone of bacterial lipids originate from dihydroxyacetone phosphate (a central metabolite in glycolysis). This is reduced to sn-glycerol 3-phosphate using NADH. In the next step fatty acids are transferred from acyl-ACP to sn-glycerol 3-phosphate to form phosphatidic acid. Finally, the hydrophilic portion of the lipid is added. One of the most common lipids formed (phosphatidyl serine) is shown in the figure below.

Figure 3 - Lipid Assembly.

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