Учебное пособие: Lipid biosynthesis

LIPID BIOSYNT

Energy Storage

Fatty acid synthesis is regulated, both in plants and animals. Excess carbohydrate and protein in the diet are converted into fat. Only a relatively small amount of energy is stored in animals as glycogen or other carbohydrates, and the level of glycogen is closely regulated.

Protein storage doesn’t take place in animals. Except for the small amount that circulates in the cells, amino acids exist in the body only in muscle or other protein-containing tissues. If the animal or human needs specific amino acids, they must either be synthesized or obtained from the breakdown of muscle protein. Adipose tissue serves as the major storage area for fats in animals. A normal human weighing 70 kg contains about 160 kcal of usable energy. Less than 1 kcalexists as glycogen, about 24 kcal exist as amino acids in muscle, and the balance-more than 80 percent of the total-exists as fat. Plants make oils for energy storage in seeds. Because plants mustsynthesize all their cellular components from simple inorganic compounds, plants-but usually not animals-can use fatty acids from these oils to make carbohydrates and amino acids for later growth after germination.

Fatty Acid Biosynthesis

The biosynthetic reaction pathway to a compound is usually not a simple opposite of its breakdown. Chapter 12 of Volume 1 discusses this concept in regard to carbohydrate metabolism and gluconeogenesis. In fatty acid synthesis, acetyl-CoA is the direct precursor only of themethyl end of the growing fatty acid chain. All the other carbons come from the acetyl group of acetyl-CoA but only after it is modified to provide the actual substrate for fatty acid synthase, malonyl-CoA.

Malonyl-CoA contains a 3-carbon dicarboxylic acid, malonate,bound to Coenzyme A. Malonate is formed from acetyl-CoA by the addition of CO2 using the biotin cofactor of the enzyme acetyl-CoA carboxylase.

HCO3

– Acetyl-CoA + HCO3

– + ATP Malonyl-CoA + ADP + Pi

Formation of malonyl-CoA is the commitment step for fatty acid synthesis, because malonyl-CoA has no metabolic role other than serving as a precursor to fatty acids.

Fatty acid synthase (FAS) carries out the chain elongation steps of fatty acid biosynthesis. FAS is a large multienzyme complex. In mammals, FAS contains two subunits, each containing multipleenzyme activities. In bacteria and plants, individual proteins, which associate into a large complex, catalyze the individual steps of the synthesis scheme.

Initiation

Fatty acid synthesis starts with acetyl-CoA, and the chain grows from the “tail end” so that carbon 1 and the alpha-carbon of the complete fatty acid are added last. The first reaction is the transfer of the acetyl group to a pantothenate group of acyl carrier protein (ACP), a region of the large mammalian FAS protein. (The acyl carrier protein is a small, independent peptide in bacterial FAS, hence the name).

The pantothenate group of ACP is the same as is found on Coenzyme A, so the transfer requires no energy input: Acetyl~S-CoA + HS-ACP® HS-CoA + Acetyl~S-ACP.

In the preceding reaction, the S and SH refer to the thio group on the end of Coenzyme A or the pantothenate groups. The ~ is a reminder that the bond between the carbonyl carbon of the acetylgroup and the thio group is a “high energy” bond (that is, the activated acetyl group is easily donated to an acceptor). The second reaction is another transfer, this time, from the pantothenate of the ACP to cysteine sulfhydral (–SH) group on FAS.

Acetyl~ACP + HS-FAS ® HS-ACP + Acetyl~S-FAS

Note that at this point, the FAS has two activated substrates, the acetyl group bound on the cysteine –SH and the malonyl group bound on the pantothenate –SH. Transfer of the 2-carbon acetyl unit from

Acetyl~S-cysteine to malonyl-CoA has two features:

Release of the CO2 group of malonyic acid that was originally

put on by acetyl-CoA carboxylase

Generation of a 4-carbon b-keto acid derivative, bound to the pantothenate of the ACP protein

The ketoacid is now reduced to the methylene (CH2) state in a

three-step reaction sequence.

The elongated 4-carbon chain is now ready to accept a new 2-carbon unit from malonyl-CoA. The 2-carbon unit, which is added to the growing fatty acid chain, becomes carbons 1 and 2 of hexanoic acid (6-carbons).

Release

The cycle of transfer, elongation, reduction, dehydration, and reduction continues until palmitoyl-ACP is made. Then the thioesterase activity of the FAS complex releases the 16-carbon fatty acid palmitate from the FAS.

Note that fatty acid synthesis provides an extreme example of the phenomenon of metabolic channeling: neither free fatty acids with more than four carbons nor their CoA derivatives can directly participate in the synthesis of palmitate. Instead they must be broken downto acetyl-CoA and reincorporated into the fatty acid.

Fatty acids are generated cytoplasmically while acetyl-CoA is made in the mitochondrion by pyruvate dehydrogenase.This implies that a shuttle system must exist to get the acetyl-CoA or its equivalent out of the mitochondrion. The shuttle system operates in the following:

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