Biosynthesis of Fatty Acids

Medical Biochemistry

Lecture #46

FattyAcids Fatty acids are a class of compounds containing a long hydrocarbon

chain and a terminal carboxylate group.

Nomenculature:

- Systematic name for a fatty acid is derived from the name of its parent hydrocarbon by the substitution of oic for the final e.

- For example, the C18 saturated fatty acid is called octadecanoic acid (18:0) because the parent hydrocarbon is octadecane.

F.A. Nomenclature (cont.)

- C18 with one double bond is called octadecenoic acid (18:1); with two double bonds is called octadecadienoic acid (18:2); with three double bonds, octadecatrienoic acid (18:3).

Fatty acids vary in chain length and

degree of unsaturation: • Usually contain an even number of carbon

atoms, typically between 14 and 24. The 16- and 18-carbon fatty acids are most common.

 • May contain one or more double bonds. The

double bonds in polyunsaturated fatty acids are separated by at least one methylene group.

 • The configuration of the double bonds in most

unsaturated fatty acids is cis.

Properties of fatty acids are markedly dependent on their chain length and on the degree of saturation.

• -Melting point of stearic acid is 69.6oC, whereas that of oleic acid (with one double bond) is 13.4oC.

 • –Melting temperature of palmitic

acid (C16) is 6.5 degrees lower than that of stearic acid (C16)

FATTY ACID SYNTHESIS

(LIPOGENESIS)• Glucose provides the primary substrate for lipogenesis • In humans, adipose tissue may not be an important site,

and liver has only low activity • Variations in fatty acid synthesis between individuals may

have a bearing on the nature and extent of obesity, and one of the lesions in type I, insulin-dependent diabetes mellitus is inhibition of lipogenesis

  DE NOVO SYNTHESIS OCCURS IN CYTOSOL • Liver, kidney, brain, lung, mammary gland, and adipose

tissue.

Reaction is catalyzed by acetyl-CoA carboxylase. It is a multienzyme protein. The enzyme contains a variable number of identical subunits, each containing biotin, biotin carboxylase, biotin carboxyl carrier protein, and transcarboxylase, as well as a regulatory allosteric site.

Step 1: Formation of Malonylcoenzyme A is the committed step in fatty acid synthesis: It takes place in two steps: carboxylation of biotin (involving ATP) and transfer of the carboxyl to acetyl-CoA to form malonyl-CoA.

Step 2:• Fatty acid synthase catalyzes the remaining steps. It is a

multienzyme polypeptide complex that contains acyl carrier protein (ACP). ACP contains the vitamin pantothenic acid in the form of 4'-phosphopantetheine. ACP takes over the role of CoA. 

• It offers great efficiency and freedom from interference by competing reactions 

• Synthesis of all enzymes in the complex is coordinated, since it is encoded by a single gene 

• It is a dimer, and each monomer is identical, consisting of one chain containing all seven enzyme activities of fatty acid synthase and an ACP with a 4'-phosphopantetheine-SH group. Dimer is arranged in a "head to tail" configuration. Monomer is not active.

Step 3: Elongation of fatty acid chains occurs in

endoplasmic reticulum• This pathways "microsomal

system" converts fatty acyl-CoA to an acyl-CoA derivative having two carbons more, using malonyl-CoA as acetyl donor and NADPH as reductant catalyzed by the microsomal fatty acid elongase system of enzymes.

Nutritional state regulates lipogenesis:

• Lipogenesis converts surplus glucose and intermediates such as pyruvate, lactate, and acetyl-CoA to fat. 

• Rate is higher in well-fed animals whose diets contains a high proportions of carbohydrates. 

• It is depressed under conditions of restricted caloric intake, on a high-fate diet, or when there is a deficiency of insulin, as in diabetes mellitus. All these conditions are associated with increased concentrations of plasma free fatty acids. 

• There is an inverse relationship between hepatic lipogenesis and the concentration of serum-free fatty acids. The greatest inhibition of lipogenesis occurs over the range of free fatty acids (0.3-0.8 µmol/mL pf plasma).

• Fat in the diet also causes depression of lipogenesis in the liver, and when there is more than 10% of fat in the diet, there is little conversion of dietary carbohydrates to fat.

SHORT AND LONG-TERM MECHANISMS REGULATE LIPOGENESIS• In the short-term, synthesis is controlled by

allosteric and covalent modification of enzymes; For long-term, there are changes in gene expression

Short-term• Acetyl-CoA carboxylase is most important in regulating

synthesis • Activated by citrate, which increases in well-fed state and

is an indicator of a plentiful supply of acetyl-CoA • Inhibited by long-chain acyl-CoA.  • Pyruvate dehydrogenase regulates availability of free

acetyl-CoA for lipogenesis. Acetyl-CoA causes an inhibition of pyruvate dehyrogenase.

Hormones (short term)• Insulin stimulates lipogenesis by several mechanisms:• a. increases transport of glucose into the cell (e.g., adipose

tissues) and thereby increases the availability of both pyruvate for fatty acid synthesis and glycerol-3-phosphate for esterification of the newly formed fatty acids. 

• b. Converts inactive form of pyruvate dehydrogenase to the active form in adipose tissues 

• c. Activates acetyl-CoA carboxylase • d. Insulin depress intracellular cAMP levels, inhibits lipolysis • e. Insulin antagonizes the actions of glucagon and

epinephrine

Long-term

• Expression is increased in response to fed state and is decreased in fasting, feeding of fat, and in diabetes (adaptive mechanism).