Fatty Acid de novo Synthesis

Much of our need for fatty acids as constituents of phospholipids and other complex lipids is met by the diet. In addition, certain lipogenic tissues are capable of the de novo synthesis of fatty acids (Figure 6). These tissues include liver (hepatocytes), adipose tissue, and lactating mammary gland. Much of the fatty acids synthesized by all three tissues is incorporated into triacylglycerol. Hepatic synthesis is primarily for export to other tissues (in very low-density lipoproteins), while synthesis in adipocytes and mammary gland is for local storage.

The carbon used for fatty-acid synthesis typically derives from the products of glycolysis. The end product of glycolysis, pyruvate, enters the mitochondria and becomes the substrate for two separate

Figure 6 Fatty-acid biosynthesis. Cytoplasmic acetyl-CoA (AcCoA) is the primary substrate for de novo fatty-acid synthesis. This two-carbon compound most commonly derives from the glycolytic degradation of glucose, and its formation is dependent upon several reactions in the mitochondria. The mitochondrial enzyme pyruvate carboxylase is found primarily in tissues that can synthesize fatty acids. AcCoA is converted to malonyl-CoA (MalCoA) by acetyl-CoA carboxylase. Using AcCoA as a primer, the fatty-acid synthase multienzyme complex carries out a series of reactions that elongate the growing fatty acid by two carbon atoms. In this process MalCoA condenses with AcCoA, yielding an enzyme-bound four-carbon ,3-ketoacid that is reduced, dehydrated, and reduced again. The product is enzyme-bound 4:0. This process is repeated six more times, after which 16:0 is released from the complex. The reductive steps require NADPH, which is derived from enzyme reactions and pathways shown in grey. Enz refers to the fatty acid synthase multienzyme complex.

Glucose

NADPH

Glucose

NADPH

Malate

Figure 6 Fatty-acid biosynthesis. Cytoplasmic acetyl-CoA (AcCoA) is the primary substrate for de novo fatty-acid synthesis. This two-carbon compound most commonly derives from the glycolytic degradation of glucose, and its formation is dependent upon several reactions in the mitochondria. The mitochondrial enzyme pyruvate carboxylase is found primarily in tissues that can synthesize fatty acids. AcCoA is converted to malonyl-CoA (MalCoA) by acetyl-CoA carboxylase. Using AcCoA as a primer, the fatty-acid synthase multienzyme complex carries out a series of reactions that elongate the growing fatty acid by two carbon atoms. In this process MalCoA condenses with AcCoA, yielding an enzyme-bound four-carbon ,3-ketoacid that is reduced, dehydrated, and reduced again. The product is enzyme-bound 4:0. This process is repeated six more times, after which 16:0 is released from the complex. The reductive steps require NADPH, which is derived from enzyme reactions and pathways shown in grey. Enz refers to the fatty acid synthase multienzyme complex.

1. Glycolysis

2. Pyruvate dehydrogenase

3. Pyruvate carboxylase

4. Citrate synthase

5. ATP citrate lyase

6. Acetyl-CoA carboxylase

7. Fatty-acid synthase multienzyme complex

8. Pentose phosphate pathway

9. Malate dehydrogenase 10. Malic enzyme

Malate

1. Glycolysis

2. Pyruvate dehydrogenase

3. Pyruvate carboxylase

4. Citrate synthase

5. ATP citrate lyase

6. Acetyl-CoA carboxylase

7. Fatty-acid synthase multienzyme complex

8. Pentose phosphate pathway

9. Malate dehydrogenase 10. Malic enzyme

reactions. In one, pyruvate is decarboxylated via the pyruvate dehydrogenase complex, yielding acetyl-CoA. Lipogenic tissues also contain another mitochondrial enzyme, pyruvate carboxylase, which converts pyruvate to the four-carbon acid oxaloacetate (OAA). Acetyl-CoA and oxaloacetate condense to form the six-carbon acid citrate. As citrate accumulates within the mitochondrion, it is exported to the cytoplasm, where it is converted back to oxaloace-tate and acetyl-CoA. Cytoplasmic acetyl-CoA is the fundamental building block for de novo synthesis of fatty acids.

The first enzyme unique to fatty-acid synthesis is acetyl-CoA carboxylase, which converts the two-carbon substrate acetyl-CoA into the three-carbon product malonyl-CoA. Citrate, in addition to being the precursor of cytoplasmic acetyl-CoA, has a regulatory role. Citrate is an allosteric activator of acetyl-CoA carboxylase and serves as a signal that there is an ample carbon supply for fatty-acid synthesis. As noted above, malonyl-CoA is a potent inhibitor of CPT1. Cytoplasmic malonyl-CoA levels will be high only when there is significant flux through glycolysis, indicative of a high cellular energy state. Under these conditions, entry of fatty acids into the mitochondria (and subsequent ^-oxidation) is prevented. Interestingly, there are two isoforms of acetyl-CoA carboxylase. One is found in the above-named lipogenic tissues. The other is found in many tissues that are not capable of synthesizing fatty acids, e.g., the heart. It is thought that the primary role of the second isozyme is to regulate mitochondrial fatty-acid ^-oxidation by synthesizing malonyl-CoA when cellular energy needs are being met by carbohydrate metabolism.

The subsequent reactions of fatty-acid synthesis in humans are catalyzed by a multienzyme

Table 1 Distinctions between fatty-acid ^-oxidation and fatty-acid synthesis

Fatty-acid 33-oxidation

Fatty-ac d synthesis

Tissues with active

Nearly all tissues

Liver, adipose,

pathway

except brain,

and lactating

nerve, and

mammary

erythrocytes

gland

Subcellular location

Mitochondria

Cytoplasm

Redox cofactors

NAD, FAD

NADPH

Acyl-group carrier

CoA

Enzyme-bound

acyl carrier

protein

Stereochemistry of

L-

D-

3-hydroxy

intermediate

complex, fatty-acid synthase. After binding of one molecule each of acetyl-CoA and malonyl-CoA to unique binding sites within the complex, a condensation reaction occurs in which carbon dioxide is released and an enzyme-bound 4-carbon 3-ketoacid is formed. Subsequent reactions include a reduction step, a dehydration step, and a second reduction step. The intermediates produced in these reactions are similar to those seen in f-oxidation (Figure 2), in reverse order. The product (enzyme bound) is the saturated fatty acid 4:0, which can then condense with another molecule of malonyl-CoA to start the process anew. After seven such cycles, the ultimate product is 16:0, which is released from the complex.

The reductive steps in fatty-acid synthesis require reduced nicotinamide adenine dinucleotide phosphate (NADPH). Some NADPH is produced during recycling of the oxaloacetate formed during the cytoplasmic hydrolysis of citrate, described above. Oxaloacetate is first converted to malate (via cyto-plasmic malate dehydrogenase). Malate is then dec-arboxylated to pyruvate in an NADP+-dependent reaction catalyzed by malic enzyme; NADPH is produced in this reaction. NADPH for fatty-acid biosynthesis also comes from reactions in the pentose phosphate pathway (hexose monophosphate shunt).

In several respects, the enzymatic reactions of fatty-acid synthesis are the converse of those in fatty-acid oxidation. However, there are key differences, which are summarized in Table 1.

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