Fatty acid biosynthesis production

Fig. 2. Fatty acid biosynthesis. Production of cytosolic acetyl-CoA at the expense of mitochondrial acetyl-CoA by the formation, transport and breakdown of citrate.

Because this enzyme catalyzes the committed step in fatty acid biosynthesis, it is carefully regulated. Palmitoyl-CoA, the final product of fatty acid biosynthesis, shifts the equilibrium toward the inactive protomers, whereas citrate, an important allosteric activator of this enzyme, shifts the equilibrium toward the active polymeric form of the enzyme. Acetyl-CoA carboxylase shows the kinetic behavior of a Monod-Wyman-Changeux V-system allosteric enzyme (Chapter 15). 

In eukaryotes, anabolic and catabolic pathways that interconvert common products may take place in specific subcellular compartments. For example, many of the enzymes that degrade proteins and polysaccharides reside inside organelles called lysosomes. Similarly, fatty acid biosynthesis occurs in the cytosol, whereas fatty... 

Production of Malonyl-CoA for the Fatty Acid Biosynthesis. Acetyl-CoA serves as a substrate in the production of malonyl-CoA. There are several routes by which acetyl-CoA is supplied to die cytoplasm. One route is the transfer of acetyl residues from the mitochondrial matrix across the mitochondrial membrane into the cyto-plasm. This process resembles a fatty acid transport and is likewise effected with the participation of carnitine and the enzyme acetyl-CoA-camitine transferase. Another route is the production of acetyl-CoA from citrate. Citrate is delivered from the mitochondria and undergoes cleavage in the cytoplasm by the action of the enzyme ATP-citrate lyase ... 

An alternative route to mevalonic acid is also possible, which differs from the former one in that the formation of P-hydroxy-P-methylglutaryl residue occurs on the surface of an acyl carrier protein (like in fatty acid biosynthesis). The intermediary product in this route, P-hydroxy-p-methylglutaryl-S-ACP, is re-duced by another enzyme to mevalonic acid. 

A natural question is "Why has this complex pathway evolved to do something that could have been done much more directly " One possibility is that the presence of too much malonyl-CoA, the product of the P oxidation pathway of propionate metabolism (Fig. 17-3, pathways a and c), would interfere with lipid metabolism. Malonyl-CoA is formed in the cytosol during fatty acid biosynthesis and retards mitochondrial P oxidation by inhibiting carnitine palmitoyltransferase i.46 70a 75 However, a relationship to mitochondrial propionate catabolism is not clear. 

Many of the unusual compounds that indicate the exciting chemistry to be discovered in marine natural products are polyketides. Polyketides are a family of structurally complex natural products that include a number of important pharmaceuticals. They are produced primarily by microorganisms through a specialized metabolism that is a variation of fatty acid biosynthesis [430]. Polyketides fall into two structural classes aromatic and complex. Polyketides are formed by enzyme complexes... 

In prokaryotes, each of the reactions of fatty acid synthesis is catalyzed by a separate enzyme. However, in eukaryotes, the enzymes of the fatty acid synthesis elongation cycle are present in a single polypeptide chain, multifunctional enzyme complex, called fatty acid synthase. The fatty acid synthase complex exists as a dimer, with the ACP moiety shuttling the fatty acyl chain between successive catalytic sites, and from one subunit of the dimer to the other. It is, in effect, a highly efficient production line for fatty acid biosynthesis. 

Vitamin B12 is essential for the methylmalonyl-CoAmutase reaction. Methylmalonyl-CoA mutase is required during the degradation of odd-chain fatty acids and of branched-chain amino acids. Odd-chained fatty acids lead to propionyl-CoA as the last step of P-oxida-tion. Methylmalonyl-CoA can be derived from propionyl-CoA by a carboxylase reaction similar to that of fatty acid biosynthesis. The cofactor for this carboxylation reaction is biotin, just as for acetyl-CoA carboxylase. The reaction of methylmalonyl-CoA mutase uses a free radical intermediate to insert the methyl group into the dicar-boxylic acid chain. The product is succinyl-CoA, a Krebs cycle intermediate. The catabolisms of branched-chain lipids and of the branched-chain amino acids also require the methylmalonyl-CoA mutase, because these pathways also generate propionyl-CoA. 

The acetyl-CoA generated from citrate is then used for fatty acid biosynthesis. In the human being, only two multifunctional enzymes are involved acetyl-CoA carboxylase (also termed malonyl-CoA synthetase) and fatty acid synthetase, with a molecular weight of 500,000, and coded by a single gene. The product of the two enzymes is palmitate. Other fatty acids may be made from palmitate by chain unsaturation, or elongation, or both (see later). The initial reaction involves the carboxylation of acetyl-CoA in two steps by acetyl-CoA carboxylase. Biotin is a cofactor, and one molecule of ATP is hydrolyzed to ADP and Pc ... 

We decided to focus our attention on de novo fatty acid biosynthesis based upon our observations and those reported in the literature (12). To determine whether fatty acid biosynthesis was inhibited, we determined the effect of the herbicides on incorporation into palmitic (16 0) acid, the first product of fatty acid biosynthesis. Maize leaf discs were incubated for 40 min in 14C -acetate, after which fatty acids were extracted. As shown in Table II, both tralkoxydim and haloxyfop significantly reduced the amount of acetate incorporated into palmitic acid. Thus, these compounds affected a step early in lipid biosynthesis. 

The malic enzyme/citrate lyase pathway is shown in Figure 5.10. The 2-carbon units acetyl groups) for fatty acid synthesis are supplied by the activity of citrate lyase, which may be considered an enzyme of fatty acid biosynthesis. The reduced NADP is Supplied at the point of malic enzyme. Figure 5.10 reveals no net production or utilization of NAD in the cytoplasm. The NADPH + H generated in the cytoplasm is used for fatly acid synthesis, which regenerates NADP. One molecule of CO is produced in the cytoplasm. The diagram reveals no net production or utilization of CO in the mitochondrion. One molecule of NAD is... 

Because they often function as virulence factors, the enzymes involved in siderophore biosynthesis are potential targets for developing antimicrobial strategies. The mechanisms of siderophore biosynthesis follow the same fundamental biosynthetic logic involving similar protein machinery, which we describe in greater detail in Chapter 5 for fatty acid biosynthesis. It is also used in the microbial biosynthesis of many important natural products polyketides and peptides (including many antibiotics). Essentially, as is illustrated in Fig. 4.20, for enterobactin, it involves... 

Figure 3. Relationship between polyketide and fatty acid biosynthesis. The simplest ( minimaV) PKSs possess ketosynthase activity and produce linear polyketide products. In contrast, FASs also catalyze successive ketoreduction-dehydration-enoyl reduction reactions following each condensation. Diverse PKSs may perform none, part, or all of this reductive sequence. KS, ketosynthase KR, ketoreductase DH, dehydratase ER, enoyl reductase.

---