Biochemistry - Chemical Reactions in the Living Cell, Volume 2 - D. Metzler 1980

Biosynthesis: How New Molecules Are Formed
Biosynthesis of Monomers
Construction of Hydrocarbon Chains from Two-Carbon Units

During ß-Oxidation, two carbon atoms are cleaved simultaneously from a fatty acid chain. Conversely, FATTY ACID Biosynthesis proceeds in the reverse direction, utilizing two-carbon acetyl units from acetyl-CoA as starting material. The coupling of this process with ATP Cleavage via a carboxylation-decarboxylation sequence, The Role of the acyl carrier protein (Section B,4), and The Use of NADPH as a reducing agent (Section C) have already been discussed above.

The complete reaction sequence for fatty acid biosynthesis is illustrated in Fig. 11-2, where it is compared with the reaction sequence of ß-oxidation. Why does ß-oxidation require CoA derivatives, whereas biosynthesis relies on a more complex compound, the acyl carrier protein (ACP)? This is likely related to regulatory mechanisms. ACP is a sophisticated molecule capable of supporting fatty acid chain elongation and facilitating its transfer from one enzyme to another. While in E. coli the various Enzymes catalyzing the reactions shown in Fig. 11-2 are found in the Cytosol and behave as independent Proteins, in Mycobacterium, Yeast, Euglena, and in pigeon and rat Tissues, they form multi-enzyme complexes. Yeast fatty acid synthetase has a Molecular Weight of 2.3 million and, under the Electron microscope, resembles the keto acid dehydrogenase complex (Chapter 8, Section K).

Evidently, the ACP molecule resides at the center of the complex, while the growing fatty acid chain, attached to the terminal phosphopantetheine prosthetic group, shuttles from one subunit to another [23]. The primer (typically acetyl-CoA in E. coli) first transfers its acyl group to the central ACP molecule (Fig. 11-2, step a) and then to a peripheral thiol (—SH) group, likely a Cysteine side chain in one of the protein subunits (step b), after which the malonyl group is transferred (step d) from malonyl-CoA to the free thiol group of ACP. Condensation (step e) takes place with the participation of the freed peripheral thiol group. However, this group cannot be reused until the resulting ß-ketoacyl group has passed through the entire sequence of reduction reactions (steps g—i). In the final stages, the growing chain is transferred back to the peripheral —SH group (step j), and a new malonyl unit is incorporated into the central ACP.

Once the chain length reaches 12 carbon atoms, the acyl group is no longer recycled into the cycle but is instead transferred to a CoA molecule (step l), thereby terminating chain growth. The probability of chain termination increases as the chain lengthens. In yeast, for instance, the resulting fatty acid chains contain 14, 16, and 18 carbon atoms [24].

Acetyl-CoA most commonly serves as the primer (or "starter piece"), although butyryl-CoA is a more suitable primer for rabbit proteins, being formed from acetyl-CoA via the reversal of ß-oxidation; the enzymes required for this are present in sufficient quantities in the cytosol [25]. In the synthesis of Branched-Chain Fatty acids (Section 10) and The formation of flavonol pigments (Supplement 12-B), other groups of compounds are used as primers.