3.
The now-vacant ACP accepts a three-carbon malonyl group from malonyl CoA. Domain: Malonyl/acetyl CoA–ACP transacylase.
4.
The acetyl group on the cysteine residue condenses with the malonyl group on ACP as the CO2 originally added by ACC is released. The result is a four-carbon unit attached to the ACP domain. The loss of free energy from the decarboxylation drives the reaction. Domain: 3Ketoacyl–ACP synthase, also known as condensing enzyme.
The next three reactions convert the 3-ketoacyl group to the corresponding saturated acyl group by a pair of NADPH-requiring reductions and a dehydration step.
1.
The keto group is reduced to an alcohol. Domain: 3-Ketoacyl–ACP reductase.
2.
A molecule of water is removed, creating a trans double bond between carbons 2 and 3 (the α-and β-carbons). Domain: 3-Hydroxyacyl–ACP dehydratase.
3.
The double bond is reduced. Domain: Enoyl–ACP reductase.
This sequence of steps results in the production of a four-carbon group (butyryl) whose three terminal carbons are fully saturated and which remains attached to the ACP domain. The steps are repeated (indicated by an asterisk), beginning with the transfer of the butyryl unit from the ACP to the cysteine residue [2*], the attachment of a malonyl group to the ACP [3*], and the condensation of the two groups liberating CO2 [4*]. The carbonyl group at the β-carbon (carbon 3, the third carbon from the sulfur) is then reduced [5*], dehydrated [6*], and reduced [7*], generating hexanoyl-ACP. This cycle of reactions is repeated five more times, each time incorporating a two-carbon unit (derived from malonyl CoA) into the growing fatty acid chain at the carboxyl end. When the fatty acid reaches a length of 16 carbons, the synthetic process is terminated with palmitoyl-S-ACP. [Note: Shorter-length fatty acids are produced in the lactating mammary gland.] Palmitoyl thioesterase, the final catalytic activity of FAS, cleaves the thioester bond, releasing a fully saturated molecule of palmitate (16:0). [Note: All the carbons in palmitic acid have passed through malonyl CoA except the two donated by the original acetyl CoA (the first acyl acceptor), which are found at the methyl (ω) end of the fatty acid. This underscores the rate-limiting nature of the ACC reaction.]
D. Reductant sources
The synthesis of one palmitate requires 14 NADPH, a reductant (reducing agent). The pentose phosphate pathway (see p. 145) is a major supplier of the NADPH. Two NADPH are produced for each molecule of glucose 6phosphate that enters this pathway. The cytosolic conversion of malate to pyruvate, in which malate is oxidized and decarboxylated by cytosolic malic enzyme (NADP+-dependent malate dehydrogenase), also produces cytosolic NADPH (and CO2), as shown in Figure 16.10. [Note: Malate can arise from the reduction of OAA by cytosolic NADH-dependent malate dehydrogenase (see Fig. 16.10). One source of the cytosolic NADH required for this reaction is glycolysis (see p. 101). OAA, in turn, can arise from citrate cleavage by ATP citrate lyase.] A summary of the interrelationship between glucose metabolism and palmitate synthesis is shown in Figure 16.11.