3-Ketoacyl-ACP synthase

FIGURE 25.7 The pathway of palmhate synthesis from acetyl-CoA and malonyl-CoA. Acetyl and malonyl building blocks are introduced as acyl carrier protein conjugates. Decarboxylation drives the /3-ketoacyl-ACP synthase and results in the addition of two-carbon units to the growing chain. Concentrations of free fatty acids are extremely low in most cells, and newly synthesized fatty acids exist primarily as acyl-CoA esters. 

FATTY ACID SYNTHETASE /3-KETOACYL-ACP SYNTHASE FATTY ACID SYNTHETASE a-KETOBUTYRATE SYNTHASE 2-Keto-3-deoxy-L-arabonate aldolase,... 

Figure 21-11 Catalytic domains within three polypeptide chains of the modular polyketide synthase that forms 6-deoxyerythronolide B, the aglycone of the widely used antibiotic erythromycin. The domains are labeled as for fatty acid synthases AT, acyltransferase ACP, acyl carrier protein KS, 3-ketoacyl-ACP synthase KR, ketoreductase DH, dehydrase ER, enoylreductase TE, thioesterase. After Pieper et al.338 Courtesy of Chaitan Khosla.

The Condensation Reaction. In the condensation reaction the acetyl group is initially transferred from ACP on to a SH group of 3-ketoacyl-ACP synthase. This acetyl moiety then reacts with malonyl-ACP (step 3 in fig. 18.12 ) so that the acetyl component becomes the methyl terminal two carbon unit of the acetoacetyl-ACP. The release of C02 in this condensation reaction provides the extra thermodynamic push to make the reaction highly favorable. 

Fatty acid synthesis begins when the substrates, acetyl-CoA and malonyl-CoA, are transferred onto the protein by malonyl-CoA acetyl-CoA-ACP transacylase (MAT, steps 1 and 2 in fig. 18.12a). The numbers in parentheses below the abbreviation of the enzyme in this figure refer to the reactions shown in fig. 18.12. (Whereas E. coli has separate enzymes that catalyze the transfer of acetyl- and malonyl-CoA to ACP, both reactions are catalyzed by the same enzymatic activity (MAT) on the animal fatty acid synthase.) Subsequently, /3-ketobutyryl-ACP and CO2 are formed in a condensation reaction catalyzed by /3-ketoacyl-ACP synthase (KS, step 3 in fig. 18.12a). 

As the name anaerobic implies, the double bond of the fatty acid is inserted in the absence of oxygen. Biosynthesis of monounsaturated fatty acids follows the pathway described previously for saturated fatty acids until the intermediate /3-hydroxydecanoyl-ACP is reached (fig. 18.15). At this point, a new enzyme, /3-hydroxydecanoyl-ACP dehydrase, becomes involved. This dehydrase can form the a-j8 trans double bond, and saturated fatty acid synthesis can occur as previously discussed. In addition, this dehydrase is capable of isomerization of the double bond to a cis /3-y double bond as shown in figure 18.15. The /3-y unsaturated fatty acyl-ACP is subsequently elongated by the normal enzymes of fatty acid synthesis to yield pal-mitoleoyl-ACP (16 1A9). The conversion of this compound to the major unsaturated fatty acid of E. coli, cA-vacccnic acid (18 1A11), requires a condensing enzyme that we have not previously discussed, /3-ketoacyl-ACP synthase II, which shows a preference for palmitoleoyl-ACP as a substrate. The subsequent conversion to vaccenyl-ACP is cata-... 

J Chuck, M McPherson, H Huang, JR Jacobsen, C Khosla, DE Cane. Molecular recognition of diketide substrates by a (3-ketoacyl-ACP synthase domain within a bimodular polyketide synthase. Chem Biol 4 757-766, 1997. 

Mekhedov, S., Cahoon, E.B. and Ohlrogge, J. (2001) An unusual seed-specific 3-ketoacyl ACP synthase associated with the biosynthesis of petroselinic acid in coriander. Plant Molecular Biology 47(4), 507-518. 

BBB, blood brain barrier BBI, Bowman-Birk serine protease inhibitor BB-R, bombesin receptor BChE, butyryl cholinesterase BDNF, brain-derived neurotrophic factor BDNF-RTK, brain-derived neurotrophic factor receptor tyrosine kinase aBgTX, a-bungarotoxin BKAS, (3-ketoacyl-ACP synthase BK-R, bradykinin receptor BZ-R, benzodiazepine receptor... 

The acetyl group is shown bound to the enzyme )3-ketoacyl-ACP synthase through a cysteine residue. The carbonyl group of the acetyl group is attacked by the central carbon on the malonyl group attached to ACP. Acetoacetyl-ACP is generated as the C—S bond is broken. 

The acetyl group on the cysteine residue condenses with the malonyl group on ACP as the CO2 originally added by acetyl CoA carboxylase is released. The result is a four-carbon unit attached to the ACP domain. The loss of flee energy from the decarboxylation drives the reaction catalyzed by 3-Ketoacyl-ACP synthase ... 

Introduction Primary Fatty Acids Fatty Acids of Plant Vegetative Parts Biosynthesis Fatty Acid Biosynthesis The Two-Pathway Model of Lipid Biosynthesis The Second 3-Ketoacyl ACP Synthase Isozyme Biosynthesis of Unsaturated Fatty Acids The Prokaryotic Pathway The Eukaryotic Pathway Biosynthesis of Triacylglycerides Degradation of Fatty Acids Unusual Fatty Acids in Plants Fatty Acids from Unusual Starter Units Fatty Acids with Unusual Patterns of Unsaturation Hydroxy Fatty Acids Epoxy Fatty Acids... 

In subsequent steps of fatty acid synthesis, a fatty acyl group that is linked by a thioester bond to the active site of 3-ketoacyl-ACP synthase condenses with malonyl-ACP. One molecule of CO2 is liberated (Browse and Somerville, 1991 Conn and Stumpt, 1972, Lehninger, 1982) (Fig. 2.4). Although acetyl-ACP has been considered to condense initially with malonyl-ACP, recent work indicates that the product of the first condensation, butyryl-ACP, is formed by the condensation of acetyl-CoA and malonyl-ACP and that acetyl-ACP is a minor participant in fatty acid biosynthesis (Jaworski et al., 1993). 

Three forms of 3-ketoacyl-ACP synthase have been discovered in plants. These forms may be distinguished by their substrate specificity they are homodimers with molecular weights of 43,000 to 45,000 per subunit. One, KAS III, appears to be responsible for the first condensation of acetyl-CoA and malonyl-ACP (Browse and Somerville, 1991 Ohlrogge et al., 1993). The activity of this enzyme in plants seems to bypass the need for acetyl-ACP, although that molecule is formed and accumulated in some plants (Ohlrogge et al., 1993). KAS I or 3-ketoacyl-ACP synthase elongates the acyl chain to palmitoyl-ACP, whereas KAS II converts palmitoyl-ACP to stearoyl-ACP (Ohlrogge et al., 1993). 

Both the de novo synthesis and the elongation step (i.e., the systems that involve isozyme I and II of 3-ketoacyl ACP synthase) occur as ACP-derivatives (Fig. 2.7). 

Dehesh, K., Edwards, R, Fillatti, J., Slabaugh, M. and Byrne J. 1998. KAS IV A 3-ketoacyl-ACP synthase from Cuphea sp. is a medium chain specific condensing enzyme. Plant J. 15 383-390. 

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