Acetoacetyl-ACP

It is also worth noting that the carbon of the carboxyl group that was added to drive this reaction is the one removed by the condensing enzyme. Thus, all the carbons of acetoacetyl-ACP (and of the fatty acids to be made) are derived from acetate units of acetyl-CoA. 

Claiscn-like condensation of malonyl ACP with acetyl synthase occurs, followed by decarboxylation to yield acetoacetyl ACP, a -keto thioester. 

Steps 6-8 of Figure 29.5 Reduction and Dehydration The ketone carbonyl group in acetoacetyl ACP is next reduced to the alcohol /S-hydroxybutyry] ACP by yS-keto thioester reductase and NADPH, a reducing coenzyme closely related to NADH. R Stereochemistry results at the newly formed chirality center in the /3-hydroxy thioester product. (Note that the systematic name of a butyryl group is biitanoyl.)... 

In step 6 of fatty-acid biosynthesis (Figure 29.5), acetoacetyl A CP is reduced steieospecifically by NADPH to yield an alcohol. Does hydride ion add to the Si face or the Re face of acetoacetyl ACP ... 

Step (2) Reduction of the Carbonyl Group The acetoacetyl-ACP formed in the condensation step now undergoes reduction of the carbonyl group at C-3 to form d-j8-hydroxybutyryl-ACP. This reaction is catalyzed by /3-ketoacyl-ACP reductase (KR) and the electron donor is NADPH. Notice that the D-j3-hydroxybutyryl group does not have the same stereoisomeric form as the l-j8-hydroxyacyl intermediate in fatty acid oxidation (see Fig. 17-8). 

Malonyl-ACP, formed from acetyl-CoA (shuttled out of mitochondria) and C02, condenses with an acetyl bound to the Cys—SH to yield acetoacetyl-ACP, with release of C02. This is followed by reduction to the D-/3-hydroxy derivative, dehydration to the trans-A2-unsaturated acyl-ACP, and reduction to butyryl-ACP. NADPH is the electron donor... 

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. 

The pathway The first committed step in fatty acid biosynthesis is the carboxylation of acetyl CoA to form malonyl CoA which is catalyzed by the biotin-containing enzyme acetyl CoA carboxylase. Acetyl CoA and malonyl CoA are then converted into their ACP derivatives. The elongation cycle in fatty acid synthesis involves four reactions condensation of acetyl-ACP and malonyl-ACP to form acetoacetyl-ACP releasing free ACP and C02, then reduction by NADPH to form D-3-hydroxybutyryl-ACP, followed by dehydration to crotonyl-ACP, and finally reduction by NADPH to form butyryl-ACP. Further rounds of elongation add more two-carbon units from malonyl-ACP on to the growing hydrocarbon chain, until the C16 palmitate is formed. Further elongation of fatty acids takes place on the cytosolic surface of the smooth endoplasmic reticulum (SER). 

Condensation of acetyl-ACP and malonyl-ACP to form acetoacetyl-ACP, releasing free ACP and C02 (catalyzed by acyl-malonyl-ACP condensing enzyme). 

Reduction of acetoacetyl-ACP to form D-3-hydroxybutyryl-ACP, using NADPH as reductant (catalyzed by (J-ketoacyl-ACP reductase). 

STEP S Condenantion of maionyl ACP with an ncety) group occurs, fbffowed by dceartmxylation, to give acetoacetyl ACP. 

JTtP 5 Condensation. The ke> carbon-carbon bond-forming reaction that builds the fatly acid chain occurs in step 5. This step is simply a Claisen condensation (Section 23,8j between acetyl synthase as the electrophilic acceptor and malonyi ACP as the nucleophilic donor An enolate ion derived from the doubly activated -CHj- group of molonyl ACF odds to the carbonyl gioup of acc l synthase, yielding on intennedioto keu> odd that loses carton dioxide to give the four-cathon product acetoacetyl ACP. 

Figure 17.4 The biological reduction of a ketone (acetoacetyl ACP) to an alcohol (/3-hydroxybutyryl ACP) by NADPH.

Problem 29.6 Does the reduction of acetoacetyl, ACP in step 6 occur on the lie face or the Si face of... 

Acetoacetyl ACP + NADPH + H+ d-3-hydroxybutyryl ACP + NADP P-Ketoacyl ACP reductase... 

STEP S Condensation of malonyl AGP with an acetyl group occurs, followed by decarboxylation, to give acetoacetyl ACP. 

STEP 6 The ketone carbonyl group of acetoacetyl ACP is reduced to give hydroxybutyiyl ACP. 

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