3. Fatty acid metabolism

Fatty acid metabolism I

Fatty acids are built from two and three carbon blocks. The two carbon blocks come from acetyl coenzyme A. The three carbon blocks come from malonyl coenzyme A.

The malonyl coenzyme A is made when acetyl CoA is carboxylated. The source of that third carbon is the carbonate (HCO3). The reaction is catalyzed by acetyl CoA carboxylase (ACC). ACC contains a coenzyme called biotin that transfers the carboxyl from carbonate to the acetyl CoA. Cost: ATP. Irreversible. Committed Step.

biotine

Malonyl coenzyme A is a “high energy” molecule, whose free energy drives Fatty Acid synthesis.

 

Assembly of Fatty Acids

A multi-step catalyzed by a single enzyme complex called the Fatty Acid Synthase (FAS), compromised of long single polypeptide chain of multiple domains, each with their own enzymatic activity.

HarvardX class slide. All rights are theirs.
HarvardX class slide. All rights are theirs.

Specifically, there are seven domains in FAS: MAT, ACP, KS, TE, ER, HD, and KR.

It starts with the MAT domains cleaves the Acetyl-CoA releasing an acetyl group, which binds to KS. MAT also cleaves a malonyl-CoA. This primes the FAS with a two carbon acetyl group bound to KS and a three carbon manonyl group bound to ACP.

Next, comes a five step reaction sequence: condensation, reduction, dehydrationreduction, and translocation that produces 4 carbons. This is coupled with two oxidations of NADPH to NADP+–NADPH is produced in part by the Pentose Phosphate Pathway.

At this point it can restart, iterating to add 2 more carbons at a time obtained from additional malonyl-CoA molecules (and which bind to the resulting thiol group). Thus, FA based on acetyl-CoA have an even number of  carbons. There are other source carbon blocks that are 3 carbon long (propionyl), resulting in odd numbered FA chains.

http://ansci.illinois.edu/static/ansc438/Milkcompsynth/milksynth_fatfasynthesis.html
http://ansci.illinois.edu/static/ansc438/Milkcompsynth/milksynth_fatfasynthesis.html

 Fatty-Acid-Synthesis-C2-to-C26-5001

Termination

The synthesis is often terminated after 16 carbons. The 16 carbon FA is called palmitate. Thus, once the initial FAS 4-carbon reaction occurs, it repeats the process six more times (4 + 6*2) with additional malonyl-CoA molecules.

Palmitate requires 8 Acetyl-CoA, 7 ATP, 14 NADPH, and 14 Hydrogen. Very demanding!

For a CN fatty acid there are N/2 Acetyl-CoA required. (reference)

Stoichiometry

From 22.4.6 of Biochemistry, 5th Edition

The stoichiometry of the synthesis of palmitate is

Image ch22e12.jpg

The equation for the synthesis of the malonyl CoA used in the preceding reaction is

Image ch22e13.jpg

Hence, the overall stoichiometry for the synthesis of palmitate is

Image ch22e14.jpg

 

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