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picture 1 (left upper corner) is the FAS or fatty acid synthase. It's the multifunctional proteïn that has all the necessary enzymes in one complex consisting of 2 monomers. (And for example; CE is the condensing enzyme). Picture 2 (at the right) is the steps you do when you are at the reduction part (green part on picture 1) And picture 3 (left bottom corner) is another scheme that shows the condensation, reduction and translocation and so on. This last picture confuses me a little.

I have a problem in my reasoning on the fatty acid synthesis in the human body. In the synthesis process you have this homodimer.

So the synthesis starts with the transfer of a acetyl group from acetyl-CoA to the sulfhydrylgroup of the condensing enzyme (CE) with help of the acetyltransferase enzyme (AT) and this on 1 of the 2 monomers.

At the same time a malonyl group from malonyl-CoA is transfered to the sulfhydryl terminus of phosphopantotheine from the ACP, and this on the other monomer and with help of the malonyltransferase (MT) enzyme.

AND HERE THE PROBLEM STARTS

The acetyl residue will be condensing with the malonylACP and at the same time there will be a decarboxylation (CO2 goes off) and CE goes off from acetyl. At the end acetoacetyl-ACP is formed. So if I got it right; the acetyl residue is being 'cut off' from the CE from the first monomere and binds to the malonylACP on the other monomere. Right?

And after that the acetoacetyl-ACP will be swept back to the other monomer (to the reduction part), is this also right?

Then the reduction-dehydration-reduction steps are happening and at the end of the road you will get butyryl-ACP which will cut off from the ACP and migrate on the same monomer to the cysteine residue at the condensing enzyme (CE) (= translocation).

And after that you can start a new condensation-reduction-translocation cycle and go on until you end up at palmitoyl-ACP.

So the actual question is; is my reasoning right about how the product is going from one monomer to the other several times? In my book it's a pretty messy explanation and so I want to be sure I'm right.

I hope somebody can help me out =)

Greetings

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It might be best if you draw a diagram of your proposed pathway and post it in your question as an edit so that it's easier to follow through your question. –  Bez May 22 at 20:53
    
I have a few pictures about it I can post eventually. I will try to fix that up in a few minutes. If that doesn't help I will draw it more in detail tomorrow and post =) –  user6812 May 22 at 21:10
    
I'm afraid this picture is too small... I'll make another one tomorrow. –  user6812 May 22 at 21:57

1 Answer 1

up vote 2 down vote accepted

The textbook descriptions of fatty acid synthesis can be confusing because although the underlying chemistry of the process is universal, the way that it is organised is different in the systems that have been characterised, which include E. coli, yeast and vertebrates.

In vertebrates: The fatty acid synthase is a dimer of identical multifunctional single polypeptides. The synthesis process involves two -SH groups: one is the terminal group of the pantothenate of the acyl carrier protein domain (Pan-SH) and the other is an -SH group of the condensing enzyme (CE-SH).

For the first condensation step the initiating acetyl group is attached to the CE-SH of one monomer and the incoming unit (malonyl CoA) is attached to the Pan-SH of the other monomer.

The condensation reaction between these two results in the new elongated unit being attached to the Pan-SH. This unit then goes through the reductase/dehydratase/reductase steps to form the new acyl CoA which is finally transferred to an CE-SH group, opening up the Pan-SH for the next incoming malonyl CoA.

This will happen repeatedly in each cycle of the process. Obviously since each monomer has both -SH groups a single fatty acid synthase dimer can be engaged in two elongations at the same time, but these will always include a transfer. It is thought that the initiating acetyl group comes in via the Pan-SH group.

You say:

And after that the acetoacetylACP will be swept back to the other monomere (to the reduction part), is this also right? Then the reduction-dehydration-reduction steps are happening and at the end of the road you will get butyrylACP which will cut off from the ACP and migrate on the same monomere to the cysteïnresidu at the condensing enzyme (CE) (= translocation).

The diagram that you included clearly shows that the acetoacetyl group is formed via the reduction-dehydration-reduction steps on the same Pan-SH where its precursor was formed by condensation. Only then is it transferred to the CE-SH group. The diagram also indicates that the acetoacetyl group is transferred to the CE-SH of the same monomer. This implies that a growing chain never transfers from one monomer to the other. I have seen other sources which seem to suggest that this step does involve a transfer between monomers.

In fact it would appear from the discussion on the WP page for fatty acid synthase that this is an unresolved issue - see for example:

Joshi et al. (2003) Engineering of an Active Animal Fatty Acid Synthase Dimer with Only One Competent Subunit Chemistry & Biology 10:169 - 173

Abstract

Animal fatty acid synthases are large polypeptides containing seven functional domains that are active only in the dimeric form. Inactivity of the monomeric form has long been attributed to the obligatory participation of domains from both subunits in catalysis of substrate loading and condensation reactions. However, we have engineered a fatty acid synthase containing one wild-type subunit and one subunit compromised by mutations in all seven functional domains that is active in fatty acid synthesis. This finding indicates that a single subunit, in the context of a dimer, is able to catalyze the entire biosynthetic pathway and suggests that, in the natural complex, each of the two subunits forms a scaffold that optimizes the conformation of the companion subunit.

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So if I got it right, everything takes place on 1 monomere? And the translocation step is also on the same monomere? –  user6812 May 23 at 9:13
    
But why does my book tell me then that the synthesis starts with the transfer of a acetylgroup from acetylCoA to the sulfhydrylgroup of the condensing enzyme (CE) with help of the acetyltransferase enzyme (AT) and this on 1 of the 2 monomeres and that at the same time a malonylgroup from malonylCoA is transfered to the sulfhydrylterminus of fosfopantetheïn from the ACP, and this on the other monomere and with help of the malonyltransferase (MT) enzyme? It clearly tells me that it occurs on the 2 monomeres... So what is the conclusion then? =S –  user6812 May 23 at 9:21
    
As I tried to hint at, I don't think anyone really knows. The cited paper concludes that a single monomer can do everything as long as it is in a dimer. But of course that doesn't mean that's the way things normally happen. It's clear however that the prevailing textbook version does describe the cooperation of two monomers, as shown in your diagram 3. –  Alan Boyd May 23 at 9:51
    
Okay I understand what you say =) Thank you very much. It makes sense now. I will follow the teacher her book that describes the cooperation of two monomers. Because if I would say like 'nobody really knows' she will be like what are you trying to say? Haha =P And her diagrams show that there is cooperation of two monomers as you say so then I'll have to explain it that way on the exam too (if she asks). Thank you very much! –  user6812 May 23 at 10:29

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