AAMC Sample Test Passage 8

[rabbott1971]

The question asks about Acetyl CoA. CoA is the same thing as Coenzyme A, yes? Isn't Coenzyme A a chiral molecule? The answer says it is not.

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[Lawpy]

Here is the structure of coenzyme A:

Chiral molecules have carbon atoms bonded to four different functional groups. The above structure shows coenzyme A consists of a variant of ADP, which consists of a ribose sugar attached to adenine and two phosphate groups. It becomes evident that the ribose has four chiral carbon centers (one attached to adenine, one attached to hydroxyl, one attached to phosphate, and one attached to the carbon attached to rest of the coenzyme A structure). There is another chiral carbon attached to another hydroxyl group (between the carbonyl carbon and the carbon with two methyl groups). So yes, coenzyme A is a chiral molecule.

But look carefully at the reactions listed:

In all the reactions, coenzyme A isn't a reactant. It serves as a product to help convert series of acetyl-CoA molecules into longer-chain fatty acids and related compounds (so mevalonate and terpenes for cholesterol synthesis). The reactants are actually the carbon structures of acetyl-CoA and acetoacetyl-CoA. And these carbon structures aren't chiral because the carbon atoms are attached to identical functional groups.

The reason why only a single stereoisomer is formed in Reaction 2 is that the enzyme is stereospecific to only one stereoisomer. This has to do with the inherent chiral nature of the enzyme involved. It's also another reason why enzymes are useful for separating racemic mixtures of stereoisomers to select for optically pure compounds.

 

[rabbott1971]

I'm not familiar with the idea that part of a reactant is not actually a reactant. That's how I understand your response.

I guess I don't get how CoA is not a reactant when Acetyl CoA is the actual reactant? If CoA is chiral, then acetyl CoA must be chiral as well, right? What is the difference between CoA and COA?

This has got me pretty lost. I don't think we touched on this in my biochem class. And I'm not even posting the question from this passage about tracking the carbon atoms through the reaction.

 

[Lawpy]

I'm not familiar with the idea that part of a reactant is not actually a reactant. That's how I understand your response.

I guess I don't get how CoA is not a reactant when Acetyl CoA is the actual reactant? If CoA is chiral, then acetyl CoA must be chiral as well, right? What is the difference between CoA and COA?

This has got me pretty lost. I don't think we touched on this in my biochem class. And I'm not even posting the question from this passage about tracking the carbon atoms through the reaction.

Acetyl-CoA is the reactant but looking at the reactions, we see CoA being removed from acetyl-CoA and the carbon backbone attaching to the carbon backbone of the other acetyl-CoA (or acetoacetyl-CoA or related molecules). The actual mechanism of the reaction is more complicated. It basically involves an aldol condensation (specifically a Claisen condensation because acetyl-CoA is a thioester, which is an ester but the oxygen is replaced by sulfur), whereby one of the acetyl-CoA molecules act as an enolate that attacks the carbonyl carbon of the other acetyl-CoA molecule. The enolate has a negative charge on the carbon atom, so the conezyme A molecule isn't involved in the reaction besides simply being eliminated.

Here's an example mechanism of how Claisen condensation works.

The reaction with acetyl-CoA is similar to visualize but replace -OEt functional group with -SH-CoA group.

Here is a better visualization:

And a good resource to follow for more information, since the topic is pretty complicated and requires an advanced understanding of organic chemistry: 13.4: Claisen reactions

But for the purposes of the MCAT, just follow what's being eliminated from the reaction. From the reactions in the passage, the arrows indicate coenzyme A is being removed, so we can view it to be the product rather than assuming it's directly involved in the reaction. The same goes for any compounds encountered in unusual reactions where the mechanism becomes complicated.

 

[rabbott1971]

Well thanks. Not sure if this is one I'll be able to achieve, but I appreciate the patient explanation.

 

[Lawpy]

Well thanks. Not sure if this is one I'll be able to achieve, but I appreciate the patient explanation.

It's a pretty complicated topic. In these cases, an effective strategy is look for the least wrong answer. Doing so should pinpoint you to D a bit faster because enzymes are stereospecific and will always pick one stereoisomer. That's one concept you can comfortably rely on.

 

[rabbott1971]

I was trying to rely on the idea that a reactant is chiral!!! haha But OK I will keep that in mind about enzymes. Thanks again.

 

[aldol16]

I was trying to rely on the idea that a reactant is chiral!!! haha But OK I will keep that in mind about enzymes. Thanks again.

It's a pretty complicated topic. In these cases, an effective strategy is look for the least wrong answer. Doing so should pinpoint you to D a bit faster because enzymes are stereospecific and will always pick one stereoisomer. That's one concept you can comfortably rely on.

I think the missing link between you two is the difference between a chirality at a single carbon center and diastereomers. Yes, coenzyme A is chiral. But we're interested in the chirality that is set in reaction 2, which occurs at a specific carbon atom. In other words, we're interested in a very specific diastereomer with a specific chirality at carbon 3. In other words, chirality in CoA doesn't affect chirality at carbon 3 because even if an enzyme were to bind the CoA part in a stereospecific way, the incoming enolate can still attack carbon 3 in the substrate (acetoacetyl-CoA) on either side - it's achiral. So in order for that attack to favor one side (pro-R or pro-S attack, in chemistry terms), the enzyme has to raise a kinetic barrier to one side so that the other face is favored. That's how you get the desired diastereomer. Even though CoA is chiral, we're talking about a specific diastereomer here in which the chirality in question is distal from CoA.

 

[aldol16]

The reaction with acetyl-CoA is similar to visualize but replace -OEt functional group with -SH-CoA group.

Here is a better visualization:

Good explanation of acetyl-CoA reactivity in general, but I should note that the mechanism you show here is not the mechanism that is operant in reaction 2 above. It is the reaction in reaction 1 though. Reaction 2 is special because it involves enolate attack at the distal carbonyl as opposed to the one bearing the CoA group in acetoacetyl-CoA.

 

[rabbott1971]

Aldol thanks, I went over this with a chemistry friend and he mentioned that the planar substrate would be kind of held by the enzyme on one side, and attacked exclusively from the other side, giving stereospecific products. That's an easier explanation for me to follow, and seems to track with your comment. Thanks for the help!