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Author Topic: Nucleotide synthesis: IMP to GMP/AMP  (Read 1246 times)

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keetner

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Nucleotide synthesis: IMP to GMP/AMP
« on: December 09, 2012, 04:59:39 PM »

Hey guys,

When synthesizing nucleotides (either purines or pyrimidines), I know some steps require you to activate a carbonyl O in order to get the amine group. In the image down below, you can see this. In this case, amine groups are coming from Asp and Glu. What I would like to know is, how do you know when to use which amino acid group? From what I've seen so far, I don't commonly see Asn or Gln being used.

I'm also confused by the intermediates produced by these two reactions (they are not shown in the image). I was told that IMP --> adenylosuccinate yields an acyl-phosphate intermediate; Xanthylate ---> GMP yields an acyl-AMP intermediate. My question is, how can you get either of these two intermediates?? The only way I can get and acyl- group at all is if the phosphates were to attach to the amino acids; not the substrates.

So yes, when activating something, I don't know if the phosphates will attach to the substrate or the amino acids, and I don't understand why Asp and Gln are always used as amine donors.

I tried looking for some mechanisms, but I couldn't find any, unfortunately. Any help would be greatly appreciated, though!

Thank you.

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Babcock_Hall

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Re: Nucleotide synthesis: IMP to GMP/AMP
« Reply #1 on: December 10, 2012, 04:41:53 AM »

There are at least three commonly encountered reactions where Asp is the donor; the other two are the urea cycle and in the synthesis of IMP itself.  Fumarate is always the product in the next step.  Gln is also a common nitrogen donor, and it shows up once or twice in the pathway to IMP.  Biochemistry, 5th ed., by Nelson and Cox has some good examples (probably in Chapter 22).  The phosphoryl group will attach to an atom that needs to be displaced, in order to turn a bad leaving group into a good leaving group.  In the case of reactions in which oxygen needs to be replaced on a purine ring, my best guess is that one type intermediate is -OPO32- group.  But I am not claiming that this is definitely what happens, only that this has biochemical precedent and chemical logic.  What does that suggest about the intermediate on the right side of your diagram?

By the way, you may have an error on the right side of your diagram.  Should that not be AMP, as opposed to ADP?
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keetner

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Re: Nucleotide synthesis: IMP to GMP/AMP
« Reply #2 on: December 10, 2012, 10:42:24 AM »

Hi, thanks for the response!

Ah, I didn't notice the diagram before! It definitely should be AMP + PPi...

Yes, you're right. Both intermediates will have some sort of phosphate group (P or AMP) attaching to the carbonyl O, which results in a good leaving group. I'm just confused by how my professor mentioned that the intermediates produce either Acyl-P or Acyl-AMP (again, not shown). I can't seem to figure out how this is so...because if the phosphate is activating the the carbonyl O, would that not produce a phosphomonoester?

In regards to the ammonia donors -- is there a particular reason why we commonly see Asp and Gln? Versus, say, Asn and Glu? Since I feel like they could potentially work the same way being N donors.

The only thing I can think of is that with all these reactions, I guess the cell is 'thinking ahead' (eg. you mentioned fumurate which could go back into the TCA).
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Babcock_Hall

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Re: Nucleotide synthesis: IMP to GMP/AMP
« Reply #3 on: December 10, 2012, 11:13:32 AM »

Recycling of fumarate is certainly one advantage of Asp over Glu.  Beyond that, I am not too certain.  Some or all of the glutamine amidotransferases are related via evolution, apparently.  I don't know why Asn would not work just as well, but maybe it is a quirk of evolution.  Sometimes the "acyl phosphate" terminology is applied a little bit loosely (Nelson and Cox, p. 859).  BTW some actual acyl phosphates do show up in biosyntheses.  For example, glycine is activated in this way in the biosynthesis of IMP.
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