I am having some trouble with certain steps in the mechanism below (from Mike Lu on Proteopedia) detailing the mechanism of action of pyruvate dehydrogenase converting pyruvate to acetyl-CoA. This reaction happens under the physiological conditions present in the human body ($\mathrm{p}H = 7.4, 37^{\circ}C$, 1 atm, various intracellular ionic concentrations: http://www.ld99.com/reference/old/text/2878909-566.html).

  • In the first step, how does the ylide of TPP form?
  • Why is the deprotonation of the hydroxyl group to form a ketone in the 6th step favoured, especially given that the $\ce{-OH}$ group normally has a very high $\mathrm{p}K_\mathrm{a}$?

Pyruvate dehydrogenase mechanism

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    $\begingroup$ TPP = thiamine pyrophosphate? Your first structure is not an anion, it is a neutral molecular species, depending on E1 being neutral, too. In this resonance form it is an ylide, there is another form without partial charges. It is a persistent carbene and an aromatic system. It would be good to know the conditions under which this forms. I cannot get my head around the fact that the anion of the alpha-keto acid would act as an electrophile. $\endgroup$ – Martin - マーチン Sep 2 '15 at 8:21
  • $\begingroup$ I would assume it happens under the physiological conditions present in the human body. $\endgroup$ – James Harrison Sep 8 '15 at 5:37
  • $\begingroup$ Unfortunately I am not educated enough in that area to know what these physiological conditions are. I can only try to understand what you have posted here and therefore I might be missing information that you can better define - or that are defined in some standard way, which you could probably link to. That would possibly enhance your question and some non biochemists might give it a chance, too. $\endgroup$ – Martin - マーチン Sep 8 '15 at 5:44

The ylide of thiamine pyrophosphate does not ‘form’; rather it is there. There are two major mesomeric structures for the five-membered ring: One including a double bond from nitrogen to the carbene carbon, the other one with a single bond (lone pair on nitrogen, sextet on the carbene carbon). As with mesomeric forms of benzene, the truth is somewhere between these two extremes.

In the carbene elimination step, you seem to assume just by the existence of the arrows that the deprotonation of the hydroxide must come first. That is not the case. In fact, I would assume the first arrow to be the recreation of the keto unit, followed by the removal of the thiamine. Only then would the proton be lost, since we are now dealing with a protonated ketone which is a very strong acid.

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