7
$\begingroup$

I am not properly educated in biochemistry so I apologize if my question makes incorrect assumptions or uses bad definitions.

I am confused about the seemingly interchangeable usage of "lactate" and "lactic acid" when talking about anaerobic glycolysis. I'm aware of a similar question on chemistry stackexchange, but I don't fully understand the answers.

I think I understand that practically, at physiological pH, lactic acid will deprotonate which results in lactate and a hydrogen ion. However, this seems meaningfully different to me than just lactate being produced. If lactic acid is produced and immediately depronated, then wouldn't the solution still be more acidic than before due to the hydrogen ion? On the other hand, if just lactate is produced, then wouldn't the solution be slightly more basic?

This question is motivated by what seems like a debate about the role of cellular acidosis in fatigue. Historically, "lactic acid" was blamed, but it seems like more recent opinions are that "lactate" actually helps buffer the ions and is thus not a cause of acidosis or fatigue directly - instead the ions are blamed. I'm confused since the ions and lactate seem to come from the same source anyway.

$\endgroup$
4
  • 3
    $\begingroup$ Welcome to StackExchange! The article Robergs, R. A. Lactate, not Lactic Acid, is Produced by Cellular Cytosolic Energy Catabolism might be of use to answering your question. $\endgroup$
    – Domen
    Feb 8, 2023 at 8:09
  • 1
    $\begingroup$ @Donen If you give the poster a link rather than providing an answer one assumes that you think the question is off-topic, perhaps as "homework" being easily answered by the online source. Glancing at it, I would think it of sufficient length and complexity that a condensed description of the argument would be helpful to the poster and others interested in the topic in relation to acidosis and exercise physiology (not my field). I would urge you to provide an answer yourself. $\endgroup$
    – David
    Feb 8, 2023 at 14:05
  • $\begingroup$ What I did not – and I should – mention to the poster is that the question is – like many others – underdeveloped as it does not show enough of prior research. Instead, I provided some suitable reference which could be read and included in the question if there are any additional subquestions. Furthermore, this could also help someone else to write a comprehensive and well-written answer, for which I currently don't have time to do. $\endgroup$
    – Domen
    Feb 8, 2023 at 18:54
  • $\begingroup$ What is the actual question here? there are several questions in this. $\endgroup$
    – John
    Feb 9, 2023 at 1:27

1 Answer 1

4
$\begingroup$

Thank you @Domen for the link. This article seems to answer my question, so I'll try to summarize my understanding of it here for anyone else that stumbles upon this. Warning that I am just a layman so I may very well get things wrong and will definitely oversimplify (but hopefully Cunningham's Law will hold).

The article criticizes a separate review that gave a history of cellular lactate production for using the term "lactic acid" instead of "lactate" and for associating this production with cellular acidosis.

To explain why the discrepancy seems to exist at all, the article points out that "lactic acid" was first discovered before there was an understanding of acid-base chemistry, so presumably they did not have the proper tools to appreciate and observe the difference between lactate and lactic acid at the time.

The article acknowledges that "lactic acid" production is correlated with acidosis, but emphasizes that correlation does not imply causation.

My first confusion was, well, if lactic acid is produced, how does it not cause things to be more acidic?

The article argues that lactic acid is not produced at all. Not that it disassociates immediately, but that it is not produced to begin with. (I'll summarize their explanation, but not just yet)

The article continues by acknowledging that anaerobic metabolism does contribute to acidosis. The crux of the question then is, where does the H+ come from?

They go into some detail on the chemistry involved here that I won't summarize because frankly I don't understand it all that well. But in short, they claim that ATP hydrolysis is what releases the H+. Since ATP is hydrolyzed during earlier steps of glycolysis, this means it is the earlier steps of glycolysis that lead to acidosis.

Interestingly, the article highlights that as pH decreases, glycolysis releases more H+:

Note, as pH decreases, there is increased fractional H+ addition to HPi for H2Pi, which accounts for the increasing fractional H+ release during the production of 1,3-bis-phosphoglycerate

The article also explains that after 3-phosphoglycerate is produced with an unprotonated carboxylic group, every intermediate afterwards also has an unprotonated caroxlylic group. This is how they explain that lactic acid is never produced to begin with it at all; instead lactate is produced:

The first carboxylic functional group intermediate of glycolysis is produced in the sixth reaction where 1,3-bisphosphoglycerate is converted to 3-phosphoglycerate (see Ref.9, Fig. 5, p. R507). This is a phosphate transfer reaction, adding the phosphate to ADP forming ATP, with the co-production of 3-phosphoglycerate having an ionized (unprotonated) carboxylic functional group at carbon-3. This is key to understanding the H+ load of glycolysis and H+ metabolic buffering from lactate production. Each glycolytic intermediate following this reaction remains in an ionic form.There is never a glycolytic production of a carboxylic acid since they are all carboxylic ions.

So in short it appears that lactate is produced and that it acts as a buffer against H+. "Lactic acid" has been the go-to term due to the history of its discovery, but it's actually lactate and it does have meaningfully different implications as the production of lactate does serve to consume H+. The earlier steps of glycolysis do lead to acidosis, presumably through ATP hydrolysis. After 3-phosphoglycerate is produced, every intermediate following is also a carboxylate (as opposed to carboxylic acid).

$\endgroup$
6
  • 1
    $\begingroup$ (+1) That indeed in an interesting link! But one sentence is very unusual, and is surely an error: " For example, the work and achievements of Haldane in acid-base chemistry did not occur until the1940s (11), ... " J. S. Haldane (the father of JBS Haldane and Naomi Mitchison) died in 1936 $\endgroup$
    – user338907
    Feb 9, 2023 at 17:16
  • 1
    $\begingroup$ Unfortunately you cannot understand the paper or acidosis in general if you do not understand the chemistry of weak acids and bases and the significance of the acid dissociation constant (and the related pKa) on their ionization. If you did you would realize that as lactic acid has a pKa of approx. 3.7 lactate cannot possibly be a physiological buffer. In order for it act as a buffer a significant amount of lactic acid would have to be formed by lactate combining with hydrogen ions at cellular or blood pH. It does not. That is why we refer to it as lactate, as the Chemistry SE answers explain. $\endgroup$
    – David
    Feb 10, 2023 at 18:15
  • $\begingroup$ Hi @David thank you for the response and context. I apologize if I misunderstood what “buffer” means, but I believe the paper claims that lactate production consumes H+. Does “buffer” mean something else? Please let me know if I’m misunderstanding both you and the paper, but it sounds like you disagree with this claim of the article? $\endgroup$ Feb 11, 2023 at 17:28
  • 1
    $\begingroup$ My reluctance to answer this question relates to your motivation — and the concern of the quoted paper — acidosis and fatigue resulting from exercise. I am a biochemist not a physiologist and cannot express any opinion on that. I would only say that I find a letter that is so critical of the terminology of others should not use the word cytosol (an artificial fraction of broken cells) instead of cytoplasm. The term "consumed" is also unscientific and "coefficient of H+ exchange" is unknown to me. What I do know is a buffer works best ±0.5 pH units from the pKa of its acid: 3.8 for lactic acid. $\endgroup$
    – David
    Feb 11, 2023 at 22:11
  • 1
    $\begingroup$ "but I believe the paper claims that lactate production consumes H+" This, I think, has nothing to do with the buffering effect of lactate (or ionization of carboxylate group of lactate in any sense) but to the fact that a proton is consumed in the LDH reaction (pyruvate + NADH + H+ = lactate + NAD(+)). Have a look at the later papers of R.A. Alberty (or Physical Chemistry by Alberty and Silby) $\endgroup$
    – user338907
    Feb 12, 2023 at 9:56

You must log in to answer this question.

Not the answer you're looking for? Browse other questions tagged .