Does Glycolysis produce lactate, or pyruvate?

Question

EDIT- Somebody suggested that this is the same question as this, it isn't. This one is asking about the definition of glycolysis. That one was asking about the definition of fermentation.

Does Glycolysis produce lactate, or pyruvate?

I'm aware that ultimately in the human body, after sugar is converted into pyruvate, then if fermentation happens it will be converted into lactate, or if aerobic respiration happens then it won't.

My question is on the term Glycolysis

I notice that most sources seem to say glycolysis ends with pyruvate

e.g.

Glycolysis.. is the metabolic pathway that converts glucose.. into pyruvate

The only time lactate comes into it is After glycolysis. (so in this wikipedia page on Glycolysis, in the Post Glycolysis part it mentions this) https://en.wikipedia.org/wiki/Glycolysis#Post-glycolysis_processes "pyruvate is converted to lactate "

However, on the other hand, I see some sources, even another wikipedia article titled "anaerobic glycolysis", which the page says isn't well sourced, it has glycolysis as ending in lactate.

https://en.wikipedia.org/wiki/Anaerobic_glycolysis "Anaerobic glycolysis is the transformation of glucose to lactate when limited amounts of oxygen (O2) are available"

Also here https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4343186/ "we contend that La− is always the end product of glycolysis"
(putting aside their controversial claim that it is always the end product, i'm interested here in the idea of theirs that it is ever an end product, so, their use of the term glycolysis)

So it seems that there are those two positions

For the purposes of this question i'll call one position the lactate position and the other position the pyruvate position.

One position, call it the lactate position, which is those sources that place lactate, as the end product of glycolysis.. thus counting not just sugar->pyruvate, but sugar->pyruvate + the whole fermentation process, as glycolysis.

While others, call this the Pyruvate position, count purely sugar->pyruvate those sources count just that, as Glycolysis.

I'm wondering if both definitions are correct.. / both usages are valid.. Or if one of those e.g. if the lactate one, is an odd one out and if most academic texts wouldn't use that definition, and would use the pyruvate position for their definition of Glycolysis.

Note- I had written that glycolysis ends with pyruvate {or pyruvic acid which dissociates into pyruvate}, and the lactic acid fermentation ends in lactate {or lactic acid which dissociates into lactate}. But what is in those curly braces there is wrong and I have been corrected on that one. Glycolysis produces pyruvate, and Lactic Acid Fermentation produces lactate. The reason (answerer David explains), why Lactic acid fermentation bears that name, is it is named after what are called "lactic acid bacteria" "Lactic acid bacteria are named for their effect on the medium in which such bacteria grow, not for the ionization state of lactic acid in the cell and when bound to enzymes (about which the namers could have had no knowledge)." and they do that type of fermentation that produces lactate. There are two types of "lactic acid fermentation", https://en.wikipedia.org/wiki/Lactic_acid_fermentation homolactic fermentation, and heretolactic fermentation. Humans do homolactic fermentation that produces lactate and no ethanol, as opposed to heterolactic fermentation that produces lactate and ethanol https://www.onlinebiologynotes.com/different-fermentation-pathway-bacteria/

Also, note that Muscle cells do what is called "lactic acid fermentation", but the idea that they produce lactic acid is a myth that has been commonly propagated in sports science(I guess perhaps partly as a result of what I think is biology's poor nomenclature, the fact that the process is called lactic acid fermentation). Muscles don't produce lactic acid, in fact, it's not lactic acid and they don't produce it. Muscle cells use lactate, they don't produce lactic acid. This is verifiable from googling humans produce lactate not lactic acid eg the first line here mentions that myth and calls it out as a myth. The body of the following question and its answers here are related and very interesting.

Answer 1

I think you will find all text books (e.g. Berg et al. Ch 16) describe glycolysis as the conversion of glucose to pyruvate, as this is how it has been defined and considered in countless biochemical papers. The subsequent reactions of pyruvate are regarded as separate metabolic steps or pathways.

The title of the short review article you cite (“Lactate is always the end product of glycolysis”) has mislead you — it was obviously meant to be controversial. It is the ambiguous term “end product” that is the (deliberate?) cause of the problem. What the article suggest is that the product of glycolysis — pyruvate — is always, at least partially, converted to lactate in animal cells. It would have been better entitled “Lactate is always produced from the pyruvate generated in glycolysis”. Whether or not that is true (and that is not your question as I understand it), the conversion of pyruvate to lactate is not considered to be part of glycolysis any more than its conversion to acetate.

There may be ambiguity in the use of the ancient term ‘fermentation’, but not with glycolysis and other metabolic pathways established in the twentieth century.

Answer 2

Lactate, not pyruvate, is the end-product of glycolysis. If pyruvate was the end-product, there would be a major problem: glycolysis would stop.

I am talking here about how cells 'obtain' ATP from the splitting of glucose under strict anaerobic conditions (glycolysis).

Glycolysis is the splitting of glucose, and occurs anaerobically without any net oxidation or reduction, and the free energy sequestered in the form of ATP is derived from the splitting reaction. In thermodynamic terms, we can envisage that entropy makes a contribution to the overall (favorable) Gibbs free energy change: splitting a molecule into two parts makes the system more disordered (to take a crude view of what entropy means). But of course the rearrangement of chemical bonds will also make a (major?) contribution.

Let's be blunt about the role of oxidation and reduction: as stated, there is no net oxidation or reduction in glycolysis. But in this last statement lies a major paradox, and therein is the reason why we must consider lactate (and in alcoholic fermentation, ethanol) the end-product of glycolysis.

Although glycolyis proceeds without net oxidation or reduction, a supply of oxidied NAD (i.e., NAD⁺) is required in order for the process to continue.

I am of course talking about the glyceraldehyde-3-phosphate dehydrogenase (GAPdh) reaction, that ubiquitous enzyme of glycolysis.

$$ \mathrm{\text{glyceraldehyde-3-phosphate}\,+\,NAD^{+}\,+\,P_i\text{ = }\text{1,3-bisphosphoglycerate} +\,\,NADH\,+\,H^+}$$

Pyruvate production from glucose is an oxidation - we have 'removed' a pair of electrons (strictly speaking, 2 pairs), but for glycolysis to proceed we (paradoxically) need a reduction - we must (somehow) get rid of the electrons from NADH, and one way (crazily at first sight) is to 'give' the electrons back to the carbon skeleton from whence they came - to pyruvate in the case of muscle (lactate) glycolysis.

One of the key steps to understanding glycolysis is to ask the question: how is the NADH produced in the GAPdh reaction oxidized back to NAD⁺?

In lactic acid fermentation and in muscle glycolysis, this it done with lactate dehydrogenase (LDH), which catalyzes the NADH -linked reduction of pyruvate to lactate, with concomitant production of NAD⁺, thus allowing glycolysis to continue. If we could 'knock out' the LDH gene, there would be no glycolysis (a lethal mutation), unless the cell could somehow find another method of regenerating NAD⁺.

The splitting of glucose into lactate may be represented stoichiometrically as follows (one glucose is split into two lactic acid molecules):

$$ \mathrm{\text{1 }C{_6}H_{12}O_6\text{ = 2 }CH_{3}\,CHOH\,COOH}$$

We may note that there is no oxidation or reduction. In aerobic respiration, glucose yields 12 pairs of electrons to the respiratory chain, and all are 'held' in either carbon-carbon or carbon-hydrogen bonds. Each lactate acid molecule (or more precisely, each lactate molecule) has six (C-C and C-H) bonds: they are all there, nothing has changed.

Furthermore, it is the above reaction that yields the free energy, no matter how we view the intricacies of the molecular processes that lead to it. That is, fundamentally, lactic acid fermentation (or muscle glycolysis) is a sequestration of Gibbs free energy, in the form of ATP, obtained by the splitting of glucose into two molecules of lactate.

In the case of pyruvate, we would need to write the equation (balanced in terms of electrons but not hydrogens) as follows:

$$ \mathrm{\text{1 }C{_6}H_{12}O_6\,+\,2\,NAD^{+}\text{ = 2 }CH_{3}\,(C\text{=}O)\,COOH +\,2\,NADH}$$

If we count the number of (C-C and C-H) bonds in pyruvate, we see there are five: one pair of electrons is 'missing' and is now 'held' by the nicotinamide cofactor.

So what of alcoholic fermentation? How is NADH re-oxidized here? In this case, pyruvate is first decarboxylated to acetaldehyde and CO₂ by the enzyme pyruvate decarboxylase, and NADH is reoxidized by the enzyme alcohol dehydrogenase acting as an aldehyde reductase. That is, the NAD⁺ necessary for the GAPdh reaction is 'regenerated' by the reduction of acetaldehdye to ethanol. As far as anaerobic fermentation in yeast is concerned, ethanol is a 'waste' product (but very useful to us humans).

$$ \mathrm{CH_{3}CHO\,+\,NADH\,+\,H^{+}\text{ = }CH_{3}CH_{2}OH\,+\,NAD^{+}}$$

If we count the number of (C-H and C-C) bonds in acetaldehyde, there are five, but in ethanol there are six. As two molecules of ethanol are produced for each glucose, the total is twelve and we have accounted for everything: once again there is no net oxidation and reduction, and the stoichiometric splitting of glucose in alcoholic fermentation may be written as follows (one glucose gives two molecules of ethanol and two molecules of carbon dioxide),

$$ \mathrm{\text{1 }C{_6}H_{12}O_6\text{ = 2 }CH_{3}CH_{2}OH\,+\,2\,CO_2}$$

and it is the Gibbs free energy 'released' in this reaction that is used to 'make' ATP.

NADH produced in glycolysis may also be regenerated 'aerobically', that is by reoxidation in mitochondria via the respiratory redox chain. The problem here is that the inner mitochondrial membrane is impermeable to NAD, and a shuttle system, such as the aspartate-malate shuttle, is required to get the electrons across the inner membrane. If NADH is regenerated via mitochondrial respiration, this is of course an alternative to the LDH reaction and lactate need not be formed (but we are no longer talking about anaerobic glycolysis). This, I suspect, is where the confusion often arises.

To make one final point about lactate glycolysis in humans. A muscle cell, perhaps obtaining as much energy as possible from glycolysis during vigorous exercise, regards lactate as a waste product. But this is not true of the organism as a whole: the lactate is taken to the liver where it may be converted back to glucose (via pyruvate) as part of the Cori cycle (which is way beyond the scope of this answer).

So why the apparent paradox of NAD oxidoreduction during glycolysis? And why oxidize a carbon skeleton with NAD⁺ and then regenerate the oxidizing agent by reducing the carbon skeleton at a later step? I have no explanation, but this is surely a great example of what Albert Lehninger called the molecular logic of living organisms.