Term label update for "fermentation"

[ddooley]

• Guidelines
  Currently the GO term "fermentation" definition focuses on anaerobic fermentation. The FoodOn ontology needs both aerobic and anaerobic fermentation terms, so we'd like to see these terms disambiguated.

BTW, we see the GO (non-planned process) "fermentation" term favours casting the objective of fermentation as an energy producing process, but our interest is in defining a subclass "food fermentation" which handles food processing objectives.

• GO term ID and label for which you request a definition update
  http://purl.obolibrary.org/obo/GO_0006113 "fermentation"

• New proposed definition (genus-differentia pattern, plus additional information if needed)
  We'd like the label changed to "anaerobic fermentation".
  We don't see the need to change the GO definition for fermentation unless a more general parent "fermentation" class is introduced.

Our FoodOn curators have been crafting a more general "fermentation" definition, though it may still require description of output compounds:
"Fermentation is a metabolic process which transforms organic substances by various living microorganisms and the enzymes they produce."

Note, CHMO "fermentation mentions bioreactor specifically, and a planned process, so we will be recommending that CHML change its label to "bioreactor fermentation".

• Reference(s)
  FoodOn issue Fermented foods FoodOntology/foodon#320
  https://pmc.ncbi.nlm.nih.gov/articles/PMC10991178/ (anaerobic / microaerobic and aerobic bacteria referenced).
  https://en.wikipedia.org/wiki/Aerobic_fermentation
  https://www.sciencedirect.com/science/article/abs/pii/B0122270703005705

• Additional information

[cmungall]

Interesting!

Let me try and unpack this a bit. First, let's examine the proposal from a GO perspective. As I understand, you want to relabel the existing fermentation term because of the phenomena of aerobic fermentation. Classic examples of aerobic fermentation are either pathological (cancer/Warburg) or industrial, so it's not surprising we don't see this represented in GO annotations (or in MetaCyc or KEGG). However, as I understand, it is present in natural strains of S cer and S pombe ("Crabtree effect")(although perhaps it is only typically activated in industrial contexts?). I would be curious to see what curators in these organisms say (@edwong57 @ValWood).

As far as coordinating with other ontologies, I have some recommendations here and urge you to be careful, but let's first sort out what is in scope for GO first.

[ValWood]

Fermantation is very little studied in fission yeast. Although I have heard that pombe exhibits crabtree effect, I haven't seen any papers describing it. @PCarme @Antonialock do you have any input here about aerobic vs anaerobic fermentation ?

[PCarme]

I don't personally know much about the topic in S. pombe, but one researcher from my previous team works on carbon metabolism. I could ask him if he knows of any sources on crabtree effect in S. pombe

[ValWood]

We could change the primary name of
http://purl.obolibrary.org/obo/GO_0006113 "fermentation"
to anaerobic fermentation to match the definition

but we would not want to change the definition to cover non-evolved gene-specific processes. Food fermentation is out of scope for GO.

[ValWood]

I could ask him if he knows of any sources on crabtree effect in S. pombe

that would be useful to know...

[Antonialock]

Pombe and cerevisiae are both capable of fermenting in the presence of oxygen. I don't know what the current thinking in the field is but from memory it at least used to be thought of as a competition strategy (when food is abundant, rapidly eat all the simple energy and produce alcohol, to starve and poison other organisms). This I suppose contrasts to some bacteria that switch strategy (fermentation/respiration) depending on whether oxygen is present.

do we need to specify if it occurs anaerobically or aerobically as part of the def?

The def of aerobic respiration states "The enzymatic release of energy from inorganic and organic compounds (especially carbohydrates and fats) which requires oxygen as the terminal electron acceptor. "

so the fermentation def could be updated to something like "The enzymatic release of energy from compounds which requires a molecule other than oxygen as the terminal electron acceptor. "

[Antonialock]

I assume the fermentation process itself is the same in yeast, regardless of whether it happens in the presence/absence of oxygen (same gene products/pathway).

I therefore do not think we need different terms for aerobic fermentation and anaerobic fermentation.

[deustp01]

Classic examples of aerobic fermentation are either pathological (cancer/Warburg) or industrial, so it's not surprising we don't see this represented in GO annotations (or in MetaCyc or KEGG). However, as I understand, it is present in natural strains of S cer and S pombe

And also, if PMID: 19748317 is right, in trypanosomes. Here's a long quote (Box 1 of that review) that aims to distinguish types of energy metabolism that may be generally helpful.

A) Aerobic energy metabolism is defined as the complete oxidation of substrates to carbon dioxide and water. The majority of ATP in aerobic energy metabolism is produced via the mitochondrial respiratory chain and oxidative phosphorylation. Oxygen acts as the final electron acceptor to re-oxidise the reduced coenzyme NADH.
B) Fermentation is defined as the degradation of substrates via processes that produce their own oxidants to balance production and re-oxidation of reduced coenzyme NADH. The fermentation of glucose to lactate is a well known example of such a process. In some cases fermentation is linked to an electron transport chain and oxidative phosphorylation (not shown in this figure). However, in that case the final electron acceptor is not oxygen, but for instance endogenously produced fumarate.
C) Aerobic fermentation is the term often used to describe the form of metabolism that is used by all trypanosomatids. In this process the substrates used in energy metabolism are not completely oxidised, but instead fermentation products such as acetate and succinate are excreted. However, in this case the electron transport chain uses oxygen as final electron acceptor. Depending on the composition of the electron-transport chain this process of oxidation of NADH can be accompanied by oxidative phosphorylation. It is remarkable that trypanosomatids on the one hand produce fermentation products under all conditions studied so far, but on the other hand need oxygen as final electron acceptor for optimal functioning and cannot really depend on true fermentative processes.

My nonexpert guess looking at these definitions is that this is yet another pathway / process boundary issue. Draw the boundaries narrowly and there is only one kind of fermentation with no meaningful sub-differentia. Draw it a bit more broadly, to include fates of the immediate product of the core fermentation process and an aerobic / anaerobic distinction may become meaningful.

[raymond91125]

From Ont Editor meeting 2025-01-13, make fermentation do-not-annotate but remove anaerobic restriction.

[ValWood]

We need a new definition, describing what is common to all fermentation processes.

CHAT GPT
Yes, all fermentation processes are designed to regenerate NAD+ from NADH. The main purpose of fermentation, especially in anaerobic conditions, is to ensure that the cell has enough NAD+ to continue glycolysis and generate ATP in the absence of oxygen.

All reduce organic compounds to produce energy?

Fermentation regenerates NAD+ from NADH, enabling producing ATP without oxygen.

@deustp01 is this true

[deustp01]

@deustp01 is this true

For pyruvate in mammals and yeasts, yes. I don't know, if one looks at obligate anaerobes or weird organisms in thermal vents, whether it's always NAD+, as opposed to some other molecule functioning in this way, that needs to be regenerated.

[ValWood]

Another problem with the term "fermentation" is that to describe the process of fermentation fully, you would need to include (for glycolytic fermentation) all of the glycolysis.

so we have terms like "glycolytic fermentation"
but nobody annotated glycolysis genes to these terms.

Perhaps we only want terms to describe the process post-glycolysis (since the glycolysis part of the pathway is shared with respiration).

I.e
Lactic acid fermentation: In animals (and some bacteria), pyruvate is converted into lactic acid (lactate) when oxygen is scarce. This process regenerates NAD+ so that glycolysis can continue producing ATP without the electron transport chain.

Alcoholic fermentation: In yeast and some plants, pyruvate is converted into ethanol and carbon dioxide. This process also regenerates NAD+, allowing glycolysis to continue.

Otherwise, it becomes difficult to model, and in the previous discussion, we said that the shared part of the pathway should be a separate process (i.e. when discussing GPI and dolichol biosynthesis recently).

For this reason, I favour the obsoletion of "fermentation" because it is a grab-bag for multiple orthogonal processes with different start and end points, including and excluding upstream pathways.

(It can be related, broad or narrow synonyms)

[deustp01]

so we have terms like "glycolytic fermentation"
but nobody annotated glycolysis genes to these terms.

Ah, this brings back wonderful memories from long ago! Look at PMID: 27589964, especially the part of the "Results" section entitled "Glycolytic fermentations couple glycolysis to NAD+ regeneration"

It's a pathway/process boundaries issue for sure, but please, it is not an issue of whether fermentation is a GO-worthy biological process - it certainly is!

[ValWood]

So here is a suggested definition for a grouping term which excludes the glycolysis part:

fermentation is a metabolic process that sustains the conversion of organic compounds into energy (ATP) through glycolysis by regenerating NAD+ from NADH, while producing byproducts such as alcohol, acids, and gases. Fermentation occurs under anaerobic or sometimes aerobic conditions, though it does not require oxygen and does not consume it.

(I'm sure at least one part of this will not be true!)

[raymond91125]

PMID:38821505 is an extensive and recent review that Wikipedia:Fermentation is primarily based on.
From that I would suggest defining fermentation as:
"A catabolic process carried out by organisms in environments without oxygen that includes oxidation-reduction reactions for the generation of adenosine triphosphate (ATP) and primarily uses organic compounds as both electron donors and acceptors."

[deustp01]

in environments without oxygen

Maybe replace this phrase with "without consumption of oxygen"

[ValWood]

For GO, based on previous recent discussions, the default 'rule' would be to represent only the 'specific' and not the 'shared' part of the pathway by the GO term
(i.e. following metacyc
https://biocyc.org/META/NEW-IMAGE?type=ECOCYC-CLASS&object=Fermentation
and
https://biocyc.org/pathway?orgid=META&id=PWY-5480

This means that for our purposes glycolysis would precede "alcoholic fermentation" and "lactic acid fermentation"

i.e. in GO-CAM

[ GOCAM glycolysis: glucose-6-p ->pyruvate] upstream of [GOCAM alcoholic fermentation: pyruvate-> ethanol & CO2*]
[ GOCAM glycolysis: glucose-6-p ->pyruvate] upstream of [GOCAM lactic acid fermentation: pyruvate-> lactic acid ]
etc
In fact , the source of pyruvate is not always absolutely glycolysis.

This likely makes these terms 'compound terms' encompassing the glycolysis and the fermentation, and are unnecessary.
(not that some of these are not under fermentation)
GO:0019659 glucose catabolic process to lactate
GO:0019661 glucose catabolic process to lactate via pyruvate
GO:0019656 glucose catabolic process to D-lactate and ethanol
GO:0019658 glucose fermentation to lactate and acetate
GO:0019660 glycolytic fermentation
GO:0019655 glycolytic fermentation to ethanol
GO:0044814 glycolytic fermentation via PFL pathway
GO:0044813 glycolytic fermentation via PFOR pathway

etc

and in this case we should make it clear in the definitions that for curation purposes this
i) begins with the reduction of the organic acid and its primary purpose is to support ATP biosynthesis by regenerating NAD+, rather than producing ATP directly.

The Wikipedia definition is too broad for GO purposes, we. are so used to thinking of fermentation as starting with glucose from brewing and baking, but this is equivalent to creating terms like "glycolytic respiration".

Summary
It would seem more in line with current practice to describe fermentation processes by the organic acid input, and the outputs.

[ValWood]

Noting also that most terms are not used and there are only 58 EXP annotation

Used terms
(14) | fermentation

• | − | (13) | glycolytic fermentation to ethanol
• | − | (6) | mixed acid fermentation
• | − | (4) | acetate ester metabolic process involved in fermentation
• | − | (3) | anaerobic glycerol catabolic process
• | − | (3) | glucose catabolic process to lactate via pyruvate
• | − | (3) | glycolytic fermentation
• | − | (3) | malolactic fermentation
• | − | (2) | D-xylose catabolic process to ethanol
• | − | (2) | glycolytic fermentation via PFL pathway
• | − | (1) | L-lysine catabolic process to acetate
• | − | (1) | acetate fermentation
• | − | (1) | anaerobic amino acid catabolic process
• | − | (1) | glutamate catabolic process via 2-hydroxyglutarate
• | − | (1) | non-glycolytic fermentation

[deustp01]

Noting also that most terms are not used and there are only 58 EXP annotation

Trying to remember some basic comparative biochemistry and microbiology, I'm pretty sure that most, maybe all, of these processes are important parts of energy metabolism in various microorganisms but not necessarily prominent in humans and popular GO model organisms.

[ValWood]

I think most of the existing terms should be represented, but there are redundancies if we begin the pathways from the organic acids.

[ValWood]

I made a model of 'fermentation' in fission yeast to illustrate some of the issues
http://noctua.geneontology.org/workbench/noctua-visual-pathway-editor/?model_id=gomodel%3A678073a900000393
we can look at this on the next editors call.

[ValWood]

see also #29465

[pgaudet]

Action points:

1. Add a comment to http://purl.obolibrary.org/obo/GO_0006113 "fermentation" that explains that this does not use oxygen (even if it occurs in the presence of oxygen)
2. Look at terms that potentially include glycolysis or begin with glucose.

[ValWood]

Chat-GPT

When referring to fermentation without including glycolysis, the process is often described as the fermentation pathway or fermentative metabolism. This focuses on the steps that occur after glycolysis, primarily the conversion of the end products of glycolysis (such as pyruvate) into various fermentation products (like ethanol, lactic acid, or other organic acids), depending on the type of fermentation.
In the case of alcoholic fermentation, for example, you could refer to the process starting from pyruvate decarboxylation and reduction to ethanol, omitting glycolysis itself. You might say:
• Alcoholic fermentation pathway: Referring specifically to the steps after glycolysis, including the decarboxylation of pyruvate and the reduction to ethanol.
• Lactic acid fermentation pathway: For lactic acid fermentation, focusing on the reduction of pyruvate to lactic acid, which occurs after glycolysis.
In general, this kind of terminology emphasises the transformation of the metabolites produced by glycolysis into specific fermentation end products, while excluding the initial breakdown of glucose.

Lactic acid – Produced during lactic acid fermentation, typically by bacteria such as Lactobacillus species. This occurs in muscles (when oxygen is limited) and in dairy products like yogurt and kefir.
Acetic acid – Involved in the production of vinegar, where alcohol undergoes fermentation to acetic acid, typically by acetic acid bacteria (e.g., Acetobacter species).
Citric acid – This can be fermented by specific microorganisms (e.g., Aspergillus fungi or some bacteria) to produce compounds like ethanol or other metabolites.
Butyric acid – Produced by certain clostridia and other bacteria through butyric acid fermentation, which occurs in some anaerobic environments and can be found in the fermentation of certain foods.
Propionic acid – Produced by Propionibacterium species during the fermentation of dairy products, such as Swiss cheese. This process also produces carbon dioxide, which is responsible for the holes in the cheese.
Formic acid – Some bacteria (e.g., Escherichia coli) can ferment glucose into formic acid, especially in anaerobic conditions.
Succinic acid – Certain bacteria, like Actinobacillus or Escherichia coli, can ferment sugars to produce succinic acid, which is used in various industrial applications.

So I propose we call these pathways
fermentation pathway OR fermentation metabolism
so that we can begin them from the organic acid, and we don't need to provide the source of the acid (which add a lot of complexity).

Does that sound OK?

[edwong57]

Would this be different than the term, non-glycolytic fermentation (https://amigo.geneontology.org/amigo/term/GO:0019662)?

definition: Fermentation that does not include the anaerobic conversion of glucose to pyruvate via the glycolytic pathway. Source: GOC:jl, MetaCyc:Fermentation

[ValWood]

I'm not sure.

This term is ambiguous. It is defined
Fermentation that does not include the anaerobic conversion of glucose to pyruvate via the glycolytic pathway. Source: GOC:jl, MetaCyc:Fermentation

But I think these terms were maybe made do differentiate fermentation of organic acids that are not sourced directly from glycolysis. It's very confusing...

[pgaudet]

The term non-glycolytic fermentation (https://amigo.geneontology.org/amigo/term/GO:0019662) is confusing

There is a single annotation by CACAO from PMID:25220241 @dsiegele

This should perhaps be changed to some 'glycerol catabolic process' and 'non-glycolytic fermentation' obsoleted?

[deustp01]

Here is what looks like a definitive review of fermentation processes in anaerobes - Decker K, Jungermann K, Thauer RK. Energy production in anaerobic organisms. Angew Chem Int Ed Engl. 1970 Feb;9(2):138-58. doi: 10.1002/anie.197001381. PMID: 4984685. The paper is copyright so I don't want to post it to this ticket but I'm happy to e-mail a copy who wants one.

[raymond91125]

GO:0006113 fermentation
New definition
"The catabolic process that includes oxidation-reduction reactions for the generation of adenosine triphosphate (ATP) and primarily uses organic compounds as both electron donors and acceptors, without consumption of oxygen." [PMID:25617754, PMID:38821505]

[pgaudet]

Looks good to me. These reviews are very nice.

[ValWood]

But does this definition work for us if we want to restrict fermentation in GO to the fermentative pathway? It could be confusing because the ATP is not generated by this part of the pathway which is to regenerate NADH. Shouldn't the definition focus on NADH regeneration from organic acids?

[deustp01]

How about, "A catabolic process in which reduced input molecules are oxidized without the involvement of oxygen, ultimately leading to the generation of ATP"?

"... primarily uses organic compounds" is weak, as it explicitly allows exceptions but does not specify what makes a valid exception. The second reference you cite, PMID: 38821505, agrees with this complaint in part:

Any definition of fermentation should be tested to see how well it distinguishes fermentation from other types of metabolism. The simple definition (catabolism with organic compounds as electron donors and acceptors) works well in many cases. ... The simple definition ... is problematic in cases where fermentation produces or consumes H2. ... The simple definition is also problematic for the secondary fermentation of butyrate, where CO2 can be used as an electron acceptor.

But then becomes vague in a way that makes a clean genus - differentia definition really hard

In sum, most cases of fermentation involve catabolism with organic compounds acting as electron donors and acceptors. For the purposes of this review, fermentation can also use protons or CO2 as electron acceptors, and it can use H2 as an electron donor alongside organic compounds. While methanogenesis and homoacetogenesis meet one or more criteria for fermentation, they are not classified as types of fermentation in this review.

My stripped-down definition above at least is not wrong, and perhaps with some or all of this language from PMID: 38821505 as a comment, and with PMID: 38821505 and perhaps also the Decker et al. paper PMID: 4984685 as references that provide exhaustive catalogs of true fermentations, curators have the information needed to identify fermentation processes accurately.

[deustp01]

Shouldn't the definition focus on NADH regeneration from organic acids?

The old authorities would disagree - the point of catabolizing reduced molecules by fermentation is not simply to dispose of them but to extract energy from them.

[raymond91125]

@deustp01 Does your proposal distinguish fermentation from GO:0009061 anaerobic respiration?
"A catabolic process in which reduced input molecules are oxidized without the involvement of oxygen, ultimately leading to the generation of ATP"

"The enzymatic release of energy from inorganic and organic compounds (especially carbohydrates and fats) which uses compounds other than oxygen (e.g. nitrate, sulfate) as the terminal electron acceptor."

I do agree that "... primarily uses organic compounds" is deliberately vague to cover the H2 and CO2 cases (PMID:38821505 Figure 1B). If we name them explicitly, there may be other caveats.

[deustp01]

Does your proposal distinguish fermentation from GO:0009061 anaerobic respiration?

No, it does not. And not to be too much of an elitist snot, I see that the authority for GO:0009061 anaerobic respiration as a distinct entity, judging from the change log of its QuickGO page is an entry in Wikipedia that is accompanied by a heated discussion as to whether the term can properly be distinguished from fermentation. I think GO would be better off relying on named and well-recognized authorities like the ones we have all gathered to cite in support of the"fermentation" term. And it is exactly those named authorities that I was relying on for my suggested definition.

[raymond91125]

The fermentation branch has 45 terms (15 have EXP annotations), 10 of 45 contains the string "glycolyt*"

GO:0019650 glycolytic fermentation to butanediol
GO:0019655 glycolytic fermentation to ethanol (13 EXP)
GO:0019657 glycolytic fermentation to propionate
GO:0019660 glycolytic fermentation (3 EXP)
GO:0019662 non-glycolytic fermentation (1 EXP)
GO:0044813 glycolytic fermentation via PFOR pathway
GO:0044814 glycolytic fermentation via PFL pathway (2 EXP)
GO:2001154 regulation of glycolytic fermentation to ethanol
GO:2001155 negative regulation of glycolytic fermentation to ethanol
GO:2001172 positive regulation of glycolytic fermentation to ethanol

[raymond91125]

GO:0019655 glycolytic fermentation to ethanol (13 EXP) has a XREF https://en.wikipedia.org/wiki/Ethanol_fermentation, which is about glucose->ethanol C6H12O6 + 2 ADP + 2 Pi → 2 C2H5OH + 2 CO2 + 2 ATP.

GO:0019660 glycolytic fermentation (3 EXP) DEF "Fermentation that includes the anaerobic conversion of glucose to pyruvate via the glycolytic pathway. " and XREFs to MetaCyc:Pyruvate-Degradation
creC, creB are bacterial two component system regulating gene expression during growth in minimal media when glycolytic carbon sources are being fermented.

GO:0019662 non-glycolytic fermentation (1 EXP) DEF "Fermentation that does not include the anaerobic conversion of glucose to pyruvate via the glycolytic pathway. "
glpD glycerol-3-phosphate dehydrogenase involves in glycerol fermentation

GO:0044814 glycolytic fermentation via PFL pathway (2 EXP) DEF "The glycolytic fermentation beginning with the anaerobic conversion of glucose to pyruvate by the glycolytic pathway, followed by pyruvate:formate lyase (PFL) activity. This pathway is found in facultative anaerobes such as E. coli." (End products are formate and ethanol.)
pflB is a formate acetyltransferase, catalyzes the conversion of pyruvate to formate and acetyl-CoA.