Talk:Coenzyme

ATP recycling
What is the relationship between ATP recycling and coenzymes ? ATP is no coenzyme !!

Lulubou (talk) 12:46, 6 March 2009 (UTC)

Thiamine diphosphate
Thiamine is a vitamine and thiamine diphosphate is definitely a cofactor and should be in the list. Therefore I added it again. Narayanese, why did you undo my previous addition of thiamine ? —Preceding unsigned comment added by 139.165.98.37 (talk) 12:42, 6 March 2009 (UTC) Lulubou (talk) 12:44, 6 March 2009 (UTC)
 * It does not follow the definition in the lead, being a prosthetic group only. While not everyone would agree to that definition, it has a source and allows an article that does self-contradict and mislead. If you think another definition of coenzyme should be used you need authorative references - I don't have a particular reason to trust your judgement. Narayanese (talk) 22:52, 6 March 2009 (UTC)

The distinction between cofactors, coenzymes and prosthetic groups
For teaching biochemistry for years I know that it is not easy to escape contradictions when talking about coenzymes and cofactors. The best way to do would be to unit the articles on cofactors and coenzymes (call it "Cofactors and coenzymes). Cofactors are the general term comprising coenzymes (organic molecules with enzymatic function) and metal factors. Some of these are prosthetic groups with enzymatic function (FAD, heme for instance). But some prosthetic groups (tightly bound non proteinic groups such as sugars or lipid) are not necessarily cofactors. For me, ATP is certainly none of these (it has no catalytic function, in constrast to NAD, and it is not a prosthetic group): it is a plain substrate, though you can call it an activated carrier of phosphate if you wish. The important point is the relationship between B vitamin and coenzymes (TPP, NAD, FAD, lipoamide ...).

Each of these coenzymes represents a case of its own: some are recycled immediately such as FAD or lipoamide, others in a second reaction (NAD, TPP). Some bind to the enzyme only during the reaction (NAD). Some are tightly, but not covalently bound (thiamine pryphosphate in transketolase very tightly, reversibly in pyruvate dehydrogenase), some are covalently bound (FAD, lipoamide).

"Prosthetic group" is a very general term, independent of enzymatic function: it can be RNA, sugars, phosphate, lipids, without enzymatic function or FAD, hemes, metals with enymatic function.

REFERENCES:
Lehninger (Biochemistry, the molecular basis of cell structure and function, 1975, Worth publishers) considered that coenzymes are: thiamine pyrophosphate, FMN, FAD, NAD, CoA, pyrodoxalphosphate, biotine, tetrahydrofolic acid, lipoic acid, cobalamine

Stryer (Biochemistry, 4th edition, 1995, W. H. Freeman and Company, New York). Lists coenzymes (Table 17.3, page 453): thiamine pyrophosphate, FMN, FAD, NAD, pyridoxal phosphate, Coenzyme A, Biotin, tetrahydrofolate, cobalamine

Both textbooks do not mention the word "cofactor".

Rawn (Biochemistry, 1989, Neil Paterson Publishers, Burlington, North Carolina) does not give a clear definition of "coenzyme", but calls FAD (page 340), thiamine pyrophosphate and lipoamide (page 333) all coenzymes.

Matthews and Van Holde (Biochemistry, 2nd edition, 1995, The Benjamin/Cummings publishing company, Menlo Park, California) lists in "coenzymes" : NAD, FAD, thiamine pyrophosphate, Coenzyme A, Biotin, pyridoxal phosphate (page 390)

Harper (Harper's Biochemistry, 2nd edition, 1990, Prentice Hall) has an even broader definition of coenzymes insofar as he defines them as cosubstrates. He includes sugar phosphates, CoA, thiamine pyrophosphate, pyridoxal phosphate, folate, biotin, cobalamine, lipoic acide, NAD, FMN, FAD, coenzyme Q

On Monday I have to check in more recent text books in my office.

You can also look in "Jordan F.Nat Prod Rep. 2003 Apr;20(2):184-201. Current mechanistic understanding of thiamin diphosphate-dependent enzymatic reactions." who calls thiamine diphosphate a coenzyme. I agree, that in the primary literature the term cofactor is also used for thiamine diphosphate, but as it is the more general term it does not exclude it to be also a coenzyme.

In summary
Cofactor, coenzyme and prosthetic group represent three different sometimes overlapping concepts:

In "coenzyme" the emphasis is on the suffix "enzyme": an organic molecule participating in the enzymatic mechanism of an enzyme. It can be tightly bound or not, recycled in the same reaction or not.

"Cofactor" designates an organic (coenzyme) or an inorganic (metal) factor required for enzyme activity.

"Prosthetic group" is a factor (organic or not) that is tightly bound to an apoprotein (enzyme or structural protein) - in contrast to coenzyme and cofactor no relation to enzyme activity

Presented like this, there is no contradiction and IT MATCHES THE SCIENTIFIC LITERATURE !!!

I think that the best way to do is to unite the three concepts in only one article, referring to articles for the individual compounds (NAD, FAD, thiamine pyrophosphate, glycoprotein, lipoiproteins,...). The way it is now is totally confusing.

I am totally willing to collaborate in your effort to make it nice and comprehensive. Lulubou (talk) 10:25, 8 March 2009 (UTC)

Lulubou (talk) 10:28, 8 March 2009 (UTC)

See also:

http://academic.brooklyn.cuny.edu/biology/bio4fv/page/coenzy_.htm

http://www.elmhurst.edu/~chm/vchembook/571cofactor.html

http://www.molecular-plant-biotechnology.info/enzyme-technology/coenzymes-and-cofactors.htm

http://www.microbiologyprocedure.com/enzymes-isozymes-coenzymes/coenzymes-cofactors.htm

http://www.webpages.uidaho.edu/~dcole/Topic%207_Vitamins.pdf

http://www.chem.qmul.ac.uk/iupac/misc/B6.html

http://www.pubmedcentral.nih.gov/pagerender.fcgi?artid=1179624&pageindex=1#page

By the way, a metal ion can be a prosthetic group (tightly bound Cu+ in the repiratory chain) or not (reversibly bound Mg2+ in kinase reactions).

Lulubou (talk) 13:33, 8 March 2009 (UTC)


 * I notice that even IUBMB contradicts itself on this question, with this page describing pyridoxal phosphate as a prosthetic group and this page describing it as a coenzyme.

YES Pyridoxal phosphate is a prothetic group and a coenzyme : there is no contradictiion in this.Lulubou (talk) 21:24, 8 March 2009 (UTC)

Due to this chronic confusion over if these terms have any fixed meaning, I'm certainly open to the idea of merging the pages prosthetic group and coenzyme into the top-level article Cofactor (biochemistry). I don't think the resulting article would be of unmanageable size, which would be the major concern. An alternative is to note in the introductions of the three separate articles that the terms are often used loosely and interchangeably. What I would be unhappy with would having three articles with redundant content - for example having TPP and FMN listed both here as coenzymes and also listed as prosthetic groups in a different article. Tim Vickers (talk) 20:37, 8 March 2009 (UTC)

I can't help it. All the textbooks agree that FMN is a coenzyme AND a prosthetic group. As both terms designate different properties (functional for the first and structural for the second) there is no contradiction.

Lulubou (talk) 15:45, 9 March 2009 (UTC)

The notions of prosthetic group and coenzyme are independent: A prosthetic group is a non proteinic group associated with an apoprotein, the two forming a heteroprotein. Thus immunoglobulins having no enzymatic activity, contain covalently bound sugars that form a prosthetic group. I surely agree that pyridoxal phosphate as a coenzyme involved in enzymatic acitivity.

I am just saying that prosthetic group are non proteinic groups of many proteins, enzymes and structural proteins. It happens that some prosthetic gropus (pyridoxal phosphate, FAD...) have a coenzyme function.

The notions of prosthethic group and coenzyme are different concepts that can be overlapping.

FAD, pyridoxal phosphate: coenzymes and prosthetic groups

NAD: a coenzyme but not a prosthetic group

Sugars in glycoproteins: prosthetic groups but not coenzymes

Lulubou (talk) 21:24, 8 March 2009 (UTC)

New references
As promised, here are more recent definitions of "coenzymes":

Metzler DE, (2001) Biochemistry. The chemical reactions of living cells, 2nd edition, Harcourt, San Diego.

On page 719 :

« Coenzymes are non protein molecules that function as essential parts of enzymes.... ...Very tightly bound coenzyme groups are often called prosthetic groups, but there is no sharp line that divides prosthetic groups from the loosely bound coenzymes. »

This is exactly my opinion.

He distinguishes three kinds of coenzymes :

° High group transfer potential such as ATP and GTP, but he states that ATP can also be regarded as substrate

° Derivatives of vitamins such as coenzyme A, pyridoxal phosphate, thiamine diphosphate, vitamin B12

° Oxidative coenzymes

A similar definition can be found in :

Lehninger. Principles of Biochemistry, Nelson DL and Cox M.M. (2000), 3rd edition, Worth Publishers, New York – page 245

They list as coenzymes Biocytin, Coenzyme A, Cobalamine, FAD, lipoate, NAD, pyridixal phosphate, tetrahydrofolat, and thiamine pyrophosphate

Finally :

Campbell and Farrell (2009) Biochemistry, Student Edition, They do not give a clear definition of coenzyme. They call it « a mixed bag of organic compounds ; many of them are vitamins or are metabolically related to vitamins » (page 194) They list as coenzymes : Biotin, coenzyme A, flavin coenzymes, lipoic acid, nicotinamide adenine nucleotides, pyridoxal phosphate, tetrahydrofolic acid and thiamine pyrophosphate.

Are these enough references for you, Narayanese ?

By the way, I found a clear stupidity in the article on "cofactor", with a figure showing "the bound "heme" cofactor of succinate dehydrogenase..." Succinate dehydrogenase is is the typical textbook example of a oxidoreductase of the respiratory chain that is NOT a heme protein but an iron-sulfur protein. This can be found in any textbook. Lulubou (talk) 09:35, 9 March 2009 (UTC)


 * The image was generated from PDB 1YQ3 and shows the haem b group bound to the small cytochrome subunit of the dehydrogenase complex. I've checked my copy of the Oxford Dictionary of Biochemistry and Molecular Biology and it defines coenzymes as "any of various nonprotein organic cofactors that are required, in addition to an enzyme and a substrate, for an enzymatic reaction to proceed. Compared with a prosthetic group a coenzyme is more easily removed from the apoenzyme. The term 'coenzyme' is frequently used imprecisely." Here a prosthetic group is contrasted with coenzymes, not included as part of this definition. Similarly, cofactors are defined as "any accessory nonprotein substance, commonly of low molecular mass, that is required for the activity of an enzyme...organic cofactors that are easily removable from an enzyme may be called coenzymes, but if they are tightly bound they may be termed prosthetic groups." Tim Vickers (talk) 16:35, 9 March 2009 (UTC)

Succinate dehydrogenase contains three different iron sulfur clusters and one covalently bound FAD: no heme! The protein you refer to is a small heme (cytochrome b560) binding protein belonging to succinate-ubiquinone reductase (complex II) and that is associated with succinate dehydrogenase. Thus the cristallographic structure shown is that of this small subunit (or anchoring protein) but not of succinate dehydrogenase.

http://www.ncbi.nlm.nih.gov/pubmed/1447196?ordinalpos=13&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum http://www.wikigenes.org/e/ref/e/1447196.html

Concerning the eternal distinction between prosthetic groups and coenzymes, I think that we should stick to the biochemical textbooks (that are the reference also for students), and I did not find one that opposes the terms coenzyme and prosthetic groups. They all consider that a coenzyme is an organic molecule loosely or tightly bound.

Consider cofactors as NAD+ or thiamine diphosphate that in some cases are loosely bound and in some cases tightly. Will you consider that in the first case they are coenzyme and in the second cofactor ? You are not out of difficulty. I changed the three articles on cofactors, coenzyme (this one could be fused with the cofactor article) and prosthetic groups in a way that they seem coherent (at least to me) and without contradiction. My main claim is that cofactors (coenzymes ) and prosthetic groups are based on different concepts (function or structure). This way you avoid many problems and you are coherent with text books. Do not forget that the notion of prosthetic group also encompasses groups (sugars, lipids...) that are not coenzymes. If you keep the previous difinition (prosthetic groups are different from coenzymes) that means that the only term to designate a "tightly bound cofactor important for catalysis" is the term "prosthetic group". But this term has a much broader definition (any non amino acids part of any protein). You will again run in trouble, as prosthetic group will take different meanings according to what you are talking about. Another way out would be to invent a new name to designate a "tightly bound cofactor important for catalysis" and oppose it to the term "coenzyme" and include it in the prosthetic group family. But first you have to get this accepted in the primary literature. Good luck !!

Lulubou (talk) 18:18, 9 March 2009 (UTC)


 * OK, so you were referring to the degraded form of complex II "soluble succinate dehydrogenase". Sorry to misunderstand you - but the difference between the succinate dehydrogenase and the succinate dehydrogenase complex is not such an obvious one! I agree in general with your changes, but I hope you now accept that any single definition of these terms is contradicted by other definitions of these terms. This is since, as you point out, there is no clear dividing line between these molecules and there will always be cases that do not fit comfortably with any one particular definition. Defining coenzymes as loosely-bound cofactors and prosthetic groups as tightly-bound cofactors is something we both agree on. I'm still unconvinced that a prosthetic group of an enzyme can simultaneously be a coenzyme, since I have never seen both terms used in the literature simultaneously to describe a single molecule, but with such loose usage it is possible that some people do use the terms to mean this. We can either spell out these two viewpoints, or remain ambiguous on that point. Which would you recommend? Tim Vickers (talk) 18:59, 9 March 2009 (UTC)

I agree that it will very difficult to eliminate all contradictions. For instance I would never call a heme a coenzyme. But why ? In general the term coenzyme is limited to vitamin derivatives (NAD, FAD, thiamine pyrophosphate, pyridoxal phosphate, coenzyme A...) Concerning prosthetic groups and coenzymes, look at these addresses:

http://www.chemistryexplained.com/Ce-Co/Coenzyme.html http://www.biologie.uni-hamburg.de/b-online/e19/19b.htm http://www.encyclopedia.com/doc/1O39-prostheticgroup.html http://fixedreference.org/en/20040424/wikipedia/Coenzyme http://www1.cleveland.edu/uploads/Bracho/CHE%20568%20UNIT%209.pdf

I have to check if I find something in the primary scientific literature. I would certainly like to write an update on this problem.

I think that your idea of mentioning the existence of opposing view points is good. Can I leave it to you ?

Lulubou (talk) 20:45, 9 March 2009 (UTC)


 * Done, - I was smiling as I wrote "Unsurprisingly, these terms are often used loosely". :) Tim Vickers (talk) 21:02, 9 March 2009 (UTC)


 * Founds another excellent source a letter in TIBS that covers much of the same ground as our discussion did above. It is a bit on the old side, but the most specific source I've found so far. Tim Vickers (talk) 22:33, 9 March 2009 (UTC)


 * I think mixing the different definitons in the table makes it less useful - I'd like a field saying whether the coenzyme is stuck to one enzyme the whole catalytic cycle or not. Narayanese (talk) 15:45, 10 March 2009 (UTC)


 * I still quite like the idea of merging both prosthetic group and coenzyme into the cofactors article. The new definitions section would go first and then we could divide the article into organic/inorganic cofactors. Tables of organic cofactors could give examples of enzymes containing the cofactor and say how tightly-bound the cofactor is to that enzyme (covalent, tightly-bound, weakly-bound substrate). Tim Vickers (talk) 17:32, 10 March 2009 (UTC)


 * That would be good. Narayanese (talk) 00:00, 11 March 2009 (UTC)

Oxidized or reduced?
The distinction (if there is one) between the reduced and oxidized form of a coenzyme could be made more clear. For example - is ATP or ADP referred to as the coenzyme? Is NAD+ or is NADH the coenzyme? Dryphi (talk) 17:05, 4 July 2008 (UTC)

Coenzyme or cofactor
Arcadian removed Ascorbic acid, Biotin, and Cyanocobalamin from the list of vitamin derived coenzymes. Is there any reason why these shouldn't be on the list? Stable attractor (talk) 07:08, 19 November 2007 (UTC)


 * I'd say that biotin and cyanocobalamin are cofactors rather than coenzymes, since they are not released from enzymes as part of the normal catalytic cycle. Ascorbic acid probably does fit the definition though. Tim Vickers (talk) 16:59, 19 November 2007 (UTC)


 * I am not sure that definition of coenzyme in the lead is correct. The cited Glossary tells the following:


 * Coenzyme.

"A low-molecular-weight, non-protein organic compound (often a nucleotide) participating in enzymatic reactions as dissociable acceptor or donor of chemical groups or electrons."


 * Cofactor

"An organic molecule or ion (usually a metal ion) that is required by an enzyme for its activity. It may be attached either loosely (coenzyme) or tightly (prosthetic group)."

That is correct. But it means that "coenzyme" is simply a "cofactor" which is involved in chemical reactions, including electron transfer (!), as I have always thought. However, glossary definition above tells than not every chemical reaction qualify. It tells: "dissociable acceptor or donor of chemical groups or electrons". Hence a cofactor such as retinal, which undergoes an isomerization (a photochemical reaction), would not qualify as a "coenzyme"? Is that right?Biophys (talk) 17:48, 28 November 2007 (UTC)

Or maybe "coenzyme" is any "cofactor" that is loosely attched to a protein? That would be different. That would mean that retinal is a "prostetic group" in bacteriorhodopsin, and who knows what in rhodopsin. Biophys (talk) 18:00, 28 November 2007 (UTC)


 * After all, I guess, "coenzymes" and "cofactors" are the same since they all are involved in enzymatic reactions, including electron transfer and isomerization. However, those of them who are covalently (not "tightly") bound to proteins are called "prostetic groups" (a sub-group of coenzymes/cofactors).Biophys (talk) 18:13, 28 November 2007 (UTC)


 * I would tell that most common and useful term is "cofactor", while word "coenzyme" is traditionally (and rather arbitrary) used for several vitamine-derived organic cofactors, such as Coenzyme Q, Coenzyme A and Coenzyme B12. Actually, we should focus more on article Cofactor.Biophys (talk) 18:31, 28 November 2007 (UTC)


 * I have always hated how loose these terms are. My preferred definition is that a coenzyme is a molecule that accepts or donates a chemical group in an enzyme reaction and is released as part of the normal catalytic cycle. The difference between a coenzyme and regular substrates is that coenzymes are used by multiple different types of enzyme to donate the same chemical group - they are general group transfer reagents. Tim Vickers (talk) 19:28, 28 November 2007 (UTC)


 * That is true. But main problem is this: you are trying to distinguish "coenzymes" and "cofactors" as two different classes of molecules (partly based on a misleading definition in the glossary), however "coenzymes" seem to be usually treated as a small sub-group of "cofactors" in the scientific literature if I understand this correctly. Biophys (talk) 17:06, 29 November 2007 (UTC)


 * The problem is that there is little consistency in the scientific literature. As the article notes, these terms are commonly used very loosely. When I wrote this I therefore used a specific and clear definition from IUPAC - the most reliable source I could find. I've tried rewriting the lead to make the sub-classifications more clear. Tim Vickers (talk) 17:19, 29 November 2007 (UTC)


 * I think you fixed this problem in new version of the article. It is much better!Biophys 00:15, 1 December 2007 (UTC)

FAD and FMN?
I think these should be classified as prosthetic groups. Flavoenzymes bind their cofactor quite tightly. Can anybody think of any reactions where a free flavin is a substrate? Tim Vickers 21:46, 1 December 2007 (UTC)

Assessment comment
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