This question arises from a student multiple choice question regarding whether certain inorganic ions present in certain enzymes (Cl in catalyse and Zn2+ in carbonic anhydrase) could be classified as coenzymes or prosthetic groups, and the poster then asked why Cl was a cofactor for amylase but not a coenzyme.

Expanding this to the general situation, the question becomes:

What is the difference between a cofactor, a coenzyme and prosthetic group, and where are inorganic ions in this hierarchy?

  • $\begingroup$ On the wikipedia page (en.wikipedia.org/wiki/Cofactor_(biochemistry)) a coenzyme is defined as a complex oranic cofactor, so Cl- doesn't count. Another thing that doesn't make it a coenzyme (as far as I know) is that the ion is not directly involved in the catalyzed reaction. $\endgroup$
    – VonBeche
    Jun 11, 2017 at 12:28
  • $\begingroup$ @VonBeche cool! Got it now. Answer that below and i'll tick it as an accepted answer. Thanks! $\endgroup$
    – vik1245
    Jun 11, 2017 at 13:12
  • $\begingroup$ I have edited the question to make it more general, but retained the specific reference to chloride and amylase as other answers have addressed that. $\endgroup$
    – David
    Aug 16, 2021 at 12:06

3 Answers 3


On the wikipedia page (en.wikipedia.org/wiki/Cofactor_(biochemistry)) a coenzyme is defined as a complex organic cofactor, so Cl⁻ doesn't count. Another thing that disqualifies it as a coenzyme is that the ion is not directly involved in the catalyzed reaction. This amylase contains both a calcium ion, involved in catalysis. The chloride is speculated only to be involved in differentiation between substrates, and is absent in other structures.


Why revive a four-year old question?

Although I do not consider nomenclature of this type terribly important, and the high-scoring answer from @VonBeche is reasonable, I decided to add my own ‘answer’ for several reasons. First this is a highly active question, probably because students are required to make this sort of distinction, second because there have been several recent incorrect answers, and third because none of the answers are supported by an authoritative source (I do not regard Wikipedia as necessarily authoritative). However, perhaps the most important reason is to emphasize that, although there has been a recent attempt to produce a standard nomenclature, in actual practice there is no generally agreed terminology for cofactors.

Authority used in this answer

Biochemical nomenclature arises in a haphazard manner from new research discoveries, and only when the dust has settled, so to speak, do committees try to standardize it. I expected to find something in the International Union of Biochemistry and Molecular Biology Recommendations on Biochemical & Organic Nomenclature but those seem confined to enzyme classification. I have therefore used as a starting point ChEBI — Chemical Entities of Biological Interest. This is a “freely available dictionary of molecular entities focused on ‘small’ chemical compounds” published on the EMBL–EBI website, and is part of the ELIXIR Core Data Resources “a set of European data resources of fundamental importance to the wider life-science community and the long-term preservation of biological data”.

ChEBI Definitions of Cofactor, Coenzyme and Prosthetic Group

URL: https://www.ebi.ac.uk/chebi/searchId.do?chebiId=23357
ChEBI Name: cofactor
Definition: 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).
ChEBI Ontology: cofactor (CHEBI:23357) is a biochemical role (CHEBI:52206)

A number of compounds are listed as having the role of cofactor, including metal ions such as chloride and organic molecules such as NAD (sub-classified as a coenzyme, below) and FAD (subclassified as a prosthetic group, below)

URL: https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:23354
ChEBI Name: coenzyme
Definition: A low-molecular-weight, non-protein organic compound participating in enzymatic reactions as dissociable acceptor or donor of chemical groups or electrons.
ChEBI Ontology: coenzyme (CHEBI:23354) is a cofactor (CHEBI:23357)

A number of compounds are listed as having the role of coenzyme (ascorbic acid, coenzyme A, NAD etc.) all of which are organic compounds.

URL: https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:26348
ChEBI Name: prosthetic group
Definition: A tightly bound, specific nonpolypeptide unit in a protein determining and involved in its biological activity.
ChEBI Ontology: prosthetic group (CHEBI:26348) is a cofactor (CHEBI:23357)

A number of compounds are listed as having the role of prosthetic groups (e.g. FAD, haem lipoic acid), but none of them are simple metal ions although they are not exclusively organic (e.g. metal-sulphur clusters).

Ontological interpretation and comparison with Wikipedia Entry

The ChEBI entry on ‘Cofactor’ reproduces the opening paragraph of the Wikipedia page on the subject, relevant sections of which I quote below:

A cofactor is a non-protein chemical compound or metallic ion that is required for an enzyme's activity as a catalyst.

Cofactors can be divided into two types: inorganic ions and complex organic molecules called coenzymes.

Coenzymes are further divided into two types. The first is called a “prosthetic group”, which consists of a coenzyme that is tightly or even covalently, and permanently bound to a protein. The second type of coenzymes are called “cosubstrates”, and are transiently bound to the protein. Cosubstrates may be released from a protein at some point, and then rebind later.

However, the nature of Wikipedia (anyone can edit it) is such that further down the page under the section on Classification, the following appears:

Cofactors can be divided into two major groups: organic cofactors, such as flavin or haem; and inorganic cofactors, such as the metal ions Mg2+, Cu+, Mn2+ and iron-sulphur clusters.

Organic cofactors are sometimes further divided into coenzymes and prosthetic groups.

The section then goes on to say:

[Bryce 1979] noted the confusion in the literature and the essentially arbitrary distinction made between prosthetic groups and coenzymes group and proposed…

…cofactors were defined as an additional substance apart from protein and substrate that is required for enzyme activity and a prosthetic group as a substance that undergoes its whole catalytic cycle attached to a single enzyme molecule.

However, the author could not arrive at a single all-encompassing definition of a “coenzyme” and proposed that this term be dropped from use in the literature.

Thus, it would seem that there are (at least) four different ways of classifying cofactors. That from ChEBI does not differ greatly from the second Wikipedia scheme (rather than the one it quotes), but the first Wikipedia scheme — distinguishing between coenzymes and prosthetic groups — certainly does.

Different Cofactor definitions

Bryce’s suggestion to discard the term coenzyme has not been adopted, but his critique of the general nomenclature is a warning against dogmatism in this area. “Fools rush in where angels fear to tread.”

  • $\begingroup$ Nice one David, I think this adds considerably to the answers already posted. I second the emphasis on your phrase Biochemical nomenclature arises in a haphazard manner from new research discoveries, and only when the dust has settled, so to speak, do committees try to standardize it. Exam questions and answers are sometimes woeful when it comes to science, especially (i) in fields where strict nomenclature is not a practical way of life, or (ii) in fields where expertise aids in intelligibility of ambiguous terms, or (iii) within frontier research, where clear pictures haven't yet emerged. $\endgroup$
    – S Pr
    Aug 16, 2021 at 12:07

Complex enzymes are made up of protein and nonprotein components. The protein part of the enzyme is called Apoenzymes or Apozyme. While the non-protein part of the enzyme is called Cofactor.

Cofactors are two types based on their chemical properties such as…..

  1. Metal cofactors (inorganic compounds)- Metalloenzymes (Metallozymes) and Metal-activated enzymes

  2. Organic cofactors – Coenzymes and Prosthetic groups

Read more here about the major difference between cofactors and Coenzymes.

  • 1
    $\begingroup$ Please read biology.stackexchange.com/help/promotion - I think there is a risk of appearing as a spammer if you are answering already-answered questions with answers that don't add to previous answers and always linking to the same reference site. $\endgroup$
    – Bryan Krause
    Aug 12, 2021 at 19:17

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