Are all enzymes proteins?

Question

So throughout my education and research career I have been taught that all enzymes are proteins. This makes sense when you consider enzyme denaturing and folding/shape etc. However, I was recently told by a biology professor that in fact, not all enzymes are proteins -- and he alluded to the RNA world hypothesis and rRNA's.

Could someone explain further how exactly an rRNA (or similar) could be (or not be) considered an enzyme, and whether or not all enzymes are proteins etc?

Thank you!

Answer 1

Until the late 1980's all enzymes* were believed to be proteins, and were often defined as protein catalysts, often in textbooks which are often not perfect representations of science. At that point every macromolecular biological catalyst known was a protein so they thought all macromolecular catalysts were proteins. But the discovery of ribozymes (RNA strands that act as catalysts) changed that. The discovery that one of the most well known enzymes ribosomes had their functional components made of RNA and not protein also played a factor.

NOW enzymes are generally defined as macromolecular biological catalysts and include ribozymes. But older works or outdated textbooks will still refer to enzymes as only proteins but newer works will not. Don't feel despondent I was taught the same thing initially, and it persisted for a several years in college. Part of this is each successive step in education tends to lag behind and/or get over simplified in scientific knowledge. Textbook manufacturers are not overly concerned with poor phrasing or outdated definitions and are rarely writtten by scientists.

*in its object form, originally and for quite a long time enzyme referred to the process not the agent responsible becasue the agent was unknown.

Answer 2

It depends on how you define "enzyme". Wiktionary says an enzyme is:

A globular protein that catalyses a biological chemical reaction.

Wikipedia says:

Enzymes are macromolecular biological catalysts.

So the first definition excludes anything but proteins and the second also allows other large biological molecules which catalyze reactions.

The important core meaning is that of a biomolecule which catalyzes a reaction, and the restriction to only proteins is somewhat arbitrary. The expectation for decades was that enzymes (bio-catalysts) were proteins because all the ones that had been discovered were in fact proteins. Hence the older definition included "protein" as part of the definition.

Once it was discovered that some RNA molecules also have enzymatic action (a discovery awarded a Nobel prize in 1989), many have used the enlarged definition for "enzyme" since the enzymatic action of RNA is important. When RNA catalysts specifically are referenced, the term "ribozyme" is typically used.

Quite a few ribozymes have now been discovered. An important and well-known one is rRNA, which forms the core of the ribosome and provides the catalytic sites necessary for translation of mRNA into protein. Another ribozyme is Ribonuclease P. Group I catalytic introns are a kind of intron which act as a ribozyme whose action is to splice itself out of the RNA transcript of a gene so that a mature mRNA can be formed.

Answer 3

Disclaimer

I voted to close this question as it struck me that the by giving the poster the magic word ‘ribozyme’ he could easily verify for himself that the answer to the question in his title was “No”. However, as this question received answers that I find incorrect or misleading, I provide my own answer to put the record straight.

History and Terminology

Although I would not necessarily regard entries in Wikipedia as authoritative, scientific dates are not particularly contentious, so I refer the reader to the entries on Enzyme and Protein for the following:

• The first enzyme to be discovered is said to have been diastase, in 1833, although the opposition of Pasteur to the idea of metabolic activity outside of living things delayed the acknowledgement of this. The word enzyme was coined in 1877 from the Greek, meaning “in yeast”. The catalytic activity of the enzymes of fermentation was studied intensively in the late 19th and early 20th century, culminating in Buchner’s Nobel Prize in Chemistry in 1907.
• Although proteins had been recognized in the 18th century, and named by Berzelius in 1838, their chemistry as polypeptides was not established until 1902, and it was not until 1926 that Sumner established that urease was a protein.

Hence, the word enzyme and the concept of its activity was introduced long before the chemical nature of most enzymes as proteins was established, and therefore the poster is correct in not including protein in the definition of enzyme. It is also correct to talk about the later discovery of enzymes that are RNA rather than protein, despite the fact that the latter confounded a general belief that had held for over a half century. Indeed, RNA enzymes are referred to by a special designation — ribozymes — just as most members of genus Cygnus are referred to as swans, but Cygnus atratus is usually referred to as black swans.

RNA enzymes (ribozymes)

A perfect example of an RNA enzyme would be one that was naturally active in the absence of protein and showed catalytic activity against a distinct substrate. As of 2002, when the topic was reviewed by Thomas Cech — who, together with Sidney Altman, received the Nobel Prize in Chemistry for the discovery of the first ribozyme in 1962 — there were no such natural examples.

• The type of catalytic RNA discovered by Cech — the self-splicing introns of Tetrahymena are completely free of protein, but act on the pre-mRNA that contains them.
• Another type of catalytic RNA, exemplified by the ribonuclease-P discovered by Altman, is active against a substrate distinct from itself — a precursor tRNA — contains protein as well as RNA. However if the protein is removed from RNase-P under appropriate conditions the RNA component retains catalytic activity.

Despite these limitations — and the fact that the only reactions catalysed are cleavage and ligation of RNA — I would have cited these as clear examples of RNA enzymes if I had been the professor to whom the poster addressed his question. Ribosomal RNA probably has catalytic activity, but is less clear-cut, as I explain below.

The ‘RNA World’ and RNA catalysis of other types of reaction

One of the results of the discovery was catalytic RNA in the early 60s was that it gave flesh to an idea that resolved some of the problems of the early evolution of biochemical processes — especially the interdependence of protein and nucleic acid. This was an ‘RNA World’ in which RNA served both as genetic material (before DNA evolved) and the enzymes for performing biochemical reactions, including that of protein synthesis. However the only reactions catalysed by the contemporary RNA enzymes that had been characterized were the cleavage or ligation of RNA itself.

One could argue that other catalytic reactions were taken over by proteins when they emerged, as they were more efficient etc., however the question remained as to whether RNA had the potential to catalyse such reactions. One step in that direction was to artificially select oligoribonucleotides (aptamers) on the basis of their ability to bind particular small molecules. There have also been reports that a small synthetic RNA can catalyse the amino acylation of AMP-activated tRNA for phe.

The peptidyl transferase activity of rRNA

It is in the context of what I have written above that the possible catalytic activity of rRNA should be viewed.

• The reaction involved is that of the peptidyl transferase (below). There are no other examples of RNA catalysing reactions other than RNA hydrolysis and ligation
• The implications for the ‘RNA World’ hypothesis (which is not universally accepted) are such that — although I personally favour it (and have lectured to students on it in relation to ribosomes) — one must be very careful not to allow this to cloud one’s scientific judgement.

The evidence for the peptidyl transferase (PT) activity of the large ribosomal RNA (23S rRNA in E.coli, 28S rRNA in H.sapiens) is as follows:

• Repeated attempts to associate particular ribosomal proteins with PT activity failed and many individual ribosomal proteins could be deleted from E.coli ribosomes without abolishing the PT activity
• Affinity labels of substrates of the PT reaction tended to label RNA rather than protein.
• The PT centre has been located in the three-dimensional structure of 23S rRNA by crystalization with analogue of the reaction intermediate. No proteins are in the vicinity of this.

This argues strongly that the PT activity of the ribosome lies in the 23S rRNA — but cannot be regarded as a rigorous proof. Not surprisingly, no protein-free RNA or fragment thereof has been shown to be able to catalyse the PT-reaction between the small substrate analogues that can be used for this.

I happen, myself, to believe that the ribosome is a ribozyme — for the little that it is worth — but I would never put forward the ribosome as an example of a ribozyme, when so much better ones exist.