[Protein-analysis] Re: why cant we say chaperone an enzyme?

Dr Engelbert Buxbaum engelbert_buxbaum at hotmail.com
Tue May 2 07:47:28 EST 2006

DK wrote:

> Partially folded states are in the equilibrium. By stabilizing one 
> of them, chaperones can be said to "catalyze" unfolding. The only
> difference with chaperonines is an extra energy energy usage and 
> the overall efficiency of the process. By way of analogy - 
> chaperone is a hammer and chaperonine is a pressure-driven 
> nail gun. Both "catalyze" nail going in because, formally speaking, 
> the nail (when positioned properly) would, eventually, get in by
> itself, just by gravity - only it would take too long :-) 

But you see, chaperones do not increase the speed of folding by
catalysing the folding process, they increase the yield by preventing
miss-folding. The high protein coincentration in the cell makes
aggregation a much more probable event than folding, by preventing
aggregation chaperones make the folding process possible, yet they do
not speed it up. A similar effect can be achieved - at least in
principle - by dilution. Indeed, that is the principle of chaperonins:
By putting their substrates into an Anfinsen cage they allow folding
under infinite dilution.

> > The concepts of prevention of miss-folding (both
> >chaperones and chaperonins), of unfolding miss-folded proteins
> >(chaperonins only) and of catalysing folding (neither) need to be
> >carefully distinguished. 
> I don't understand the principal distinction you make between 
> chaperones and chaperonines. The latter are just a subset of the former. 
> Essentially a more complexed and evolved way of doing the same 
> thing. 

No, by definition chaperonins can use the energy of ATP-hydrolysis to
actively unfold miss-folded proteins, chaperones can not do that. This
is the reason why two different words were coined for the thingies.

> >Yes, of course there is no doubt that protein disulphide isomerases (or
> >peptidyl prolyl cis/trans-isomerases for that matter) are enzymes, but
> >they are no chaperones. 
> I wasn't talking about isomerization at all. I brought up Cys-Cys just to 
> make purists happy: chemical catalysis involves chemical reaction 
> which means change in covalent bonds. Thus, any chaperon that 
> catalyze protein folding in a way that two Cys become stabilized 
> opposing each other and then dimerize spontaneously. Which means
> that the chaperone did catalyze  chemical reaction after all :-)

That is a hen-and-egg question which would have to be answered for each
protein separately: does a disulphide bond form because two Cys come
next to each other after folding, or is folding made more efficient
after stabilisation of gross structure by a disulphide bond. In any
case, disulphide bond formation is catalysed by PDIs, which are proper

> As you can see, the concepts developed for small molecules lose 
> their strict clarity whenever large polymer with their qualitatively new
> set of phenomena is considered. Boundaries blur and it's no longer
> never easy to what is and what is not an enzyme or a chemical reaction.

No, there are really no entirely new concepts, even hydrogen bonds
between molecules exist in small molecules and have structural
significance, water is a case in point.
> >A chaperone may hold the client protein for the
> >PDI or PPI to work on (Hsp90 or Bip for example), it is then like a lath
> >on which different tools may be used. But the actual work is done by the
> >tool, not the lath.
> The actual work is done by both. Case in point: enzymatic catalysis 
> is done by *proteins*, not just their active sites. 

This is not an appropriate comparison. Here you have two different
entities with different purposes: An enzyme which catalyses bond
formation (PPI, PDI) and a chaperone that prevents things from going in
the wrong direction. One helps in forming a bond, the other prevents the
formation of unwanted bonds. These are two different concepts, whether
you see the difference or not. And that is the reason why the scientific
community decided that chaperones are not considered enzymes, at least
with respect to the folding process (ATPase and transport activities
are, as discussed, enzymatic processes). 

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