Pedro Mendes prm at ABER.AC.UK
Fri Apr 25 04:57:26 EST 1997

On 17 Apr 1997 at 09:08 Yang-Seok Kim wrote

> Vitamin B1 synthetic genes are scattered in E.coli chromosome. However, I
> found, two of them are joined and bacame bifunctional protein in plant.
> Does anybody know the benifit of bifuntionallity in evolution or the
> reference papers about bifuntionallity?"

Bifunctional (or even multifunctional) proteins are ubiquitous in Nature.
Some time ago I became interested in this subject and started collecting
papers on multifunctional proteins (I was looking for examples where there
was also channelling between the different active sites in the
polypeptide). There are quite a large number of multifunctional enzymes,
many more than I was expecting, and they are widespread through bacteria,
yeasts, plants, animals, etc.

On 25 Apr 97 at 1:39, Athel wrote:

> If the two enzymes catalyse non-consecutive reactions it isn't easy to
> think of advantages, but if they are consecutive then in principle having
> a bifunctional protein allows direct transfer of the common intermediate
> from one active site to another (i.e. channelling).

I will make no comments on their "advantage" as that dependends on the
environment in which the organisms in question live. But I can make some
comments on the properties that bifunctional enzymes have different to the
equivalent pair of independent enzymes:

1- as pointed by Athel one can think that fusion of the two enzymes 
 facilitates some form of channelling of their common intermediate (if they 
 are consecutive enzymes). This does not have to ocurr through an actual 
 physical channel (like in the Tryptophan synthase of E.coli and 
 S.typhimurium), in  fact there is one example of a bifunctional enzyme 
 that apparently channels the intermediate between the two active sites 
 through electrostatic interactions on its surface (the enzyme is 
 dihydrofolate reductase:thymidylate synthase from Leishmania major see 
 Knighton et al. (1994) Nature Struct.Biol. 1, 186-194). Another example 
 of a bifunctional enzyme where channelling seems to take place is E.coli's 
 phosphoribosylanthranilate isomerase:indoleglycerolphosphate synthase 
 (Wilmans et al. (1992) J.Mol.Bio. 223, 477-507).

2- even if the two enzymes don't catalyse consecutive steps in metabolism, 
 their expression cannot be controled independently and their concentration 
 will always be equimolar. This in itself is a form of "enzyme-enzyme"  
 interaction (I have never seen this discussed in the literature, if anyone 
 has I'd like a reference). This is something I have studied in my PhD but  
 have so far not yet got around publishing. The paper by Cascante et al.  
 (1990) Eur.J.Biochem. 192, 369-371 might also be relevant on this.

3- in the bifunctional enzyme one can imagine situations in which 
 ligand binding on one activite site has effects on the conformation of 
 the polypeptide affecting the activity of the other active site. In 
 addition, the fusion might have provided one active site to respond 
 allosterically to a third ligand that was only an allosteric modulator of 
 the other active site. Again this will result in some form of 
 "enzyme-enzyme" interaction.

4- a bifunctional enzyme costs less to express than the corresponding pair  
 of independent enzymes. However I don't think this is that important as  
 the difference must be small.

I'm sure one can think of other properties that are novel to the 
bifunctional enzyme (in relation with the independent pair).

On 25 Apr 97 at 1:39, Athel also wrote:

> In the published literature you would find it useful to look up papers
> and reviews by (among others) Paul Srere or Judit Ovadi... Judit has a
> recent book (sorry, I can't find it at this moment so I can't quote the
> title) published by R. G. Landes (1995).

Ovadi, J. (1995) "Cell architecture and metabolic channeling" R.G Landes 
Company, Austin, Texas.

see also:

Welch, G.R. (Ed.) (1985) Organized multienzyme systems. Catalytic
properties. Academic Press, New york.

Welch, G.R. and Clegg, J.S. (Eds.) (1987) Organization of cell metabolism.
Plenum Press, New York.

see also the following web pages for more references on this subject:

Pedro Mendes                                     Inst. Biological Sciences
prm at (home: pedro at  Univ. Wales, Aberystwyth,   Ceredigion SY23 3DA, U.K.   FAX: +44 (0)1970 622350

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