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Fersht A. Structure and mechanism in protein science.. a guide to enzyme catalysis and protein folding (Freeman, 1999)(L)(T)(327s).djvu |
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nitro and amino groups, is variable and depends on the other groups attached
...
These numbers are useful in understanding, for
example, how mutations in proteins affect the energies of the denatured state
(Chapter 17)...
These show directly that the removal of a hydrogen bond donor or ac-
acceptor weakens binding by only 2-6 kJ/mol @.5-1.5 kcal/mol), providing there
are no unpaired ions formed, despite the enthalpy of an individual bond being
some 20 kJ/mol E kcal/mol)...
It
was pointed out earlier that the dispersion energy of a methylene group in a crys-
crystalline hydrocarbon is 8.4 kJ/mol B kcal/mol)...
When a single A
and U associate, they gain the energy of the complementary base pairing but lose
the energy of hydrogen bonding with water...
The theory is used
to calculate changes in activation energies rather than absolute values, so it is
quite rigorous...
Because these ideas are crucial to the understanding of the role of binding en-
energy in enzyme catalysis, they are amplified in the remainder of this section...
Enzyme complementarity to the transition state
Here the full binding energy AGb is realized only in the transition state...
The increase in the binding energy
of the larger substrates is distributed between lowering the dissociation constant
of the enzyme-substrate complex and increasing the acylation and deacylation
rate constants...
Chapter
11 showed that small groups can involve large binding energies when a specific
binding site is involved...
Enzymes are very
sophisticated catalysts, often using the binding energy of subsites far removed
the seat of reaction, often using residues spread widely around the active
site (Chapter 15), and sometimes using the induced-fit process (section D2), and
so it is difficult to mimic the combined effects of all their tricks...
The two additional
proofs that follow emphasize the importance of high KM's, and the figures indi-
indicates the physical reason...
One particular case is carbonic anhy-
drase, because the concentrations of carbon dioxide and bicarbonate in the blood
are easily measured...
This
point stems from the Haldane equation (Chapter 3, section H), which states that
the equilibrium constant for a reaction in solution is given by the ratio of the val-
values of kc&t/KM for the forward and reverse reactions...
In the classic strain mechanism, the KM is increased by binding
energy being used to distort the substrate; in induced fit, it is increased bv bind-
ing energy being used to distort the enzyme...
This could be
Enzyme-Substrate Complementarity and Binding Energy in Catalysis
373
due either to the substrate and the enzyme having unfavorable interactions that
are relieved in the transition state, or to the transition state having additional
binding interactions that are not realized in the enzyme - substrate complex...
It should be noted that if the physiological
concentration of the substrate is below its KM value, an intermediate does not accumulate, even if it
would at saturating concentrations...
As we discussed in Chapter 12
and as we shall amplify below, these do not affect biological specificity, since they
alter kcat and KM in a mutually compensating manner without altering kcai/KM...
We shall see that if the smaller or
isosteric substrate differs from the specific substrate by lacking an element that
has a structure R and a potential binding energy of AAG&, the maximum possible
discrimination due to this difference in stereochemistry is exp (— AAGb/RT), and
this cannot be amplified by strain, by induced fit, by a series of conformational
changes, by an additional series of chemical steps, or by two (or more) sites func-
functioning simultaneously...
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