BIOL 200 Lecture Notes - Lecture 3: Dihydrofolic Acid, Integrase, Hexokinase

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The efficiency of an enzyme can be expressed in terms of kcat/Km. This is also called the
specificity constant and incorporates the rate constants for all steps in the reaction. Because the
specificity constant reflects both affinity and catalytic ability, it is useful for comparing different
enzymes against each other, or the same enzyme with different substrates. The theoretical
maximum for the specificity constant is called the diffusion limit and is about 108 to
109(M−1 s−1). At this point every collision of the enzyme with its substrate will result in catalysis,
and the rate of product formation is not limited by the reaction rate but by the diffusion rate.
Enzymes with this property are calledcatalytically perfect or kinetically perfect. Example of such
enzymes are triose-phosphate isomerase, carbonic anhydrase, acetylcholinesterase, catalase,
fumarase, β-lactamase, and superoxide dismutase.Michaelis-Menten kinetics relies on the law of
mass action, which is derived from the assumptions of free diffusion and thermodynamically
driven random collision. However, many biochemical or cellular processes deviate significantly
from these conditions, because of macromolecular crowding, phase-separation of the
enzyme/substrate/product, or one or two-dimensional molecular movement. In these situations,
a fractal Michaelis-Menten kinetics may be applied. Some enzymes operate with kinetics, which
are faster than diffusion rates, which would seem to be impossible. Several mechanisms have
been invoked to explain this phenomenon. Some proteins are believed to accelerate catalysis by
drawing their substrate in and pre-orienting them by using dipolar electric fields. Other models
invoke a quantum-mechanical tunneling explanation, whereby a proton or an electron can tunnel
through activation barriers, although for proton tunneling this model remains somewhat
controversial.[69][70] Quantum tunneling for protons has been observed in tryptamine.[71] This
suggests that enzyme catalysis may be more accurately characterized as "through the barrier"
rather than the traditional model, which requires substrates to go "over" a lowered energy barrier.
In competitive inhibition, the inhibitor and substrate compete for the enzyme (i.e., they can not
bind at the same time). Often competitive inhibitors strongly resemble the real substrate of the
enzyme. For example,methotrexate is a competitive inhibitor of the enzyme dihydrofolate
reductase, which catalyzes the reduction of dihydrofolate to tetrahydrofolate. The similarity
between the structures of folic acid and this drug are shown in the figure to the right bottom. In
some cases, the inhibitor can bind to a site other than the binding-site of the usual substrate and
exert an allosteric effect to change the shape of the usual binding-site. For
example, strychnine acts as an allosteric inhibitor of the glycine receptor in the mammalian
spinal cord and brain stem. Glycine is a major post-synaptic inhibitory neurotransmitter with a
specific receptor site. Strychnine binds to an alternate site that reduces the affinity of the glycine
receptor for glycine, resulting in convulsions due to lessened inhibition by the glycine. In
competitive inhibition the maximal rate of the reaction is not changed, but higher substrate
concentrations are required to reach a given maximum rate, increasing the apparent Km.In
uncompetitive inhibition, the inhibitor cannot bind to the free enzyme, only to the ES-complex.
The EIS-complex thus formed is enzymatically inactive. This type of inhibition is rare, but may
occur in multimeric enzymes.Non-competitive inhibitors can bind to the enzyme at the binding
site at the same time as the substrate,but not to the active site. Both the EI and EIS complexes are
enzymatically inactive. Because the inhibitor can not be driven from the enzyme by higher
substrate concentration (in contrast to competitive inhibition), the apparent Vmax changes. But
because the substrate can still bind to the enzyme, the Km stays the same.This type of inhibition
resembles the non-competitive, except that the EIS-complex has residual enzymatic activity.This
type of inhibitor does not follow Michaelis-Menten equation.In many organisms, inhibitors may
act as part of a feedback mechanism. If an enzyme produces too much of one substance in the
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Document Summary

The efficiency of an enzyme can be expressed in terms of kcat/km. This is also called the specificity constant and incorporates the rate constants for all steps in the reaction. Because the specificity constant reflects both affinity and catalytic ability, it is useful for comparing different enzymes against each other, or the same enzyme with different substrates. The theoretical maximum for the specificity constant is called the diffusion limit and is about 108 to. At this point every collision of the enzyme with its substrate will result in catalysis, and the rate of product formation is not limited by the reaction rate but by the diffusion rate. Enzymes with this property are calledcatalytically perfect or kinetically perfect. Example of such enzymes are triose-phosphate isomerase, carbonic anhydrase, acetylcholinesterase, catalase, fumarase, -lactamase, and superoxide dismutase. michaelis-menten kinetics relies on the law of mass action, which is derived from the assumptions of free diffusion and thermodynamically driven random collision.

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