Enzymes can be regulated by changing the activity of a
preexisting enzyme or changing the amount of an enzyme.
A. Changing the activity of
a pre-existing enzyme: The quickest way to modulate the
activity of an enzyme is to alter the activity of an enzyme that
already exists in the cell. The list below, illustrated in the
following figure, gives common ways to regulate enzyme activity
- Substrate availability: Substrates
(reactants) bind to enzymes with a characteristic affinity
(characterized by a dissociation constant) and a kinetic parameter
called Km (units of molarity). If the actual concentration of a
substrate in a cell is much less than the Km, the activity of the
enzyme is very low. If the substrate concentration is much greater
than Km, the enzyme active site is saturated with substrate and the
enzyme is maximally active.
- Product inhibition: A
product of an enzyme-catalyzed reaction often resembles a starting
reactant, so it should be clear that the product should also bind
to the activity site, albeit probably with lower affinity. Under
conditions in which the product of a reaction is present in high
concentration, it would be energetically advantageous to the cell
if no more product was synthesized. Product inhibition is hence
commonly observed. Likewise it be energetically
advantageous to a cell if the end product of an entire pathway
could likewise bind to the initial enzyme in the pathways and
inhibit it, allowing the whole pathway to be
inhibited.
- Allosteric regulation: As many
pathways are interconnected, it would be optimal if the molecules
of one pathway affected the activity of enzymes in another
interconnected pathway, even if the molecules in the first pathway
are structurally dissimilar to reactants or products in a second
pathway. Molecules that bind to sites on target enzymes other than
the active site (allosteric sites) can regulate the activity of the
target enzyme. These molecules can be structurally dissimilar to
those that bind at the active site. They do so my conformational
changes which can either activate or inhibit the target enzyme's
activity.
- pH and enzyme conformation: Changes
in pH which can accompany metabolic process such as respiration
(aerobic glycolysis for example) can alter the conformation of an
enzyme and hence enzyme activity. The initial changes are covalent
(change in protonation state of the protein) which can lead to an
alteration in the delicate balance of forces that affect protein
structure.
- pH and active site protonation
state: Changes in pH can affect the protonation state of key amino
acid side chains in the active site of proteins without affecting
the local or global conformation of the protein. Catalysis may be
affected if the mechanism of catalysis involves an active site
nucleophile (for example), that must be deprotonated for
activity.
- Covalent modification: Many if not
most proteins are subjected to post-translational modifications
which can affect enzyme activity through local or global shape
changes, by promoting or inhibiting binding interaction of
substrates and allosteric regulators, and even by changing the
location of the protein within the cell. Proteins may be
phosphorylated, acetylated, methylated, sulfated, glycosylated,
amidated, hydroxylated, prenylated, myristolated, often in a
reversible fashion. Some of these modifications are reversible.
Regulation by phosphorylation through the action of kinases, and
dephosphorylation by phosphates is extremely common. Control of
phosphorylation state is mediated through signal transduction
process starting at the cell membrane, leading to the activation or
inhibition of protein kinases and phosphatases within the
cell.
B. Changing the amount of an
enzyme: Another and less immediate but longer duration
method to modulate the activity of an enzyme is to alter the
activity of an enzyme that already exists in the cell. The list
below, illustrated in the following figure, shows way in which
enzyme concentration is regulated.
- Alternation in transcription of
enzyme's gene: Extracellular signal (hormones, neurotransmitters,
etc) can lead to signal transductions responses and ultimate
activation or inhibition of the transcription of the gene for a
protein enzyme. These changes result from recruitment of
transcription factors (proteins) to DNA sequences that regulate
transcription of the enzyme gene.
- Degradation of messenger RNA for
the enzyme: The levels of messenger RNA for a protein will directly
determin the amount of that protein synthesized. Small inhibitor
RNAs, derived from microRNA molecules transcribed from cellular
DNA, can bind to specific sequences in the mRNA of a target enzyme.
The resulting double-stranded RNA complex recruits an enzyme
(Dicer) that cleaves the complex with the effect of decreasing
translation of the protein enzyme from its mRNA.
- Co/Post translational changes: Once
a protein enzymes is translated from its mRNA, it can undergo a
changes to affect enzyme levels. Some proteins are synthesized in a
"pre"form which must be cleaved in a targeted and limited fashion
by proteases to active the protein enzyme. Some proteins are not
fully folded and must bind to other factors in the cell to adopted
a catalytically active form. Finally, fully active protein can be
fully proteolyzed by the proteasome, a complex within cells, or in
lysosomes, which are organelles within cells containing proteolytic
enzymes.