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Regulatory Strategies: Regulation of Metabolism

Mechanism of enzyme
regulation

Mechanism of enzyme regulation
 The regulation of the reaction velocity of enzymes is essential if an
organism is to coordinate its numerous metabolic processes
...

 An increase in substrate concentration prompts an increase in reaction
rate, which tends to return the concentration of substrate toward normal
...


Mechanism of enzyme regulation
 The biological activity of proteins is regulated in four principal ways:

 1
...
Multiple forms of enzymes (Isozymes)
 3
...
Proteolytic activation
 Product inhibition

 Feed back inhibition

Product inhibition

• ↑Substrate  ↑activity of the enzyme  ↑product
...


End Product Inhibition (Negative feed back)

End Product Inhibition (Negative feed back)

Feed back inhibition
 The ultimate product of a long metabolic pathway inhibits the first enzyme in
the early step in the pathway
...


Feed back inhibition

 The end product synthesized of the pathway becomes an inhibitor that
binds at allosteric site of the first enzyme
 affects the shape of the enzyme
...

 The metabolic pathway is then switch off and can no longer produce the
end products

Feed back inhibition
 The amino acid threonine is converted
to another amino acid isoleucine through a
series of reactions
...

 Threonine deaminase is inhibited by
isoleucine to prevent an over production of
isoleucine
...
mcgrawhill
...
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Metabolic Pathway Product/ Feedback Inhibition

Allosteric control
First What are allosteric enzymes?
 In Greek )Allos = other , Steres = site)
...
Active site  Substrate binds (Catalysis)
2
...

 Binding by these molecules can either
 inhibit or stimulate enzyme activity

Modulators : Two types
1
...
Heterotropic: not identical

Allosteric control
• Effectors bind to the allostric site
...


Allosteric control
 Some allosteric regulators, activators, stabilize the conformation that
has a functional active site
...


 In enzymes with multiple catalytic subunits
 binding by a substrate to one active site stabilizes favorable
conformational changes at all other subunits, a process called
cooperativity
...

• -Ve Effector: When effector binding causes decrease in the
enzyme activity
...
(coenzyme)
• Heterotropic effector: when the effector has diffirent structure
than the substrate
...

 Allostric enzymes show cooperativity
 Usually the Active site & Allostric site are present in the same
subunit
...
K class : ex PFK
2
...


It is down-regulated by:
palmitoyl CoA (endproduct
regulation)
...

It is up-regulated by:
citrate (allosteric)
dephosphorylation of the enzyme
(influenced by the insulin/glucagon
ratio)
...

 The enzyme exists in equilibrium between two forms
 A T form (taut) with a low affinity for its substrate
 And an R form (relaxed) with a high affinity for the substrate
...

 The first effector to bind changes the conformation of all the

protomers simultaneously thereby greatly promoting activation or
inhibition
...

 Substrates and activators bind easily to the R form while
inhibitors bind more easily to the T form
...


The sequential Model
 The sequential model is needed to explain negative cooperativity,
a situation in which the binding of the first ligand reduces the
affinity for similar ligands
...


 Neither model above fully explains all allosteric enzyme activity
...

 This transition affects the affinity of the other subunits for the ligand
...


concerted
T form

T 6P2-29
form

sequential

R form

R form

 Cooperativity - in relation to multiple subunit enzymes,
changes in the conformation of one subunit leads to
conformational changes in adjacent subunits
...


Sequential Models Also Can Account for Allosteric Effects
In the concerted model, an allosteric enzyme can exist in one of only
two states, T and R; no intermediate states are allowed
...


The binding of substrate to one site influences the substrate affinity of
neighboring active sites without necessarily inducing a transition

encompassing the entire enzyme
...

 The results of studies of a number of allosteric proteins suggest that
most behave according to some combination of the sequential and
cooperative models
...
2

+
cAMP

6
...
4

Glycogen
phosphorylase b
(inactive)

AMP (+)
ATP (-)
Glc-6-P (-)
Juang RH (2004) BCbasics

4
...

• Eg
...

• Organelles also allow for concentration of specific
reagents
...
Lysosomes require a low pH (~5)
+] inside
...

• Both enzymes exist in multiple forms called
isozymes which have slightly different AA
sequences
...

6P2-58

Medical Apps: Diagnosis-2
• Dimeric CK has two types
of protomers, muscle (M)
and brain (B)
...
Only CK2 is
found exclusively in heart
muscle
...
)

6P2-59

Medical Apps: Diagnosis-3
• LDH is a tetramer composed of two
protomers, heart (H) and muscle (M)
...

• Again, electrophoresis patterns can be used to
diagnose an infarct
...

6P2-60

Medical Apps: Diagnosis-4

Normal LDH
electrophoresis
pattern
6P2-61

LDH
electrophoresis
pattern after infarct

Medical Apps: Therapy
• Streptokinase and human tissue plasminogen
activator (tPA) are both used to treat heart
attack because they dissolve blood clots
• Asparaginase does not occur in human blood
...
Infusing the
enzyme can cause cancer cell death due to
lack of asparagine
...

6P2-62

Allosteric control
First What are allosteric enzymes?
 contain distinct regulatory sites and multiple functional sites
 Regulation by small signal molecules
 The binding of these regulatory molecules at sites distinct from the
active site triggers conformational changes that are transmitted to the
active site
...

 As a consequence, a slight change in substrate concentration can
produce substantial changes in activity
...

 enzyme aspartate transcarbamoylase (ATCase) and the oxygencarrying protein hemoglobin
...
Protease enzymes (enzymes
that degrade proteins) like pepsin, trypsin and chymotrypsin are
synthesized first as larger, inactive precursor proteins termed
zymogens (specifically pepsinogen, trypsinogen, and
chymotrypsinogen, respectively)
...
Zymogen forms allow proteins to be transported or stored in
inactive forms that can be readily converted to active forms in response
to some type of cellular signal
...
Other examples of zymogens include proinsulin,

procollagen and many blood clotting enzymes (the latter will be
discussed in the next lecture)

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