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Activator groups
Activators may act on Active site of the enzyme or on Allosteric site (allosteric activators)
Activation of enzymes.
One group of activators is made up of compounds affecting the active center region of an enzyme.
This group includes 1) substrates and 2) enzyme cofactors (metal ions, coenzymes and prosthetic groups)
(ex. metals with variable valence (Fe+2) in cytochromes electron transport). 2) the metal links with the substrate rather than with the enzyme forming thereby a
metallosubstrate complex
which is more advantageous for the enzyme activity (ex.Mg+2 or Mn+2 form complexes with ATP for creatin kinase and ATPase).
Activation by metal ions metal ions facilitate the binding of a substrate to the enzyme active center or coenzyme to the apoenzyme by forming a kind of bridge bonds. 4) metal ions can stabilize the conformation of apoenzyme (protein part of enzyme).
3)
Activation by coenzymes
The specific involvement of coenzymes (and prosthetic groups) in binding and catalyzing the substrate explains their activation of enzymic reactions. The majority of coenzymes are synthesized from vitamins. That is why we can use vitamins to increase the metabolism of several substances in the organism.
Activation by substrates
The substrate enhances the enzyme stability and facilitates the adoption of an appropriate conformation by the active center of the enzyme.
Allosteric activation
The number of activators influence allosteric center (allosteric activators). These are different products of metabolism in cells.
Inhibition of enzymes.
The majority of inhibitors are divided into: reversible and irreversible inhibitors.
Inhibitors
Reversible Irreversible
Competitive
Noncompetitive
removal of inhibitor, it is
reversible
inhibitor
inhibitor).
Acetylcholine + H2O
DFP reacts with the OH group of serine residue of the active center (of cholinesterase) .
OCH(CH3)2 Active OH +
enzyme
FP=O OCH(CH3)2
As the result acetylcholine is accumulated and the transmission of nerve impulses is impaired.
E + S ES
E +I EI
The competing compound present in excess binds preferably to the active center. The enzyme becomes bound either to the substrate, or to the inhibitor.
The inhibition occurs as substrate-like inhibitors bind a certain member of enzyme molecules, leading to incapability of forming an enzyme-substrate complex.
Therefore, competitive inhibitor influences the binding of the substrate with the enzyme. The distinctive sign of competitive inhibition: the removal of inhibitory blocking can be accomplished by an excess of the substrate whose molecules eliminate the
inhibitor from the active center of the enzyme molecules and reactivate the latter to catalytic activity.
Inhibition of succinate dehydrogenase is an example of competitive inhibition. For succinate dehydrogenase (SDH), succinate is a natural substrate, while the structurally related oxaloacetate (an intermediate in the Krebs cycle), exhibits a competitive inhibitory action.
FAD FADH2
Succinate
SDH
fumarate
oxaloacetate
(Inhibitor)
malonate
(inhibitor)
In presence of inhibitor the rate of reaction will decrease, but we can remove the inhibition by an excess of substrate. E + S ES E + I EI EI + S ES + I That is why, the value of Vmax in case of competitive inhibition (VmaxI), doesnt change. But Km increases. Because this inhibitor affects the affinity of enzyme for substrate.
Heavy
metal ions and their organic compounds belong to noncompetitive inhibitors of enzymes. For this reaction, the
ions of heavy metals (mercury, lead, cadmium, arsenic and some others) are very toxic. For example, they can block the S-H
groups that make part of the catalytic site of an enzyme. We cannot remove this
inhibitor by means of the increase of substrate concentration, only with the help of compounds called reactivators.
EI + reactivator E + reactivator + I
Heavy metals act as noncompetitive inhibitors only when taken in small concentrations. Taken in excess, they act as inactivators, or denaturants (this denaturation).
Sulphanilamides are used for treatment of certain infectious diseases caused by bacteria.
In bacteria para-aminobenzoic acid is used for the synthesis of folic acid (the folic acid is the factor of growth for bacteria). Owing to the structural congenerity, sulphanilamide blocks reaction of folic acid synthesis, leading to the inhibition of bacterial growth
For humas folic acid is a vitamin. It is not synthesized in the organism. That is why, sulphanilamides do not effect the human cells. To create the saturation, and to eliminate paminobenzoic acid from the enzyme in bacteria, first we must use the large dose (several tablets at once). And then to prevent metabolism of the drug and its secretion out of the organism we must use the usual doses.
The allosteric regulation is characteristic only a special group of enzymes with quaternary structure possessing regulatory centers for binding allosteric effectors.
enzymes are: 1) They have quarternary structure, consist of 2 and above subunits. 2) They have allosteric center (some of the enzymes may possess several allosteric centers). 3) They do not have hyperbolic shape on the graph of Michaelis-Menten.
V
enzyme
[S]
They
characteristic sigmoidal curve (as in case of hemoglobin saturation with oxygen). Because the active centers of enzyme subunits function cooperatively . The affinity of every next active center for substrate is defined by the saturation degree of the previously involved centers.
have
Allosteric enzyme can be regulated by the system of negative feed-back (inhibition of the initial enzyme I the conversion chain by the end product). In such a manner the first enzyme in the reaction chain is switched off as the end product concentration increases. Such enzyme (E1) is called heterotropic (because the substrate A and allosteric effector (D)) are different substances. When the substrate serves as positive effector (allosteric activator) ABCD such enzyme is called homotropic. If the enzyme has both regulation it is called homoheterotropic.
Covalent regulation
The activation of certain enzymes can be accomplished via structural modifications non in the active center. It can be: 1) the activation of an inactive precursor refered to as proenzyme, or zymogen (Activation of zymogens). 2) the activation via addition of a specific modifying group to the enzyme molecule (chemical modification).
Activation of zymogens
Example digestive enzymes. The conversion of inactive precursor (proenzyme, zymogen) takes place by means of proteolysis.
+
peptide, which prevents the interaction of S with active center
chymotrypsin (in the small intestine)
Trypsinogen
trypsin
Chymotrypsinogen
This is non reversible process. For what purpose these enzymes are synthesized firsty in inactive form? The pancreatic production of trypsin (and of other proteinases) in an inactive form has a definite biological sense, since otherwise typsin, produced in its active form, could inflict a destructive proteolytic action both on the pancreatic cells and on the enzymes synthesized by pancreas (amylase, lipase and others). These enzymes exhibit relative group substrate specificity. They are specific towards the peptide bonds and catalyze proteolysis of various proteins and also proteins of pancreas itself.
Einactive
(phosphorylase B) protein kinase H3PO4H2O protein
Eactive
(phosphorylase A)
This is reversible process. This is regulation by means of reversible chemical modification. The chemical modification can involve methylation, glycosylation (of course phosphorylation) and other reactions.
Multienzyme systems.
Each cell in the organism possesses its specific set of enzymes. And each organell has specific set of enzymes. That is why, each enzyme has the definite localization in the cell, and functions in the definite compartment of the cell. These compartments are separated by the membranes (for example mitochondria). The enzyme cannot go out of this compartment and functions their. Compartmentalization is a distinctive feature of enzyme catalysis.
For example, the breakdown of fatty acids taked place in mitochondria, but their synthesis in cytoplasm. These processes are separated in the cell by means of compartmentalization of enzymes. Otherwise, the effect of conversions would be equal to zero.
In the cell, each enzyme performs its function not independently, but rather in a close cooperation with other enzymes. Thus, functionally interdependent individual enzymes, compose multienzyme systems, or complexes. There are 1) functional 2) structure-functional 3) combined types of multienzyme system organization.
The functional organization is remarkable in that the individual enzymes are united in a functionoriented multienzyme system through the agency of metabolites that are capable of diffusing from one enzyme to another. In a functionally organized multienzyme system, the reaction product of the first enzyme in the conversion chain serves as a substrate for the second enzyme. Glycolysis serves as an example for functional organization of multienzyme systems. All of the glycolysis enzymes persist in a state of dissolution. Each reaction is catalyzed by individual enzymes.
The structure-functional organization consists in that the enzymes form structural functonoriented systems via enzyme-enzyme (proteinpotein) interactions. In such a manner, structural multienzyme supermolecular complexes are built up. For example, pyruvate dehydrogenase multienzyme complex composed of several enzymes engaged in the oxidation of pyruvic acid or structurally related enzymes involved in a common function, the synthesis of fatty acids. Such multienzyme complexes are tightly bound and resist decomposition into constituent enzymes. This is their major distinction from functionally organized multienzyme systems.
Enzymes also may become fixed on the biomembrane to form a chain. This is an example for the mitochondrial respiratory chain involved in energy generation and transport of electrons and protons. A separation of enzymes constitutive of such systems puts an end to their activity. The combined type of multienzyme system oganization is a combination of the two above types i.e. one part of the multienzyme system has a structural, and the other one, a functional organization. The example is the multienzyme system of Krebs cycle in which some of the enzymes are united into a structural complex (2-oxoglutarate dehydrogenase complex), while other enzymes are functionally interrelated through metabolite mediators.