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41 Cards in this Set
- Front
- Back
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How does a competitive inhibitor work?
slide 3 |
occurs when the inhibitor binds REVERSIBLY to the SAME site that the substrate would normally occupy and therefore competes with the substrate for that site.
Sometimes can have similar shape to the normal substrate. When it binds it forms an inactive EI complex |
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How does a Competitive Inhibitor affect Vmax and how can this be reversed?
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It does not affect Vmax
The effect of the inhibitor is reversed by increasing [S] |
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What is the effect of a Competitive inhibitors affect on Km?
What does this mean? slide 7 |
Competitive inhibitor increases the apparent Km for a given substrate
Means that, in the presence of a competitive inhibitor, more substrate is needed to achieve 1/2 Vmax |
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How does Competitive Inhibition affect Km and Vmax
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Vmax is NOT changed
Apparent Km is INCREASED |
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What are the general principles for competitive inhibitors?
Slide 7 |
-Competitive inhibitor causes increase in the apparent Km of the substrate
-As [I] increases, Km apparent increases, Vmax remains UNchanged, but in the presence of [I] a much greater [S] is needed to attain any fraction of Vmax -the degree of inhibition caused by competitive inhibitor depends on [S], [I], Km and Ki - the lower the value of Ki, the greater is the degree of inhibition at any given [S] and [I] |
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What does the degree of inhibition by a competitive inhibitor depend on?
Slide 7 |
Depends on [S], [I], Km and Ki
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What does a high Ki versus a lower Ki mean?
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LOW Ki means MORE inhibition
HIGH Ki means LOWER degree inhibition |
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What are some drugs that act as competitive inhibitors?
slide 8 |
Captopril
Cilazapril Enalapril Fosinopril Lisinopril Ramipril These drugs lower the BP by inhibiting the enzyme that cleaves angiotensin I to angiotensin II which is a potent vasoconstrictor |
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Non Competitive Reversible Inhibition prime characteristic.
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Recognize by its lowering affect on Vmax.
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How do Non Competitive Inhibitors work?
slide 11 |
Non competitive inhibitors binds to the Enzyme on a DIFFERENT site than the substrate binding site.
Inhibitor and Substrate can be bound at the same time Vmax is decreased without affecting Km. A portion of the enzyme is in non-productive ESI complex and thus affects Vmax |
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How do Non competitive inhibitors affect Vmax and Km respectively?
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Vmax is LOWERED
Km is UNchanged |
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Why does Km not change with NONCompetitive Inhibitors?
slide 11 |
because both [E] and [EI] have the same affinity for [S]
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Can Non competitive inhibition be overcome by increasing substrate concentration?
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NOOOOOOOO which is why the apparent Vmax is also reduced
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Why do Noncompetitive inhibitors have no affect on KM?
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Because noncompetitive inhibitors do not interfere with the binding of the substrate to the enzyme(ie they do not affect the affinity of the substrate for the enzyme). Thus, the enzyme shows the same Km in the presence or absence of the noncompetitive inhibitor
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what are the general principles of non competitive inhibitors?
slide 14 |
1. Have no effect on substrate binding
2. Inhibitor and substrate bind to E Reversibly, randomly and independently at different site 3. Inhibitor binds to both E and ES complex, Substrate binds to both E and EI complex 4. The resulting ESI complex is inactive 5. The only effect of a noncompetitive inhibitor is to DECREASE Vmax. The Km remains UNCHANGED |
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IRreversible NONcompetitive Inhibition
explain what happens and how to distinguish with reversible noncompetitive inhibition. |
an inhibitor which combines irreversibly with an enzyme may resemble classical noncompetitive inhibitor because Vmax is decreased while KM remains unchanged
Vmax decreases because some enzyme is completely removed from the system A plot will distinguish IRreversible and Reversible non competitive inhibitors |
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Name some Irreversible Inhibitors of Baterial Transpeptidases
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Penicilin
Amoxicillin Clavulinic Acid Penicillin G, V etc |
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How do B-Lactam Antibiotics work?
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They are IRreversible Inhibitors
They block the formation of peptidoglycan cross links which weakens the bacterial cell wall and causes cell cytolysis when bacterium divides |
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How does Aspirin work
slide 20 |
Irreversible Inhibitor of cyclooxygenase (COX-1 and COX-2)
Forms covalent bonds within the active site Inhibits prostolandin synthesis |
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How does Allopurinol Work?
When used? Slide 20 |
Used in Gout
Allopurinol binds to xanthine oxidase and is converted to oxopurinol which remains bound to the active site of the enzyme with high affinity and keeps the enzyme in an inactive state |
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How does 5-Flourouracil work?
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It is an anti-cancer drug
Binds irreversibly inhibits thymidlyate synthetase |
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Where does UNcompetitive Inhibitor bind to the enzyme?
slide 21 |
Inhibitor does not bind to free E but binds reversibly to ES complex
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How will UNcompetitive Inhibition be affected by high substrate concentration?
slide 21 |
At any [I], an infinitely high [S] will not drive all the enzyme to the ES form; some nonproductive ESI complex will always be present
Apparent Km is decreased because some portion of ES complex is removed from the system to form inactive ESI complex Apparent Vmax ALSO DECREASED |
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How does UNcompetitive inhibition affect Km and Vmax respectively?
slide 21 |
Apparent Km is DECREASED because some portion of ES complex is removed from the system to form inactive ESI complex-
Apparent Vmax also DECREASED |
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How are many biosynthetic pathways regulated?
slide 25 |
By feedback inhibition.
the end products control the metabolic flux by inhibiting one ore more early reactions in the pathway. Inhibition can be in a cooperative (synergistic), cumulative, additive or sequential manner |
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Describe Cooperative (synergistic inhibition)
slide 26 |
Example: phosphoriboslyaminie synthetase
- each end product X and I inhibits E1 -Cooperative inhibition implies that X and I are not mutually exclusive At saturating level of either one, the velocity of E1 can be driven to zero Mixture of both X and I at low concentration are more inhibitory than the same total specific concentration of X or I alone |
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Describe Cumlative (partial inhibition)
slide 27 |
ex: Glutamin synthetase
each end product is a PARTIAL inhibitor A saturating level of X alone or I alone cannot drive the velocity to zero |
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How are allosteric enzymes regulated?
slide 28 |
allosteric enzymes are regulated by effectors or modifiers that bind to the enzyme at sites different from the active site
In the presence of allosteric effectors, the substrate binding affinity and/or catalytic activity of the enzyme are significantly modified |
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what happens to allosteric enzymes in the presence of allosteric effectors?
slide 28 |
the substrate binding affinity and/or catalytic activity of the enzyme is modified
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what is an "effector" when discussing allosteric enzymes?
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they are molecules that regulate allosteric enzymes
they bind NONcovalently at a site other than the active site Regulatory subunit might be located on a subunit that is not catalytic itself |
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What is a homotropic Effector?
slide 29 |
When the substrate itself serves as an effector.
Most often acts as a positive effector. In such instances, the presence of a substrate molecule at one site on enzyme can enhance the catalytic properties of the other substrate binding sites. (cooperative binding) |
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What is the shape of the curve for positive and negative Allosteric enzymes?
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Sigmoidal.
Positive and negative effectors of allosteric enzymes can affect either Km, or Vmax or both |
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What is a heterotropic Effector?
Slide 29 |
the effector is DIFFERENT from the substrate.
Feedback inhibitors in multistep pathways are often heterotropic effectors. |
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Feedback inhibitors in multistep pathways are often what type of inhibitors?
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Allosteric Heteotropic Effectors
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What are types of covalent modifications to enzymes?
slide 32 |
phosphorlyation and dephosphorylation usually to serine, threonine or tyrosine residue of the enzyme
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What is one of the primary ways cellular processes are regulated?
slide 32 |
protein phosphorylation with kinases
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What is phosphorylation catalyzed by?
Do they need energy to do their job? If so what? slide 32 |
protein kinases
yes they do need energy they use ATP, use it for phosphate donor |
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Who carries out dephosphorylation?
slide 32 |
Family of phosphoprotein phosphotases that cleave the phosphate group from phosphorylated proteins
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What is the response of an enzyme to phosphorylation... ie. is it more or less active?
slide 32 |
Depends on the specific enzyme, the phosphorylated form can be more or less active than the dephosphorylated form.
Phosphorylation of glycogen degrading enzyme glycogen phophorylase activates this enzyme Phosphorylation of glycogen synthase decreases its activity |
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Regulation of Enzyme by Gene Expression (Induction and Repression)
explain |
The amount of enzymes in cells can be regulated by altering their synthesis
The increased (induction) or decreased (repression) synthesis of an enzyme is a common regulator mechanism |
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Examples of reasons to increase/decrease enzyme gene expression
slide 33 |
-those enzymes which are needed only under certain physiological conditions
-high blood glucose levels cause an increase in the synthesis of glucose metabolizing enzymes -low blood glucose levels cause a decrease in synthesis levels of these enzymes |
