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PDA Exam 2, Part 5
Molecular Mechanisms- modification of enzymes
38
Pharmacology
Professional
03/01/2012

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Cards

Term
List the three types of enzyme inhibition
Definition
1. Classical reversible
2. Mechanism-Based
3. Irreversible
Term
Describe the two methods classical reversible enzyme inhibition
Definition

1. Competitive (binding to active site)

2. Non-competitive (binging to allosteric site and [ES] complex)

Term
Describe the two methods of mechanism-based enzyme inhibition
Definition
1. Inhibiting transition state with analogs
2. Inhibiting reaction coordinate with analogues (forms covalent complex [EI] which is reversible but can't form product
Term
Describe the two methods of irreversible enzyme inhibition
Definition
1. Affinity labels- alkylates enzyme (mostly used for ID in labs)
2. Mechanism based and irreversible- irreversible reaction coordinate inhibitors and suicide substrate inhibitors
Term
Give an example of a drug that uses irreversible reaction coordinate inhibitors
Definition
Penicillin binding and 5-FU
Term
Give an example of suicide substrate inhibitors
Definition
-Beta lactamase inhibitor
-Clauvanic acid
Term
Give the Michaelis-Menton equation
Definition
V=Vmax[S]/([S]+Km)
Term
Define Km
Definition
The concentration of substrate necessary to achieve Vmax/2
Term
Which would you want to be reversible, chemotherapeutic agents or pharmacotherapeutic agents?
Definition
Pharmacotherapeutic should be reversible, because it treats symptoms whereas chemotherapeutic kills the source of disease
Term
Give the equation for a Lineweaver-Burk plot
Definition
1/V = Km/Vmax(1/[S]) + 1/Vmax
Term
In competitive inhbition, what factors in the Michaelis-Menton and Lineweaver-Burk plot are affected?
Definition

Km is increased

Slope of Linewaver-Burk plot is increased

Term
In NON-competitive inhbition, what factors in the Michaelis-Menton and Lineweaver-Burk plot are affected?
Definition
Vmax is decreased

Slope and y-intercept of Linewaver-Burk plot is increased
Term
What is the clinical role of sulfanilamides
Definition
To competitively inhibit Dihydropteroate synthase, preventing bacteria from making dihydropeteroic acid (a folic acid) for DNA
Term
What is the key difference in how bacteria and humans get folic acid?
Definition
Humans get them from the diet and convert it to tetrahydrofolic acid

Bacteria synthesize folic acid using Dihydropteroate synthase
Term
How do bacteria become resistant to sulfonamides?
Definition
By producing a lot of PABA (the molecule that sulfonamides structurally mimic)
Term
What is a major side effect of sulfanilamides?
Definition
Crystal urea, which can block kidney tubules

Fluid intake should be increased. Or we can try a more soluble sulfonamides.
Term
When bacteria become resistant to sulfanilamides, what drug can then be given for antibiotic synergism?
Definition
A drug which inhibits DHFR, which is the next enzyme in the step
Term
What enzyme converts phosphoribosyl pyrophosphate to phosphoribosylamine?
Definition
PRA synthase
Term
What controls the action of PRA synthase?
Definition
Inosine monophosphate, through non-competitive negative feedback
Term
What is the significance of inosine monophosphate?
Definition
It is a precursor of purines and can also be used to sub in for several of the base pairs
Term
What is the role of HPRT?
Definition
An enzyme that converts 6-mercaptopurine to thio inosine monophosphate
Term
What is the significance of thioinosine monophosphate?
Definition
It is very similar (bioisoteres) to inosine monophosphate, so also non-competively inhibits PRA synthase
Term
Define bioisoteres
Definition
Molecules that are very similar, they only differ by one chemically similar atom
Term
How can 6-mercaptopurine be used clinically?
Definition
It can be used as an anti-cancer drug since it inhibits PRA synthase, thus inhibiting DNA synthesis
Term
Are transition state analogs reversible or irreversible?
Definition
Transition state analogues are reversible
Term
Give an example of a transition state analogue
Definition
Pentostatin is a mimic of the transition state of adenosine, involved in DNA synthesis
Term
Describe reaction coordinate analogs
Definition
-Resemble the target enzyme's substrate
-Reacts with active site to form EI complex
-Reversible, but can't go on to form product
Term
Give an example of reaction coordinate analogs
Definition
Peptidyl trifluromethyl ketone and elastinal both inhibit human leukocyte elastase
Term
What is the function of elastase?
Definition
It is a serine protease released by neutrophils, which chews up damaged elastin in connective lung tissue
Term
What enzyme keeps elastase in check?
Definition
Alpha-1-antitrypsin

Interestingly, this enzyme is damaged by cigarette smoke
Term
In the Northern European population deficient in alpha-1-antitrypsin, what happens?
Definition
It leads to a high incidence of emphysema
Term
How do chloromethyl ketones (R-CO-CH2Cl) affect a reaction?
Definition
They act as an irreversible inhibitor, R resembles any natural substance but the ketone is extremely electrophilic and readily alkylate neutrophilic groups of enzymes
Term
How are chloromethyl ketones (R-CO-CH2Cl) used clinically?
Definition
They are too non-specific to be used as a drug

They are used in labs to identify active sites of enzymes
Term
What kind of competitor is penicillin
Definition
D-ala-D-ala is built into a cell wall with transpeptidase

Penicillin binds to transpeptidase, irreversibly inhibiting as a coordinate
Term
What kind of competitor is flourine, when used as a cancer drug?
Definition
Irreversible reaction coordinate inhibitor

It binds to dUMP at the 5-position, and this prevents the enzyme from converting it to dTMP (precursor of thymine)
Term
What is the function of beta-lactamase?
Definition
To open the beta-lactam ring in penicillin

This is found in penicillin-resistant bacteria
Term
Give an example of a suicide substrate (kcat) inhibitor
Definition
Clavulanic acid- a beta lactamase inhibitor
Term
Does clavulanic acid act as an antibiotic in itself?
Definition
No, it prevents bacteria from being resistant to penicillin
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