Term
| List the three types of enzyme inhibition |
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Definition
1. Classical reversible
2. Mechanism-Based
3. Irreversible |
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Term
| Describe the two methods classical reversible enzyme inhibition |
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Definition
1. Competitive (binding to active site)
2. Non-competitive (binging to allosteric site and [ES] complex) |
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Term
| Describe the two methods of mechanism-based enzyme inhibition |
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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 |
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Term
| Describe the two methods of irreversible enzyme inhibition |
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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 |
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Term
| Give an example of a drug that uses irreversible reaction coordinate inhibitors |
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Definition
| Penicillin binding and 5-FU |
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Term
| Give an example of suicide substrate inhibitors |
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Definition
-Beta lactamase inhibitor
-Clauvanic acid |
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Term
| Give the Michaelis-Menton equation |
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Definition
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Term
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Definition
| The concentration of substrate necessary to achieve Vmax/2 |
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Term
| Which would you want to be reversible, chemotherapeutic agents or pharmacotherapeutic agents? |
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Definition
| Pharmacotherapeutic should be reversible, because it treats symptoms whereas chemotherapeutic kills the source of disease |
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Term
| Give the equation for a Lineweaver-Burk plot |
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Definition
| 1/V = Km/Vmax(1/[S]) + 1/Vmax |
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Term
| In competitive inhbition, what factors in the Michaelis-Menton and Lineweaver-Burk plot are affected? |
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Definition
Km is increased
Slope of Linewaver-Burk plot is increased |
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Term
| In NON-competitive inhbition, what factors in the Michaelis-Menton and Lineweaver-Burk plot are affected? |
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Definition
Vmax is decreased
Slope and y-intercept of Linewaver-Burk plot is increased |
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Term
| What is the clinical role of sulfanilamides |
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Definition
| To competitively inhibit Dihydropteroate synthase, preventing bacteria from making dihydropeteroic acid (a folic acid) for DNA |
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Term
| What is the key difference in how bacteria and humans get folic acid? |
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Definition
Humans get them from the diet and convert it to tetrahydrofolic acid
Bacteria synthesize folic acid using Dihydropteroate synthase |
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Term
| How do bacteria become resistant to sulfonamides? |
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Definition
| By producing a lot of PABA (the molecule that sulfonamides structurally mimic) |
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Term
| What is a major side effect of sulfanilamides? |
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Definition
Crystal urea, which can block kidney tubules
Fluid intake should be increased. Or we can try a more soluble sulfonamides. |
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Term
| When bacteria become resistant to sulfanilamides, what drug can then be given for antibiotic synergism? |
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Definition
| A drug which inhibits DHFR, which is the next enzyme in the step |
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Term
| What enzyme converts phosphoribosyl pyrophosphate to phosphoribosylamine? |
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Definition
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Term
| What controls the action of PRA synthase? |
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Definition
| Inosine monophosphate, through non-competitive negative feedback |
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Term
| What is the significance of inosine monophosphate? |
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Definition
| It is a precursor of purines and can also be used to sub in for several of the base pairs |
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Term
| What is the role of HPRT? |
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Definition
| An enzyme that converts 6-mercaptopurine to thio inosine monophosphate |
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Term
| What is the significance of thioinosine monophosphate? |
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Definition
| It is very similar (bioisoteres) to inosine monophosphate, so also non-competively inhibits PRA synthase |
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Term
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Definition
| Molecules that are very similar, they only differ by one chemically similar atom |
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Term
| How can 6-mercaptopurine be used clinically? |
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Definition
| It can be used as an anti-cancer drug since it inhibits PRA synthase, thus inhibiting DNA synthesis |
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Term
| Are transition state analogs reversible or irreversible? |
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Definition
| Transition state analogues are reversible |
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Term
| Give an example of a transition state analogue |
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Definition
| Pentostatin is a mimic of the transition state of adenosine, involved in DNA synthesis |
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Term
| Describe reaction coordinate analogs |
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Definition
-Resemble the target enzyme's substrate
-Reacts with active site to form EI complex
-Reversible, but can't go on to form product |
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Term
| Give an example of reaction coordinate analogs |
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Definition
| Peptidyl trifluromethyl ketone and elastinal both inhibit human leukocyte elastase |
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Term
| What is the function of elastase? |
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Definition
| It is a serine protease released by neutrophils, which chews up damaged elastin in connective lung tissue |
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Term
| What enzyme keeps elastase in check? |
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Definition
Alpha-1-antitrypsin
Interestingly, this enzyme is damaged by cigarette smoke |
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Term
| In the Northern European population deficient in alpha-1-antitrypsin, what happens? |
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Definition
| It leads to a high incidence of emphysema |
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Term
| How do chloromethyl ketones (R-CO-CH2Cl) affect a reaction? |
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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 |
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Term
| How are chloromethyl ketones (R-CO-CH2Cl) used clinically? |
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Definition
They are too non-specific to be used as a drug
They are used in labs to identify active sites of enzymes |
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Term
| What kind of competitor is penicillin |
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Definition
D-ala-D-ala is built into a cell wall with transpeptidase
Penicillin binds to transpeptidase, irreversibly inhibiting as a coordinate |
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Term
| What kind of competitor is flourine, when used as a cancer drug? |
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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) |
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Term
| What is the function of beta-lactamase? |
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Definition
To open the beta-lactam ring in penicillin
This is found in penicillin-resistant bacteria |
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Term
| Give an example of a suicide substrate (kcat) inhibitor |
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Definition
| Clavulanic acid- a beta lactamase inhibitor |
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Term
| Does clavulanic acid act as an antibiotic in itself? |
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Definition
| No, it prevents bacteria from being resistant to penicillin |
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