Term
| Which Phase enzymes are Ester & Amide Hydrolases? |
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Definition
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Term
| General names for amide/ester hydrolysis enzymes? |
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Definition
carboxylesterases
(peptides are hydrolyzed by highly selective peptidases) |
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Term
| Are esters difficult to hydrolyze? |
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Definition
| No - they're usually hydrolyzed readily, including by non-enzymatic hydrolysis at high pH (stomach) and low pH (GI tract) |
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Term
Order of stability:
Esters, Amides, Peptides |
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Definition
Stability
Peptides > Amides > Esters |
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Term
| Why is it bad for peptide drugs to be taken orally? |
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Definition
| They will be digested by peptidases in the GI tract |
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Term
| Why don't people eat cocaine? |
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Definition
| Cocaine has two ester groups which can undergo ester hydrolysis (to form ecgonine and benzoic acid) which terminates its action. |
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Term
| Describe a minor pathway of acetaminophen which can lead to a highly toxic metabolite. |
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Definition
| Amide Hydrolysis to form p-hydroxyaniline |
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Term
| Why does aspartame have a low shelf life? |
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Definition
| Aspartame has a peptide bond which is unusually unstable. It can undergo non-enzymatic hydrolysis or peptidase hydrolysis --> phenylalanine methyl ester + aspartic acid |
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Term
Type A, B, or C hydrolase?
Water Soluble |
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Definition
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Term
Type A, B, or C hydrolase?
Metabolize Organophosphates |
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Definition
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Term
Type A, B, or C hydrolase?
Has a wide range of substrates but prefers aromatic esters? |
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Definition
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Term
Type A, B, or C hydrolase?
Uses 2 histidine residues + 2 Ca2+ ions taht assist in deprotonation fo water to give a hydroxyl anion that attacks the ester bond? |
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Definition
| A - complete mechanism not fully understood |
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Term
Type A, B, or C hydrolase?
Is a paraoxonase? |
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Definition
| A (Paraoxon inhibits Type B but is a substrate for Type A... it is hydrolyzed (detoxified) into p-nitrophenol and bis-ethylphosphate) |
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Term
Type A, B, or C hydrolase?
Located in microsomal fraction (sometimes plasma membrane/mitochondria) |
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Definition
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Term
Type A, B, or C hydrolase?
Do not metabolyze organophosphates? |
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Definition
| B and C (B is inhibited, C is not) |
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Term
Type A, B, or C hydrolase?
Exists as a trimer? |
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Definition
| B - with a momomeric MW of 60,000 |
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Term
Type A, B, or C hydrolase?
Inhibited by organophosphates? |
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Definition
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Term
Type A, B, or C hydrolase?
Operates as a "Catalytic Triad"? |
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Definition
| B and C - Serine, Histidine, & Aspartic (sometimes glutamic) Acid |
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Term
Type A, B, or C hydrolase?
"Serine Hydrolase"? |
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Definition
| B and C - Use Serine, Histidine, Aspartic Acid in catalytic triad |
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Term
Type A, B, or C hydrolase?
Common substrate: acetyl-esters? |
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Definition
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Term
| Why do organophosphates inhibit B esterases? |
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Definition
| Acylated enzyme stage is relatively stable and only very slowly hydrolyzed... this explains neurotoxicity of paraoxon - inhibits acetylcholinesterase and leads to 'aging' where the enzyme is deactivated... if it's not hydrolyzed in the blood it will get into BBB and deactivate acetylcholinesterase) |
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Term
| What inhibits A esterases? |
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Definition
| Mercuric Salt - perhaps by the need for Ca2+ -- somehow displacing calcium |
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Term
| What do Mercuric salts do to esterases? |
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Definition
| Inhibit A Esterases and sometimes stimulate C Esterase activity |
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Term
| What do Mercuric salts do to esterases? |
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Definition
| Inhibit A Esterases and sometimes stimulate C Esterase activity |
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Term
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Definition
Xenobiotic that is toxic to insects but not ppl.
In Insects activated by P450 to toxic oxon-type metabolite that can inhibit acetylcholinesterase if it gets into the brain
In people, the malathion is a good substrate for carboxylesterases so it gets hydrolyzed into a nontoxic, water soluble metabolite - which could not cross blood brain barrier with carboxylate gp |
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Term
| Why is it beneficial to have an ester in a prodrug? |
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Definition
It makes the drug more lipophilic.
ex. Bambuterol (asthma drug) |
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Term
| Describe Trans-esterification (with cocaine) |
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Definition
| When an ester forms the acyl-enzyme and another alcohol comes in.. instead of hydrolyzing it goes back to the 'parent molecule' with a different alcohol substituent.... Cocaine (with methyl ester) + Ethanol --> Ethyl Cocaine |
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Term
| Describe metabolism with an ester group... When will it first get metabolized? second? |
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Definition
| Widespread metabolism -- will get ester drug & prodrugs with ester groups are meatbolized during absorption (first during GI and liver.. in blood we will still get metabolism) |
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