Lipases are enzymes that hydrolyze the ester bonds of triacylglycerols, while proteases hydrolyze th — Organic Chemistry Chemistry Question
Lipases
Lipases are enzymes that hydrolyze the ester bonds of triacylglycerols, while proteases hydrolyze the amide bonds in proteins and peptides. Compounds that inhibit the hydrolysis of triacylglycerols and peptides may be useful for the treatment of various diseases.
The mechanism of action of the above enzymes starts with the attack of the hydroxyl group of serine to the ester or amide bond.
One approach for the development of serine protease inhibitors involves the replacement of the scissile amide bond by an activated carbonyl group. Thus, the hydroxyl of the active site serine reacts with the activated carbonyl forming a stable acyl enzyme adduct, which is not further hydrolyzed.
Rank the following carbonyl groups in order of decreasing reactivity against the hydroxyl group of serine:
[VISUAL]
Model Answer
1 > 2 > 3 > 4 > 5 > 6 (or (1) > (2) > (3) > (4) > (5) > (6))
Explanation:
- Electronic effects (inductive effect): Strongly electronegative fluorine and chlorine atoms are electron-withdrawing, which increases the partial positive charge on the carbonyl carbon, making it more electrophilic and reactive. Since fluorine is more electronegative than chlorine, and the pentafluoroethyl group (-CF2CF3) has more electron-withdrawing fluorine atoms than the trifluoromethyl group (-CF3), the order of reactivity is: -COCF2CF3 (1) > -COCF3 (2) > -COCCl3 (3) > -COCH2Cl (4).
- Steric and inductive effects in aldehydes vs ketones: Carbonyl compounds with hydrogen (aldehydes, 5) are more reactive than ketones (-COCH3, 6) because the hydrogen atom is much smaller than a methyl group (less steric hindrance) and the methyl group is electron-donating by induction, which reduces the electrophilicity of the carbonyl carbon.
Tetrahydrolipstatin is a potent inhibitor of digestive lipases (in clinical use for the treatment of obesity). Indicate with an arrow the carbonyl group of tetrahydrolipstatin that is attacked by the active site serine of lipases.
[VISUAL]
Model Answer
The active site serine of lipases attacks the carbonyl group of the highly strained four-membered β-lactone (beta-lactone) ring of tetrahydrolipstatin.
Esters and amides can be hydrolyzed under acidic or basic conditions. Rank the following compounds in order of decreasing reactivity towards aqueous hydroxide anion.
[VISUAL]
Model Answer
3 > 1 > 2 > 4 (or 1 > 3 > 2 > 4 depending on whether electronic or steric effects dominate)
Explanation:
- tert-Butyl acetate (4) is the least reactive due to severe steric hindrance from the bulky tert-butyl group.
- Ethyl acetate (2) is less reactive than methyl acetate (1) due to greater steric hindrance and a slightly stronger electron-donating inductive effect of the ethyl group.
- Benzyl acetate (3) has a strongly electron-withdrawing phenyl ring by induction. This increases the electrophilicity of the carbonyl carbon and stabilizes the leaving group, making it highly reactive. Depending on the reaction conditions, the electronic activation of the benzyl group makes it more reactive than ethyl acetate (2) and often even more reactive than methyl acetate (1), leading to the order: 3 > 1 > 2 > 4.