3. Acetylcholinesterase is a serine hydrolase enzyme im- portant in nerve signal transmission, hydrolyzing acetylcho- line, an ester molecule with a positively charged quaternary nitrogen group. The structure of the physiologically relevant substrate of this enzyme is shown on the right. The quater- H₂C nary nitrogen group serves to anchor the molecule in the active site Gly121 Oxy- anion hole Gly122 Ala204 Substrate ACh His447 Catalytic triad Ser203 Glu202 Glu334 Ser229 CH3 N+ CH3 CH3 The a Scale document down rine protease family, consisting of a catalytic triad Ser203- His447-Glu334 with Ser203 supplying the nucleophilic hydroxyl group and an oxyanion hole com- prised of peptide NH groups of Gly121, Gly122, and Ala204, illustrated in the diagram above, for which carbon (green), nitrogen (blue), and oxygen (red) atoms are shown while hydrogen atoms are white. The enzyme catalyzed reaction can be represented by the following scheme: (a)( k1 K2 E + S = ES K-1 K3 EYE + P where ES represents the noncovalent Michaelis complex and EY, a covalent acylenzyme intermediate. Starting with the diagrammatic representation of the ES complex given below, draw an arrow-pushing mechanism in the style of the chymotrypsin reaction (cf., p. 206. 8th edition), to show how the ES com- plex is converted into the EY intermediate. Indicate all hydrogen bonds with dashed lines, and label the enzyme residues involved with their name and sequence number. Question #3, continued: Gly. L -HN. རྒྱ་ Ser203 CR' His 447 NH ES Michaelis Complex C- 0644334 (b) ( Binding of the inhibitor trifluoroacetophenone (TFK*) to acetylcholin- esterase is characterized by the kinetic constants k₁ = 2.8 x 108 M-1s-1 and k-1 = 1.8 x 10-5 s-1. What is the inhibitor binding constant and what interactions be- tween the enzyme and the inhibitor must occur to account for this high binding affinity? Supplement your answer with a schematic of the enzyme-inhibitor com- plex, showing the critical active site relationships that account for binding of TFK*. TFK* CF3 (c) ) The molecule illustrated on the right was released in gase- ous form by terrorists in the Tokyo subway system in 1995, causing H₂C. many injuries. If sarin reacts like di-isopropyl-phospho-fluoridate (DIPF), what can you state about the basis of its action? CH-O-P-F H₁C CH3 Sarin

3. Acetylcholinesterase is a serine hydrolase enzyme im- portant in nerve signal transmission, hydrolyzing acetylcho- line, an ester molecule with a positively charged quaternary nitrogen group. The structure of the physiologically relevant substrate of this enzyme is shown on the right. The quater- H₂C nary nitrogen group serves to anchor the molecule in the active site Gly121 Oxy- anion hole Gly122 Ala204 Substrate ACh His447 Catalytic triad Ser203 Glu202 Glu334 Ser229 CH3 N+ CH3 CH3 The a Scale document down rine protease family, consisting of a catalytic triad Ser203- His447-Glu334 with Ser203 supplying the nucleophilic hydroxyl group and an oxyanion hole com- prised of peptide NH groups of Gly121, Gly122, and Ala204, illustrated in the diagram above, for which carbon (green), nitrogen (blue), and oxygen (red) atoms are shown while hydrogen atoms are white. The enzyme catalyzed reaction can be represented by the following scheme: (a)( k1 K2 E + S = ES K-1 K3 EYE + P where ES represents the noncovalent Michaelis complex and EY, a covalent acylenzyme intermediate. Starting with the diagrammatic representation of the ES complex given below, draw an arrow-pushing mechanism in the style of the chymotrypsin reaction (cf., p. 206. 8th edition), to show how the ES com- plex is converted into the EY intermediate. Indicate all hydrogen bonds with dashed lines, and label the enzyme residues involved with their name and sequence number. Question #3, continued: Gly. L -HN. རྒྱ་ Ser203 CR' His 447 NH ES Michaelis Complex C- 0644334 (b) ( Binding of the inhibitor trifluoroacetophenone (TFK) to acetylcholin- esterase is characterized by the kinetic constants k₁ = 2.8 x 108 M-1s-1 and k-1 = 1.8 x 10-5 s-1. What is the inhibitor binding constant and what interactions be- tween the enzyme and the inhibitor must occur to account for this high binding affinity? Supplement your answer with a schematic of the enzyme-inhibitor com- plex, showing the critical active site relationships that account for binding of TFK. TFK* CF3 (c) ) The molecule illustrated on the right was released in gase- ous form by terrorists in the Tokyo subway system in 1995, causing H₂C. many injuries. If sarin reacts like di-isopropyl-phospho-fluoridate (DIPF), what can you state about the basis of its action? CH-O-P-F H₁C CH3 Sarin

Biochemistry

6th Edition

ISBN:9781305577206

Author:Reginald H. Garrett, Charles M. Grisham

Publisher:Reginald H. Garrett, Charles M. Grisham

Chapter26: Synthesis And Degradation Of Nucleotides

Section: Chapter Questions

Problem 16P

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