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10.02 - Zhang - Enzyme Mechanism and Regulation

10.02 - Zhang - Enzyme Mechanism and Regulation - Enzyme...

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1 Dr. Zhang BSB Room 107 954-4728 [email protected] Enzyme Mechanism and Regulation !!!" $%&’(&)*+,- &./-,0,)*’01 2’( &0345& +,),-41*1 6" 78’+9 ,0: ;&47 <" =(’.*5*)4 > 7-’+,- +’0+&0)(,)*’07 ?" @(*&0),)*’0 &22&+)1 > ,-*A05&0) ’2 B’0:1 )’ 2,+*-*),)& +,),-41*1 C" !0:D+&: 2*) > E&.’9*0,1& F&0345& +’02’(51 )’ 1DB1)(,)&G H" !0:D+&: 1)(,*0 > 841’345& F1DB1)(,)& +’02’(51 )’ &0345&G I" $(,01*)*’0 1),)& 1),B*-*3,)*’0 F$JJG <" $(,01*)*’0 1),)& ,0,-’A1 ,(& &.+&--&0) &0345& *0%*B*)’(1 ?" I(DA :&1*A0 B,1&: ’0 $(,01*)*’0 J),)& ,0,-’A1 K" 6B345&1L ,0)*B’:*&1 ,A,*01) )(,01*)*’0 1),)& ,0,-’A1 %,M& &0345,)*+ ,+)*M*)4 !N" O0345,)*+ +,),-41*1 5&+%,0*151 6" 6+*:>B,1& +,),-41*1 C" H’M,-&0) +,),-41*1L *0)&(5&:*,)& P*)% +’M,-&0) B’0: B&)P&&0 O ,0: J H" Q&),- *’0 +,),-41*1 No enzyme
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2 With enzyme No enzyme Enzyme complementary to substrate Enzyme complementary to transition state
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3 Weak-bonding interactions provide a major driving force for enzymatic catalysis ln K RT G ! " # E + S ES P + E k 1 k -1 k 2 1 1 ] ][ [ ] [ ! " " k k S E ES K ] ][ [ ] [ ] ][ [ / 2 2 S E e k ES k S E k v RT G # ! " " " ] ][ [ / 2 S E e k v RT G # ! " 10-fold enhancement DDG =5.69 kJ/mol 1,000,000-fold enhancement DDG =34.25 kJ/mol Binding energy contributes to rate acceleration ] ][ [ ] [ S E K ES " RT G e K / # ! " Transition state theory Entropy Reduction <" =(’.*5*)4 > 7-’+,- +’0+&0)(,)*’07 ?" @(*&0),)*’0 &22&+)1 > ,-*A05&0) ’2 B’0:1 )’ 2,+*-*),)& +,),-41*1 Unimolecular reaction
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4 Rate enhancement by constraining molecular motion Specific acid catalysis General acid catalysis Acid- base catalysis Amino acids in general acid-base catalysis Chymotrypsin cleaves proteins on the carboxyl side of aromatic or large hydrophobic amino acids
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5 Only one of the 28 serines in chymotrypsin reacts with DIPF The chymotrypsin active site Side chain of reactive Ser 195 is hydrogen bonded to His 57 , which is likewise bonded to Asp 102 The Catalytic Triad Chymotrypsin Mechanism
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6 Substrate is bound at the active site Step 1: Binding NH groups of Gly 193 and Ser 195 stabilize the negatively charged tetrahydral intermediate in the oxyanion hole His 57 acts as a general base to deprotonate Ser 195 Step 2: Transition state stabilization Alkoxide ion acts as a powerful nucleophile Negatively charged Asp 102 stabilizes positively charged His Step 3: Covalent catalysis His 57 now acts as a general acid and donates a proton to the first product, the N- terminal peptide A covalent Acyl enzyme intermediate is formed Step 4: General Acid Catalysis
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7 The second substrate (water) binds to the active site Step 5: Binding His 57 accepts a proton from water, OH - attacks acyl-enzyme intermediate Step 6: General Base Catalysis Tetrahydral intermediate breaks down to release the c- terminal peptide Step 7: General Acid Catalysis Step 8: Product release
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8 Chymotrypsin Mechanism Oxyanion Hole Overlay of the structures of cymotrypsin (red) and
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