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Entry M0031    2.1.1.45    thymidylate synthase

Previous Step

Step 06

The negatively charged nitrogen of dihydrofolate eliminates a hydride ion, which adds to the CH2=C group of the covalently attached methyl-dUMP, causing the elimination of Cys198.

GIF of Reaction Step M0031.stg06


Comment: There are two alternative mechanisms proposed for this hydride transfer step. The first is a single step transfer in which the Trp82 stabilises a positively charged trsnaition state. The second is that the hydride transfer may occur by two single-electron transfers with Trp82 stabilising the radical cation intermediate through long-range electrostatic effects. The precise positioning of H-C6 over the site of htydride transfer suggests that the singe step (shown here) is likely [5].



Mechanisms

Unimolecular Elimination by the Conjugate Base
Hydride Transfer
Bimolecular Nucleophilic Substitution

Mechanism Components

Bond Cleavage
Bond Formation
Bond Order Change
Overall Product Formed
Intermediate Terminated
Intermediate Collapse
Enzyme-Substrate Bond Cleavage
Enzyme Regenerated

Amino acids involved in the reaction step.

Amino Acid Location of Function Activity Function
Asp221 Side Chain spectator Hydrogen Bond Acceptor
Steric Role
Arg218 Side Chain spectator Not Active
Cys198 Side Chain reactant Nucleofuge
Tyr146 Side Chain spectator Hydrogen Bond Donor
Glu60 Side Chain spectator Hydrogen Bond Donor
Trp82 Side Chain spectator Hydrogen Bond Donor
van der Waals interaction
Electrostatic Stabiliser

Reactive Centre

Bonds Formed Bonds Cleaved Bonds Changed in Order Atom Types Involved
C-H
C-H
C-S
The C-C bond changes from a single to double bond
The C-N bond changes from a single to double bond
The C-C bond changes from a double to single bond
C
H
N
S

View similar reactions in MACiE.


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