How does fluorouracil inhibit thymidylate synthase?

I'm curious to know how just by adding a fluorine atom to uracil (to form 5-fluorouracil) permanently inhibits the enzyme thymidylate synthase when they bind together. This molecule is widely used as an antimetabolite in chemotherapy as it stops the synthesis of thymine.


             
                  
                    
             
       ![5-fluorouracil](https://i.stack.imgur.com/Dq9bK.png)


What changes undergoes the enzyme-inhibitor compound so it is permanently bonded to the fluorouracil? Probably the chemistry is too complicated to be explained in this Q&A format, if that is the case, references like books or papers would be great.




The inhibition comes about because:


1. Uracil and $5$-fluorouracil are sufficiently similar that both moieties have a strong binding affinity for the active site of thymidylate synthase.
2. The presence of the fluorine prevents $5$-methylation of the uracil core by a folate cofactor, which otherwise would turn it into a thymine moiety.
3. This inability of the enzyme to convert the $5$-fluorouracil moiety into a thymine moiety (which has a much lower affinity for the active site) means that the enzyme has no way to reject the $5$-fluorouracil or the methylating folate species, once bound.


The particulars of this interaction are nicely spelled out in Mishanina et al.$^\dagger$, conveniently available in [preprint](http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3315608/):



> 
> [5-fluorodeoxyuridylate] reacts [as normal] with the active site cysteine and undergoes condensation with [N,N-methylene-tetrahydrofolate] but prevents proton abstraction and elimination of the tetrahydrofolate [product], as a consequence stalling the reaction at the covalent ternary complex [of enzyme, inhibitor, and folate species].
> 
> 
> 


Scheme 4A from the preprint linked above illustrates well the specifics of the chemistry. (I refrain from reproducing it here due to uncertainty regarding its copyright/license status.)


As well, Figure 2 from the [Mechanism Description](https://en.wikipedia.org/wiki/Thymidylate_synthase#Mechanism_Description) section of the Wikipedia page on thymidylate synthase shows very nicely the enzyme interactions with the normal deoxyuridylate substrate (click image for larger version):


$\hspace{20pt}$ [![dUMP in thymidylate synthase active site](https://i.stack.imgur.com/FBC8Lm.png)](https://i.stack.imgur.com/FBC8L.png)  

*Image by CJerc (Own work) [CC BY-SA 3.0 (<http://creativecommons.org/licenses/by-sa/3.0> )], via [Wikimedia Commons](https://commons.wikimedia.org/wiki/File%3AActive_site_of_Thymidylate_Synthase.png)*


$^\dagger$ Mishanina et al. *Bioorganic Chemistry* **43**: 37 (2012). [doi:10.1016/j.bioorg.2011.11.005](http://dx.doi.org/10.1016/j.bioorg.2011.11.005)


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