Thymine Photodimerization: An Organic Chemist’s View

DA

In the Diels-Alder Reaction, a landmark reaction known to any organic chemistry student, a conjugated diene can react with a compound containing a carbon-carbon double bond, dubbed the “dienophile” (and rightfully so!), with relative ease to form a six-membered, unsaturated ring.  This reaction is a [4+2] cycloaddition because of the 6 pi electrons that form the aromatic transition state, four pi electrons coming from the conjugated diene and two from the dienophile.

DAMO

The Diels-Alder (DA) reaction is part of a class of reactions called pericyclic reactions. These reactions are described by a theory called the conservation of orbital symmetry. This theory dictates that pericyclic reactions occur as a result of the overlap of in-phase HOMO (highest-occupied-molecular orbital)and LUMO (lowest-occupied-molecular orbital) orbitals. In other words, they must both of symmetric or both be antisymmetric. The figure below shows that regardless of which pair of HOMO or LUMO we choose, the overlap will be in-phase. Thus, this reaction proceeds with ease.

Intriguingly, dimerization of consecutive thymines, or any other pyrimidines for that matter, in a strand of DNA or RNA can form a four membered ring via a mechanism very similar to the Diels-Alder! Such reactions are of great biological interest because of the consequences these molecular lesions can bring about. For one, fidelity in DNA replication can be compromised. Mutation rates can rise, and we’ve all been told that mutations can compromise protein function and even lead to cancer. It is therefore of great benefit to study such reactions and the cell’s subsequent response.

Let us first inspect the reactants and products of this dimerization reaction. Click on the picture to get a closer view.

 

Thymine

 

We see that 2 pi bonds are broken and 2 sigma bonds are formed. What is distinctly different from DA is the necessity of UV light for this reaction to proceed. (So I guess there is truth to the “Too much sun exposure can give you skin cancer” statement!) The elephant in the room then becomes “what role does UV light play in this reaction?” Let’s do some detective work: this reaction seems to be a pericyclic reaction. It must then be described by the conservation of orbital symmetry, but this seems implausible as the HOMO of one thymine (focusing on the carbon-carbon double bond) is the opposite symmetry of the LUMO of the other thymine. (See first part of figure below). Also, we know that UV light can excite electrons to orbitals of higher energies. Alas, in doing so, the HOMO of one thymine and the LUMO of the other thymine are both antisymmetric (see second part of figure below), and thus this pericyclic [2+2] cycloaddition reaction can occur. Click on the picture below to get a closer view.

2+2

 

How do cells deal with this unfavorable reaction? Cells employ a collection of proteins to remove and rewrite DNA or reverse the cycloaddition. In the first option, DNA nucleases can excise the damaged segment of DNA and then use polymerase and ligase to rewrite and glue the DNA. In the second, more selective option, the cell uses an enzyme called photolyase. This enzyme breaks the cyclobutane bridge, utilizing visible light energy!

As I was perusing nearby stores for sunscreen products for protection from the intense Miami sun, I came across an interesting brand named Priana Skin Care Products. I was surprised to find the enzyme Photolyase listed under the ingredients catalog. Subsequent research informed me that photolyase was harvested from engineered sea plankton and delivered trans-dermally using liposomes! Props to this company for their research.

 

-KU

 

 

Sources:

 

http://www.pnas.org/content/108/23/9402

 

http://www.sciencemag.org/content/153/3734/379

 

http://theoncologist.alphamedpress.org/content/6/3/298

 

http://priana.com/store/

Bruice, P. (2010). Organic chemistry. (6th ed.). Prentice Hall.

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