Dr. Glaser's "Chemistry is in the News"
To Accompany Bruice, Organic Chemistry, 3/e.
Chapter 28. Pericyclic Reactions.
Editorial Comments
"Skin cancer is the most common cancer in the US, affecting some 600,000 white Americans every year," (e.g. about 1 in 500) is the first sentence of the Skin Cancer pages of the Northeast Dermatology Associates. Many facts also can be found on the home pages of the Skincancer Research Foundation.
Most skin cancers are caused by UV damage to the skin as the result of prolonged exposure to sun light. The sun light causes a photoreaction between neighboring thymine molecules to form thymine dimers. A similar [2+2] pericyclic reaction also can occur for uracil and lead to uracil dimer. Evolution has taken care of the problem in part in that a repair mechanism exists that can reverse the dimerization reaction. This DNA repair mechanism also is a photochemical process and involves the enzyme photolyase and the coenzyme FAD. Serious problems start when the repair process cannot keep up with the rate of damage.
Photolyase helps to repair UV damage to DNA by splitting the cyclobutane ring of the thymine dimers. The E. coli photolyase contains the co-factors FAD and the pterin derivative 5,10-metheny-6-hydrofolic acid (MHF). MHF serves to harvest UV light and transfer its energy to the catalytic cofactor, FAD. FAD and FADH2 are redox coenzymes much like the pair NAD+ ands NADH. Both pairs of redox coenzymes add two H-atoms but they do it in different ways. FAD adds two H-radicals to turn into FADH2 while NAD+ adds a hydride to form NADH and leaves a proton.
In 1995, the first crystal structure of photolyase was determined and reported in Science. (1) Park, H.-W., Kim, S.-T., Sancar, A., and Deisenhofer, J. "Crystal Structure of DNA Photolyase from Escherichia coli". Science 1995, 268, 1866-1872. (2) See also Hearst, P. E. "The Structure of Photolyase: Using Photon Energy for DNA Repair". Science 1995, 268, 1858-1859. The X-ray structure shows the structural arrangements between MTHF, FAD, and the thymine dimer binding site and this knowledge now allows for a more detailed examination of the mechanism. There is evidence that the ring opening reaction might occur in the radical cation of the dimer. A study of such a recation path for the ring opening can be found in the first volume (1997) of the Internet Journal of Science - Biological Chemistry. Take a look at the article by Wiest and Largoza.
Questions
Question 1:
What types of skin cancers are there? How frequent are the various types?
How curable are these types of skin cancer?
Answer 1:
Read the Skin
Cancer pages of the Northeast Dermatology Associates to learn about
basal cell carcinoma, squamous cell carcinoma, and melanoma (carcinoma of
the melanine containing colored cells). The skin cancers differ in the
types of skin cells. All skin cancers are highly curable. Only melanoma
is a killer but again only for a small percentage of patients.
Question 2:
Explain how sun light is responsible for the chemical carcinogenesis that
leads to skin cancers. What are "thymine dimers" and how are they
formed? [Hint: View the structures of thymine
and thymine dimer
in the Visualization Center accompanying Chapter
28.
Answer 2:
Sun light can cause a [2+2] cycloaddition between two neighboring thymine
molecules in a common strand of DNA. See the Visualization Center accompanying Chapter
28 for the structures of thymine and thymine dimer.
Question 3:
What enzyme helps to repair UV photodamage to DNA? By what kind of
mechanism does the "cycloreversion" proceed?
Answer 3:
View the structure of photolyase in the
Visualization Center accompanying Chapter
28, read the editorial comments and read the article cited there.
Question 4:
According to the article, what types of treatments exist for skin cancer?
Answer 4:
Surgery. Chemotherapy (DTIC). Activation of the immune system using
interleukin-2. Boosting the immune system by way of vaccination.