Electron tunneling pathways and role of adenine in repair of cyclobutane pyrimidine dimer by DNA photolyase

J Am Chem Soc. 2012 May 16;134(19):8104-14. doi: 10.1021/ja2105009. Epub 2012 May 4.

Abstract

Electron tunneling pathways in enzymes are critical to their catalytic efficiency. Through electron tunneling, photolyase, a photoenzyme, splits UV-induced cyclobutane pyrimidine dimer into two normal bases. Here, we report our systematic characterization and analyses of photoinitiated three electron transfer processes and cyclobutane ring splitting by following the entire dynamical evolution during enzymatic repair with femtosecond resolution. We observed the complete dynamics of the reactants, all intermediates and final products, and determined their reaction time scales. Using (deoxy)uracil and thymine as dimer substrates, we unambiguously determined the electron tunneling pathways for the forward electron transfer to initiate repair and for the final electron return to restore the active cofactor and complete the catalytic photocycle. Significantly, we found that the adenine moiety of the unusual bent flavin cofactor is essential to mediating all electron-transfer dynamics through a superexchange mechanism, leading to a delicate balance of time scales. The cyclobutane ring splitting takes tens of picoseconds, while electron-transfer dynamics all occur on a longer time scale. The active-site structural integrity, unique electron tunneling pathways, and the critical role of adenine ensure the synergy of these elementary steps in this complex photorepair machinery to achieve maximum repair efficiency which is close to unity. Finally, we used the Marcus electron-transfer theory to evaluate all three electron-transfer processes and thus obtained their reaction driving forces (free energies), reorganization energies, and electronic coupling constants, concluding that the forward and futile back-electron transfer is in the normal region and that the final electron return of the catalytic cycle is in the inverted region.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine*
  • Biocatalysis
  • Catalytic Domain
  • DNA Repair* / radiation effects
  • Deoxyribodipyrimidine Photo-Lyase / chemistry*
  • Deoxyribodipyrimidine Photo-Lyase / metabolism*
  • Electron Transport / radiation effects
  • Escherichia coli / enzymology
  • Light
  • Models, Molecular
  • Pyrimidine Dimers / metabolism*

Substances

  • Pyrimidine Dimers
  • Deoxyribodipyrimidine Photo-Lyase
  • Adenine