In the current issue of the journal Science, the team demonstrates that antibodies can catalyze the formation of hydrogen peroxide from singlet oxygen.
All antibodies have the ability to do this," says Professors Paul Wentworth Jr., Ph.D. and Kim Janda, Ph.D., two of the lead authors on the paper. "Singlet oxygen is not something you want around."
Singlet oxygen is an electronically excited form of oxygen that forms spontaneously during normal metabolic processes or when oxygen is subjected to visible or ultraviolet light in the presence of a sensitizer. Singlet oxygen is highly reactive, making it potentially dangerous to an organism. Throughout evolution, animals have developed various mechanisms for removing singlet oxygen in order to survive. Also called immunoglobins, antibodies are produced by the immune system's B cells. The body has a large pool of B cells that recognize a wide range of foreign proteins, and after a pathogen enters the bloodstream, B cells produce specific antibodies that circulate through the blood and track down, bind to, and help eliminate the viral or bacterial invaders.
In the report, the team speculates that before this antibody-mediated immune response evolved in vertebrates hundreds of millions of years ago, an ancient form of antibodies may have existed--molecules whose role was to catalyze singlet oxygen destruction.
"Antibodies could have played a role as ancient proteins whose function was to remove singlet oxygen," says Janda.
The ability to convert oxygen into hydrogen peroxide may also be part of a previously unrecognized killing mechanism that would enhance the defensive role of antibodies by allowing them to subject pathogens to hydrogen peroxide and participate directly in their killing.
Lerner and Wentworth comment, "This heretofore unknown and intrinsic capacity of antibodies opens up exciting possibilities for new antibody-mediated therapies for conditions ranging from bacterial and viral infection to cancer. Furthermore, the ability of antibodies to generate toxic compounds may be linked to a number of autoimmune disease states, such as lupus."
Based on their examination of antibody and T-cell receptor x-ray crystal structures, the authors propose a conserved site within the antibody structure where they believe the singlet oxygen binds and where the catalytic process is initiated.
Another interesting finding is that the antibodies carry the reaction through an unusual intermediate called dihydrogen trioxide that is formed from the addition of water and oxygen. Dihydrogen trioxide has never before been observed in biological systems. "Although its presence has been a source of considerable speculation," says Wentworth.
The research article, "Antibodies Catalyze the Oxidation of Water" is authored by Paul Wentworth, Jr., Lyn H. Jones, Anita D. Wentworth, Xueyong Zhu, Nicholas A. Larsen, Ian A. Wilson, Xin Xu, William A. Goddard III, Kim D. Janda, Albert Eschenmoser, and Richard A. Lerner, and appears in the September 7, 2001 issue of the journal Science.
The research was funded in part by the National Institutes of Health and The Skaggs Institute for Chemical Biology.