More Chemical Evidence for an Antibody Killing Mechanism.

By Jason Socrates Bardi

Last year Professor Richard A. Lerner, Associate Professor Paul Wentworth, Jr., and a team of investigators at The Scripps Research Institute (TSRI) reported that antibodies can themselves destroy bacteria, and that when they do they appear to produce the reactive gas ozone.

The ozone, which was never considered part of biology before, seems to be part of a previously unrecognized killing mechanism that would enhance the defensive role of antibodies by allowing them to subject pathogens to oxidation and participate directly in their killing. Previously, antibodies were believed only to signal an immune response.

Now the same team is reporting, in an article published online by the Proceedings of the National Academy of Sciences, that antibodies can chemically modify their bound antigens during the antibody-catalyzed water oxidation pathway. More specifically, they regioselectively hydroxylate benzoic acid-when it is bound within the antibody binding site. Furthermore, they found a hydroxylated tryptophan residue in the interfacial domain of one of the antibodies they looked at, which offered further evidence that this region of the antibody structure is where the process is taking place.

By showing that antibodies can chemically modify something to which they are bound and that this modification may be taking place where the antibody binds to antigen, they are providing further evidence for their mechanistic interpretation of how antibodies kill bacteria.

The latest study suggests that the antibodies may be producing a long-lived hydroxy radical (HO•) surrogate, the hydrotrioxy radical (HO3•), that diffuses along a channel from the interfacial region, between the constant and variable domains, to the combining site of the antibody molecule. When the hydroxyl radical goes through the channel, it can either react with the bacterial antigen or trigger a radical cascade on the surface of the bacterial membrane.
To read the article, "Evidence for the production of trioxygen species during antibody-catalyzed chemical modification of antigens" by Paul Wentworth, Jr., Anita D. Wentworth, Xueyong Zhu, Ian A. Wilson, Kim D. Janda, Albert Eschenmoser, and Richard A. Lerner, please see:

http://www.pnas.org/cgi/content/abstract/0437831100v1.

The AbOx pathway in human neutrophils: Antibodies generate both hydrogen peroxide and ozone during the water-oxidation pathway which are bactericidal in combination and which makes immunoglobulins the third enzyme in the microbicidal pathway of neutrophils, after the phagocyte oxidase (Phox) and myeloperoxidase (MPO). Inset is an electron micrograph of an E. coli bacterium killed by the antibody-catalyzed water-oxidation pathway. There is remarkable simile in the morphology of cell wall and membrane rupture to that of when bacteria are phagocytosed.

HME