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Danishefsky Group Synthesizes Protein Important in Red Blood Cell Production

Researchers in the group of Centennial Professor of Chemistry, Samuel Danishefsky, have synthesized what is arguably the largest and most complex biological molecule ever assembled by the methods of organic chemistry.   The molecule is a version of erythropoietin (EPO), a protein critical to the production of red blood cells in mammals and consisting of a folded chain of 166 amino acids with carbohydrates attached at well-defined sites along the chain.

Professor Danishefsky’s group includes researchers at Columbia and in the Molecular Pharmacology and Chemistry Program at Sloan-Kettering Institute, where Professor Danishefsky is the incumbent of a Eugene W. Kettering Chair.   His group’s work on this project was assisted by enabling advances made by Dr. Xianping Tan of Professor Virginia Cornish’s group at Columbia and by Dr. Gong Chen in the Columbia group of Professor Dalibor Sames.

Naturally occurring erythropoietin is actually a highly complex family of molecules, all of which have the same basic chain structure and which differ only in the nature of the attached carbohydrates.   The Danishefsky synthesis produces the exact amino acid chain with truncated forms of the carbohydrates attached at the correct locations and with the correct bonding mechanisms.   In vitro experiments demonstrate that the synthesized EPO is capable of stimulating the production of red blood cells. 

The Danishefsky effort represents the first time a homogenous form of native EPO containing all of the carbohydrates has been obtained. The ability to create a unique variant of EPO, rather than the mix of EPO structures that occur naturally, is a breakthrough that points to eventual progress at systematically isolating, testing, and understanding the behavior of each variant.     It also provides a path to address a general question that has potential therapeutic significance  -- namely, why does nature produce mixtures of proteins with a unique, underlying structure but which vary only in the nature of a small number of attached carbohydrates?

The new synthesis, which was originally reported online in Angewandte Chemie (1), has subsequently been covered in Science (2), the Royal Society of Chemistry's Chemistry World (3), and C & E News (4) and it will also be reported in Nature.  The work is recognized asa breakthrough not only for its success at synthesizing EPO but also for the new techniques developed by the Danishefsky group for fabricating the segments of the EPO structure, for linking them together, and for bonding the carbohydrates at the correct locations.   The work represents an effort by the group that started in 2002.

(1) Angew. Chem. Int. Ed. 51, 1 -10, 2012

(2) Science 338, 28, Oct. 2012

(3) RSC Chemistry World, Oct. 10, 2012

(4) C & E News 90, 41, 11, Oct 8, 2012