Control of oxygen affinity of the heme by the globin. The oxygen affinities of vertebrate myoglobins and free hemoglobin subunits are of the order of p5O - 0.5-1.0 mm Hg. Physiological cofactors such as hydrogen and chloride ions, C02 and organic phosphates lower the oxygen affinity, but no vertebrate hemoglobin or synthetic iron porphyrin has been found whose oxygen affinity is raised significantly above that level. On the other hand, the oxygen affinity of the hemoglobin of the root nodules of legumes is 10 times higher and in Ascaris it is over a hundred times higher. This poses a chemical mystery which Perutz is trying to solve. Species adaptation in the hemoglobin molecule. Some animals' adaptation to their environment includes the respiratory functions of their haemoglobins. Did such molecular adaptation evolve gradually by the cumulative effect of many amino acid substitutions, or more abruptly, by a few substitutions in key positions, while most of the differences in amino acid sequence between the haemoglobins of different species are selectively neutral? Recombinant DNA technology together with X-ray crystallography now allows us to mimic molecular evolution in vitro in order to find answers to these questions. Drugs that lower the oxygen affinity. Drugs that lower the oxygen affinity would be useful to administer after shock, and to increase oxygen delivery to infarcted tissues and to tumours before irradiation. Perutz & Poyart's discovery that the antilipidemic drug bezafibrate lowers the oxygen affinity of hemoglobin has lid to the synthesis of a series of increasingly powerful compounds, but competition by serum albumin has prevented their application. Work to overcome this obstacle in collaboration with an American group is in progress. Hemoglobin as an oxygen sensor. Dr. Gilles-Gonzales has discovered a protein in rhizobium which is both a hemoglobin and an ATP-ase. It is an oxygen sensor that regulates the transcription of the genes for the nitrogen-fixing proteins. This hemoglobin may be a model for other sensor-regulated transcription factors, including the oxygen sensor that regulates synthesis of hematopoietin in the kidneys. Dr. Gilles-Gonzales and Perutz want to determine its structure in order to find out how it works.
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