2007 Fiscal Year Final Research Report Summary
Molecular Design of Artificial Oxygen Carrier Utilizing Myoglobin
| Project/Area Number |
18590094
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Drug development chemistry
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| Research Institution | Chiba University |
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Principal Investigator |
NEYA Saburo Chiba University, Graduate School of Pharmaceutical Sciences, Professor (10156169)
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| Project Period (FY) |
2006 – 2007
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| Keywords | artificial oxygen carrier / myoglobin / oxygen affinity control / corrphycene / ligand field / ligand binding constant |
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| Research Abstract |
Sufficient blood supply in medical service and disaster occasion is important. In the present research, we attempted the functional conversion of myoglobin, a biological oxygen reservoir to serve it as a novel oxygen carrier. Since myoglobin is a monomer while hemoglobin is tetrameric, the application of myoglobin as a artificial oxygen carrier could enhance the stability of the the products. We synthesized a new porphyrin isomer corrphycene and the iron complex. The iron corrphycene was coupled with apomyoglobin to create the semi-artificial myoglobin with the lowered oxygen affinity and increased oxygen carrying ability. The artificial prosthetic was found to be successfully incorporated into the protein pocket of apomyoglobin to afford the reconstituted protein as evidenced from several spectroscopic evidence. The oxygen affinity of the myoglobin was found to be P_50 = 6.7 mmHg, corresponding to a 1/10 oxygen affinity as compared with that of native myoglobin. The observation demons
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trates that the oxygen transport ability of the new myoglobin is 8 times larger than native myoglobin. When we introduced two ethoxycarbonyl (-CO_2C_2H_5) substituents into the corrphycene molecule, the oxygen transport ability of the myoglobin with P_50 = 37 mmHg was further increased to 21-fold. These observations demonstrate that myoglobin was successfully converted from oxygen storage molecules into an efficient oxygen carrier like hemoglobin. It is now evident that myoglobin is a promising candidate to develop the artificial oxygen carrier. When the ethoxycarbonyl substituents were attached to the bipyrrole moiety in corrphycene, the P_50 value of the reconstituted myoglobin decreased down to 300 mmHg. The result indicates that the oxygen transport of the third myoglobin became worse owing to the significant decrease oxygen affinity. The above observations, taken together, indicate that the oxygen affinity of myoglobin was be efficiently controlled with the alteration of the structure of the heme macrocycle and the introduction of the electron-withdrawing substituents. The present research provides the first concrete evidence to construct the artificial oxygen carrier based on myoglobin. Less
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