Myoglobin as a model system for designing heme protein based blood substitutes.
The ligand binding properties and resistances to denaturation of >300 different site-directed mutants of sperm whale, pig, and human myoglobin have been examined over the past 15 years. This library of recombinant proteins has been used to derive chemical mechanisms for ligand binding and to examine the factors governing holo- and apoglobin stability. We have also examined the effects of mutagenesis on the dioxygenation of NO by MbO(2) to form NO(3)(-) and metMb. This reaction rapidly detoxifies NO and is a key physiological function of both myoglobins and hemoglobins. The mechanisms derived for O(2) binding and NO dioxygenation have been used to design safer, more efficient, and more stable heme protein-prototypes for use as O(2) delivery pharmaceuticals in transfusion therapy (i.e. blood substitutes). An interactive database is being developed (http://olsonnt1.bioc.rice.edu/web/myoglobinhome.asp) to allow rapid access to the ligand binding parameters, stability properties, and crystal structures of the entire set of recombinant myoglobins. The long-range goal is to use this library for developing general protein engineering principles and for designing individual heme proteins for specific pharmacological and industrial uses.
Dou
Yi
Y
Department of Biochemistry and Cell Biology, Rice University, Houston, TX 77005, USA.
Maillett
David H
DH
Eich
Raymund F
RF
Olson
John S
JS
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001802:Blood Substitutes / Q000138:chemical synthesis* / Q000494:pharmacology; D015195:Drug Design; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D006420:Hemeproteins / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D006454:Hemoglobins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009211:Myoglobin / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D009569:Nitric Oxide / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D015202:Protein Engineering / Q000379:methods; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013816:Thermodynamics; D014907:Whales
D001802:Blood Substitutes; D006420:Hemeproteins; D006454:Hemoglobins; D009211:Myoglobin; D011994:Recombinant Proteins; D009569:Nitric Oxide; D010100:Oxygen