title: Modulation of the oxygen affinity of cobalt-porphyrin by globin.
abstract: We have combined two extreme effects which influence the oxygen affinity to obtain a cobalt-based oxygen carrier with an affinity similar to that of human adult hemoglobin (HbA). The goal was to obtain an oxygen transporter with a lower oxidation rate. Exchange of the heme group (Fe-protoporphyrin IX) in Hb with a cobalt-porphyrin leads to a reduction in oxygen affinity by over a factor of 10, an oxygen affinity too low for use as a blood substitute. At the other extreme, certain globin sequences are known to provide a very high oxygen affinity; for example, Hb Ascaris displays an oxygen affinity 1000 times higher than HbA. We demonstrate here that these opposing effects can be additive, yielding an oxygen affinity similar to that of HbA, but with oxygen binding to a cobalt atom. We have tested the effect of substitution of cobalt-porphyrin for heme in normal HbA, sperm whale (SW) Mb (Mb), and high affinity globins for leghemoglobin, two trematode Hbs: Paramphistomum epiclitum (Pe) and Gastrothylax crumenifer (Gc). As for HbA or SW Mb, the transition from heme to cobalt-porphyrin in the trematode Hbs leads to a large decrease in the oxygen affinity, with oxygen partial pressures for half saturation (P(50)) of 5 and 25 mm Hg at 37 degrees C for cobalt-Pe and cobalt-Gc, respectively. A critical parameter for Hb-based blood substitutes is the autoxidation rate; while both metals oxidize to an inactive state, we observed a decrease in the oxidation rate of over an order of magnitude for cobalt versus iron, for similar oxygen affinities. The time constants for autoxidation at 37 degrees C were 250 and 100 h for Pe and Gc, respectively.
authors.affiliation: INSERM U473, 84 rue du Général Leclerc, 94276, Le Kremlin Bicêtre, France. marden@kb.inserm.fr
authors.forename: M C
authors.initials: MC
authors.lastname: Marden
authors.forename: L
authors.initials: L
authors.lastname: Kiger
authors.forename: C
authors.initials: C
authors.lastname: Poyart
authors.forename: A K
authors.initials: AK
authors.lastname: Rashid
authors.forename: J
authors.initials: J
authors.lastname: Kister
authors.forename: F
authors.initials: F
authors.lastname: Stetzkowski-Marden
authors.forename: G
authors.initials: G
authors.lastname: Caron
authors.forename: M
authors.initials: M
authors.lastname: Haque
authors.forename: L
authors.initials: L
authors.lastname: Moens
mesh_terms: D000818:Animals; D001802:Blood Substitutes / Q000378:metabolism*; D002248:Carbon Monoxide / Q000378:metabolism; D003035:Cobalt / Q000378:metabolism*; D005914:Globins / Q000378:metabolism*; D015801:Helminth Proteins / Q000378:metabolism; D006801:Humans; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism*; D010250:Paramphistomatidae; D011166:Porphyrins / Q000378:metabolism*; D014200:Trematoda
chemical_list: D001802:Blood Substitutes; D015801:Helminth Proteins; D011166:Porphyrins; D003035:Cobalt; D002248:Carbon Monoxide; D005914:Globins; D010100:Oxygen