2001 Lemieux Award Lecture Organic chemistry and hemoglobin: Benefits from controlled alteration

Kluger, Ronald
March 2002
Canadian Journal of Chemistry;Mar2002, Vol. 80 Issue 3, p217
Academic Journal
Hemoglobin carries oxygen in circulation within red cells but does not function outside the cells because it fails not only to release oxygen but also dissociates into dimers that make up the tetrameric protein. Bifunctional anionic acylating agents that contain a structurally rigid bridge introduce cross-links that stabilize hemoglobin and alter its oxygen affinity so that it could be used to carry oxygen outside cells. Nitric oxide binds to hemoglobin and in circulation this causes undesirable increases in blood pressure. It had been reported that higher weight collections of hemoglobin do not cause vasoconstriction. Reagents with two pairs of reaction sites joined by a rigid link connect and cross-link two hemoglobins. The resulting bis-tetramers lack the cooperativity of the native protein and bind oxygen too tightly to be useful; occupation by oxygen blocks the sites from nitric oxide. Nitric oxide may be delivered from thionitrosyl groups, which occur in hemoglobin in the red cell. Cross-linked hemoglobin can be specifically nitrosylated. These species can then serve as circulating sources of nitric oxide resulting from an internal electron transfer.Key words: proteins, hemoglobin, cross-link, red cells, cooperativity, connecting.Dans la circulation sanguine, l'h�moglobine transporte l'oxyg�ne � l'int�rieur des cellules rouges, mais � l'ext�rieur elle ne fonctionne pas parce qu'elle n'est pas en mesure de lib�rer l'oxyg�ne et, de plus, elle se dissocie en dim�res qui forment la prot�ine t�tram�re. Les agents acylants anioniques bifonctionnels qui contiennent un pont structuralement rigide permettent d'introduire des liens de r�ticulation qui stabilisent l'h�moglobine et qui alt�rent son affinit� pour l'oxyg�ne de fa�on � la rendre utilisable pour le transport d'oxyg�ne � l'ext�rieur des cellules. L'oxyde nitrique se lie � l'h�moglobine et dans la circulation ce qui provoque des augmentations ind�sirables de la pression sanguine. Il a �t� rapport� que des collections d'h�moglobines de masses mol�culaires plus �lev�es ne provoquent pas de vasoconstriction. Des r�actifs avec deux paires de sites r�actionnels li�s par une jonction rigide permettent de raccorder et de r�ticuler deux h�moglobines. Les bis-t�tram�res qui en r�sultent ne donnent pas lieu � la coop�ration qui existe dans la prot�ine naturelle et ils se lient trop fortement � l'oxyg�ne pour �tre utiles, mais ils ne peuvent donc pas se lier � l'oxyde nitrique. Une extension des raccordements pourrait permettre de r�soudre ces probl�mes. L'oxyde nitrique peut �tre obtenu � partir de groupes thionitrosyles que l'on retrouve dans l'h�moglobine des cellules rouges. Il est possible d'effectuer une nitrosilylation sp�cifique de l'h�moglobine r�ticul�e. Ces esp�ces servent de sources circulantes d'oxyde nitrique et elles r�sultent d'un transfert d'�lectron interne.Mots cl�s : prot�ines, h�moglobine, r�ticulation, cellules rouges, possibilit� de coop�ration, raccordement.[Traduit par la R�daction]


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