TITLE

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

AUTHOR(S)
Kluger, Ronald
PUB. DATE
March 2002
SOURCE
Canadian Journal of Chemistry;Mar2002, Vol. 80 Issue 3, p217
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
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'hémoglobine transporte l'oxygène à l'intérieur des cellules rouges, mais à l'extérieur elle ne fonctionne pas parce qu'elle n'est pas en mesure de libérer l'oxygène et, de plus, elle se dissocie en dimères qui forment la protéine tétramère. Les agents acylants anioniques bifonctionnels qui contiennent un pont structuralement rigide permettent d'introduire des liens de réticulation qui stabilisent l'hémoglobine et qui altèrent son affinité pour l'oxygène de façon à la rendre utilisable pour le transport d'oxygène à l'extérieur des cellules. L'oxyde nitrique se lie à l'hémoglobine et dans la circulation ce qui provoque des augmentations indésirables de la pression sanguine. Il a été rapporté que des collections d'hémoglobines de masses moléculaires plus élevées ne provoquent pas de vasoconstriction. Des réactifs avec deux paires de sites réactionnels liés par une jonction rigide permettent de raccorder et de réticuler deux hémoglobines. Les bis-tétramères qui en résultent ne donnent pas lieu à la coopération qui existe dans la protéine naturelle et ils se lient trop fortement à l'oxygène pour être utiles, mais ils ne peuvent donc pas se lier à l'oxyde nitrique. Une extension des raccordements pourrait permettre de résoudre ces problèmes. L'oxyde nitrique peut être obtenu à partir de groupes thionitrosyles que l'on retrouve dans l'hémoglobine des cellules rouges. Il est possible d'effectuer une nitrosilylation spécifique de l'hémoglobine réticulée. Ces espèces servent de sources circulantes d'oxyde nitrique et elles résultent d'un transfert d'électron interne.Mots clés : protéines, hémoglobine, réticulation, cellules rouges, possibilité de coopération, raccordement.[Traduit par la Rédaction]
ACCESSION #
10577117

 

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