Journal
ORGANIC & BIOMOLECULAR CHEMISTRY
Volume 20, Issue 41, Pages 8083-8091Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/d2ob01372j
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Funding
- Natural Sciences and Engineering Research Council of Canada (NSERC) [RGPIN-2020-04113]
- Cette recherche a ete financee par le Conseil de recherches en sciences naturelles et en genie du Canada (CRSNG) [RGPIN-2020-04113]
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Chemical cross-linking of human adult hemoglobin prevents dissociation and enables it to be an acellular oxygen carrier, but may lead to hypertension. By specific chemical reactions, bis-tetramers can be formed to block the interaction with nitric oxide.
Chemical cross-linking of human adult hemoglobin (Hb) prevents dissociation of the tetrameric (alpha beta)(2) protein into its constituent non-functional alpha beta dimers when present outside red cells, providing the possibility of being an acellular oxygen carrier in circulation. However, studies of cross-linked Hb (xlHb) in circulation established effects consistent with scavenging of endogenous nitric oxide, leading to hypertension. Bis-tetramers, composed of coupled Hb tetramers, are sufficiently large to avoid penetration of endothelia, thereby blocking access to endogenous nitric oxide. Cu(i)-catalyzed azide-alkyne cycloaddition (CuAAC) joins two azide-functionalized xlHbs to each end of a bis-alkyne to form bis-tetramers. The process critically depends on formation of a cross-link between lysyl amino groups of the beta-subunits while avoiding reactions with amino groups in the alpha-subunits. Highly selective acetylation of alpha-subunit amino groups with methyl acetyl phosphate (MAP) effectively directs subsequent cross-linking to the beta-subunits. This outcome leads to efficient production of hemoglobin bis-tetramers by CuAAC.
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