Journal article
Five-coordinate H64Q neuroglobin as a ligand-trap antidote for carbon monoxide poisoning
Science translational medicine, Vol.8(368), pp.368ra173-368ra173
12/07/2016
DOI: 10.1126/scitranslmed.aah6571
PMCID: PMC5206801
PMID: 27928027
Abstract
Carbon monoxide (CO) is a leading cause of poisoning deaths worldwide, with no available antidotal therapy. We introduce a potential treatment paradigm for CO poisoning, based on near-irreversible binding of CO by an engineered human neuroglobin (Ngb). Ngb is a six-coordinate hemoprotein, with the heme iron coordinated by two histidine residues. We mutated the distal histidine to glutamine (H64Q) and substituted three surface cysteines with less reactive amino acids to form a five-coordinate heme protein (Ngb-H64Q-CCC). This molecule exhibited an unusually high affinity for gaseous ligands, with a P
(partial pressure of O
at which hemoglobin is half-saturated) value for oxygen of 0.015 mmHg. Ngb-H64Q-CCC bound CO about 500 times more strongly than did hemoglobin. Incubation of Ngb-H64Q-CCC with 100% CO-saturated hemoglobin, either cell-free or encapsulated in human red blood cells, reduced the half-life of carboxyhemoglobin to 0.11 and 0.41 min, respectively, from ≥200 min when the hemoglobin or red blood cells were exposed only to air. Infusion of Ngb-H64Q-CCC to CO-poisoned mice enhanced CO removal from red blood cells, restored heart rate and blood pressure, increased survival, and was followed by rapid renal elimination of CO-bound Ngb-H64Q-CCC. Heme-based scavenger molecules with very high CO binding affinity, such as our mutant five-coordinate Ngb, are potential antidotes for CO poisoning by virtue of their ability to bind and eliminate CO.
Details
- Title: Subtitle
- Five-coordinate H64Q neuroglobin as a ligand-trap antidote for carbon monoxide poisoning
- Creators
- Ivan Azarov - University of PittsburghLing Wang - University of PittsburghJason J Rose - University of PittsburghQinzi Xu - University of PittsburghXueyin N Huang - University of PittsburghAndrea Belanger - Wake Forest UniversityYing Wang - University of Pittsburgh Medical CenterLanping Guo - University of Pittsburgh Medical CenterChen Liu - Wake Forest UniversityKamil B Ucer - Wake Forest UniversityCharles F McTiernan - University of PittsburghChristopher P O'Donnell - University of PittsburghSruti Shiva - University of PittsburghJesús Tejero - University of PittsburghDaniel B Kim-Shapiro - Wake Forest UniversityMark T Gladwin - University of Pittsburgh
- Resource Type
- Journal article
- Publication Details
- Science translational medicine, Vol.8(368), pp.368ra173-368ra173
- DOI
- 10.1126/scitranslmed.aah6571
- PMID
- 27928027
- PMCID
- PMC5206801
- NLM abbreviation
- Sci Transl Med
- ISSN
- 1946-6234
- eISSN
- 1946-6242
- Grant note
- T32 HL110849 / NHLBI NIH HHS F32 HL132418 / NHLBI NIH HHS R01 HL125886 / NHLBI NIH HHS R01 HL111706 / NHLBI NIH HHS R01 HL098032 / NHLBI NIH HHS T32 HL007563 / NHLBI NIH HHS P01 HL103455 / NHLBI NIH HHS R37 HL058091 / NHLBI NIH HHS R01 GM113816 / NIGMS NIH HHS R21 ES027390 / NIEHS NIH HHS R01 HL058091 / NHLBI NIH HHS
- Language
- English
- Date published
- 12/07/2016
- Academic Unit
- Orthopedics and Rehabilitation
- Record Identifier
- 9984304690002771
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