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Engineering tyrosin...
Engineering tyrosine residues into hemoglobin enhances heme reduction, decreases oxidative stress and increases vascular retention of a hemoglobin based blood substitute
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- Cooper, Chris E. (författare)
- University of Essex
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- Silkstone, Gary G.A. (författare)
- University of Essex
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- Simons, Michelle (författare)
- University of Essex
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- Rajagopal, Badri (författare)
- University of Essex
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- Syrett, Natalie (författare)
- University of Essex
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- Shaik, Thoufieq (författare)
- University of Essex
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- Gretton, Svetlana (författare)
- University of Essex
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- Welbourn, Elizabeth (författare)
- University of Essex
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- Bülow, Leif (författare)
- Lund University,Lunds universitet,Tillämpad biokemi,Centrum för tillämpade biovetenskaper,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Pure and Applied Biochemistry,Center for Applied Life Sciences,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH
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- Eriksson, Nélida Leiva (författare)
- Lund University,Lunds universitet,Tillämpad biokemi,Centrum för tillämpade biovetenskaper,Kemiska institutionen,Institutioner vid LTH,Lunds Tekniska Högskola,Pure and Applied Biochemistry,Center for Applied Life Sciences,Department of Chemistry,Departments at LTH,Faculty of Engineering, LTH
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- Ronda, Luca (författare)
- University of Parma
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- Mozzarelli, Andrea (författare)
- CNR Institute of Biophysics (IBF),University of Parma
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- Eke, Andras (författare)
- Semmelweis University
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- Mathe, Domokos (författare)
- Semmelweis University
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- Reeder, Brandon J. (författare)
- University of Essex
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(creator_code:org_t)
- Elsevier BV, 2019
- 2019
- Engelska 13 s.
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Ingår i: Free Radical Biology and Medicine. - : Elsevier BV. - 0891-5849. ; 134, s. 106-118
- Relaterad länk:
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http://dx.doi.org/10... (free)
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https://doi.org/10.1...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Hemoglobin (Hb)-based oxygen carriers (HBOC) are modified extracellular proteins, designed to replace or augment the oxygen-carrying capacity of erythrocytes. However, clinical results have generally been disappointing due to adverse side effects, in part linked to the intrinsic oxidative toxicity of Hb. Previously a redox-active tyrosine residue was engineered into the Hb β subunit (βF41Y) to facilitate electron transfer between endogenous antioxidants such as ascorbate and the oxidative ferryl heme species, converting the highly oxidizing ferryl species into the less reactive ferric (met) form. We inserted different single tyrosine mutations into the α and β subunits of Hb to determine if this effect of βF41Y was unique. Every mutation that was inserted within electron transfer range of the protein surface and the heme increased the rate of ferryl reduction. However, surprisingly, three of the mutations (βT84Y, αL91Y and βF85Y) also increased the rate of ascorbate reduction of ferric(met) Hb to ferrous(oxy) Hb. The rate enhancement was most evident at ascorbate concentrations equivalent to that found in plasma (< 100 μM), suggesting that it might be of benefit in decreasing oxidative stress in vivo. The most promising mutant (βT84Y) was stable with no increase in autoxidation or heme loss. A decrease in membrane damage following Hb addition to HEK cells correlated with the ability of βT84Y to maintain the protein in its oxygenated form. When PEGylated and injected into mice, βT84Y was shown to have an increased vascular half time compared to wild type PEGylated Hb. βT84Y represents a new class of mutations with the ability to enhance reduction of both ferryl and ferric Hb, and thus has potential to decrease adverse side effects as one component of a final HBOC product.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
Nyckelord
- Blood substitute
- Electron transfer
- HBOC
- Hemoglobin
- Oxidative stress
- PEGylation
Publikations- och innehållstyp
- art (ämneskategori)
- ref (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Cooper, Chris E.
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Silkstone, Gary ...
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Simons, Michelle
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Rajagopal, Badri
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Syrett, Natalie
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Shaik, Thoufieq
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visa fler...
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Gretton, Svetlan ...
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Welbourn, Elizab ...
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Bülow, Leif
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Eriksson, Nélida ...
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Ronda, Luca
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Mozzarelli, Andr ...
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Eke, Andras
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Mathe, Domokos
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Reeder, Brandon ...
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visa färre...
- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Medicinska och f ...
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och Läkemedelskemi
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Hematologi
- Artiklar i publikationen
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Free Radical Bio ...
- Av lärosätet
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Lunds universitet