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Engineering tyrosine electron transfer pathways decreases oxidative toxicity in hemoglobin: implications for blood substitute design.
Silkstone, Gary G A; Silkstone, Rebecca S; Wilson, Michael T; Simons, Michelle; Bülow, Leif; Kallberg, Kristian; Ratanasopa, Khuanpiroon; Ronda, Luca; Mozzarelli, Andrea; Reeder, Brandon J; Cooper, Chris E.
Afiliación
  • Silkstone GG; School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, Essex CO4 3SQ, U.K.
  • Silkstone RS; School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, Essex CO4 3SQ, U.K.
  • Wilson MT; School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, Essex CO4 3SQ, U.K.
  • Simons M; School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, Essex CO4 3SQ, U.K.
  • Bülow L; Department of Pure and Applied Biochemistry, Lund University, Box 124, 221 00 Lund, Sweden.
  • Kallberg K; Department of Pure and Applied Biochemistry, Lund University, Box 124, 221 00 Lund, Sweden.
  • Ratanasopa K; Department of Pure and Applied Biochemistry, Lund University, Box 124, 221 00 Lund, Sweden.
  • Ronda L; Department of Neurosciences, University of Parma, Parma, Italy.
  • Mozzarelli A; Department of Pharmacy, University of Parma, Parma, Italy Institute of Biophysics, National Research Council (CNR), Pisa, Italy.
  • Reeder BJ; School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, Essex CO4 3SQ, U.K.
  • Cooper CE; School of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, Essex CO4 3SQ, U.K.
Biochem J ; 473(19): 3371-83, 2016 10 01.
Article en En | MEDLINE | ID: mdl-27470146
Hemoglobin (Hb)-based oxygen carriers (HBOC) have been engineered to replace or augment the oxygen-carrying capacity of erythrocytes. However, clinical results have generally been disappointing due to adverse side effects linked to intrinsic heme-mediated oxidative toxicity and nitric oxide (NO) scavenging. Redox-active tyrosine residues can facilitate electron transfer between endogenous antioxidants and oxidative ferryl heme species. A suitable residue is present in the α-subunit (Y42) of Hb, but absent from the homologous position in the ß-subunit (F41). We therefore replaced this residue with a tyrosine (ßF41Y, Hb Mequon). The ßF41Y mutation had no effect on the intrinsic rate of lipid peroxidation as measured by conjugated diene and singlet oxygen formation following the addition of ferric(met) Hb to liposomes. However, ßF41Y significantly decreased these rates in the presence of physiological levels of ascorbate. Additionally, heme damage in the ß-subunit following the addition of the lipid peroxide hydroperoxyoctadecadieoic acid was five-fold slower in ßF41Y. NO bioavailability was enhanced in ßF41Y by a combination of a 20% decrease in NO dioxygenase activity and a doubling of the rate of nitrite reductase activity. The intrinsic rate of heme loss from methemoglobin was doubled in the ß-subunit, but unchanged in the α-subunit. We conclude that the addition of a redox-active tyrosine mutation in Hb able to transfer electrons from plasma antioxidants decreases heme-mediated oxidative reactivity and enhances NO bioavailability. This class of mutations has the potential to decrease adverse side effects as one component of a HBOC product.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tirosina / Sustitutos Sanguíneos / Hemoglobinas Idioma: En Revista: Biochem J Año: 2016 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Tirosina / Sustitutos Sanguíneos / Hemoglobinas Idioma: En Revista: Biochem J Año: 2016 Tipo del documento: Article Pais de publicación: Reino Unido