dc.contributor.authorYeo, Tsin W.
dc.contributor.authorLampah, Daniel A.
dc.contributor.authorKenangalem, Enny
dc.contributor.authorTjitra, Emiliana
dc.contributor.authorPrice, Ric N.
dc.contributor.authorWeinberg, J. Brice
dc.contributor.authorHyland, Keith
dc.contributor.authorGranger, Donald L.
dc.contributor.authorAnstey, Nicholas M.
dc.contributor.editorKim, Kami*
dc.date.accessioned2015-04-22T07:58:46Z
dc.date.available2015-04-22T07:58:46Z
dc.date.copyright2015en_US
dc.date.issued2015
dc.identifier.citationYeo, T. W., Lampah, D. A., Kenangalem, E., Tjitra, E., Price, R. N., Weinberg, J. B., et al. (2015). Impaired systemic tetrahydrobiopterin bioavailability and increased dihydrobiopterin in adult falciparum malaria : association with disease severity, impaired microvascular function and increased endothelial activation. PLOS pathogens, 11(3), e1004667-.en_US
dc.identifier.issn1553-7374en_US
dc.identifier.urihttp://hdl.handle.net/10220/25446
dc.description.abstractTetrahydrobiopterin (BH4) is a co-factor required for catalytic activity of nitric oxide synthase (NOS) and amino acid-monooxygenases, including phenylalanine hydroxylase. BH4 is unstable: during oxidative stress it is non-enzymatically oxidized to dihydrobiopterin (BH2), which inhibits NOS. Depending on BH4 availability, NOS oscillates between NO synthase and NADPH oxidase: as the BH4/BH2 ratio decreases, NO production falls and is replaced by superoxide. In African children and Asian adults with severe malaria, NO bioavailability decreases and plasma phenylalanine increases, together suggesting possible BH4 deficiency. The primary three biopterin metabolites (BH4, BH2 and B0 [biopterin]) and their association with disease severity have not been assessed in falciparum malaria. We measured pterin metabolites in urine of adults with severe falciparum malaria (SM; n=12), moderately-severe malaria (MSM, n=17), severe sepsis (SS; n=5) and healthy subjects (HC; n=20) as controls. In SM, urinary BH4 was decreased (median 0.16 ¼mol/mmol creatinine) compared to MSM (median 0.27), SS (median 0.54), and HC (median 0.34)]; p<0.001. Conversely, BH2 was increased in SM (median 0.91 ¼mol/mmol creatinine), compared to MSM (median 0.67), SS (median 0.39), and HC (median 0.52); p<0.001, suggesting increased oxidative stress and insufficient recycling of BH2 back to BH4 in severe malaria. Overall, the median BH4/BH2 ratio was lowest in SM [0.18 (IQR: 0.04-0.32)] compared to MSM (0.45, IQR 0.27-61), SS (1.03; IQR 0.54-2.38) and controls (0.66; IQR 0.43-1.07); p<0.001. In malaria, a lower BH4/BH2 ratio correlated with decreased microvascular reactivity (r=0.41; p=0.03) and increased ICAM-1 (r=-0.52; p=0.005). Decreased BH4 and increased BH2 in severe malaria (but not in severe sepsis) uncouples NOS, leading to impaired NO bioavailability and potentially increased oxidative stress. Adjunctive therapy to regenerate BH4 may have a role in improving NO bioavailability and microvascular perfusion in severe falciparum malaria.en_US
dc.format.extent13 p.en_US
dc.language.isoenen_US
dc.relation.ispartofseriesPLOS pathogensen_US
dc.rightsThis is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.en_US
dc.subjectDRNTU::Science::Biological sciences::Microbiology::Bacteria
dc.titleImpaired systemic tetrahydrobiopterin bioavailability and increased dihydrobiopterin in adult falciparum malaria : association with disease severity, impaired microvascular function and increased endothelial activationen_US
dc.typeJournal Article
dc.contributor.schoolLee Kong Chian School of Medicine
dc.identifier.doihttp://dx.doi.org/10.1371/journal.ppat.1004667
dc.description.versionPublished versionen_US


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