Charles Darwin University

CDU eSpace
Institutional Repository

 
CDU Staff and Student only
 

Impaired Systemic Tetrahydrobiopterin Bioavailability and Increased Dihydrobiopterin in Adult Falciparum Malaria: Association with Disease Severity, Impaired Microvascular Function and Increased Endothelial Activation

Yeo, Tsin W., Lampah, Daniel A., Kenangalem, Enny, Tjitra, Emiliana, Price, Ric N., Weinberg, J. Brice, Hyland, Keith, Granger, Donald L. and Anstey, Nicholas M. (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 - Article No. e1004667).

Document type: Journal Article
Citation counts: Altmetric Score Altmetric Score is 11
Google Scholar Search Google Scholar
Attached Files (Some files may be inaccessible until you login with your CDU eSpace credentials)
Name Description MIMEType Size Downloads
Download this reading Yeo_59489.pdf Published version application/pdf 295.22KB 10
Reading the attached file works best in Firefox, Chrome and IE 9 or later.

IRMA ID 75039815xPUB790
NHMRC Grant No. 605807
1037304
ICRG ID 283321
NMA 1042072
TWY 605831
Title Impaired Systemic Tetrahydrobiopterin Bioavailability and Increased Dihydrobiopterin in Adult Falciparum Malaria: Association with Disease Severity, Impaired Microvascular Function and Increased Endothelial Activation
Author Yeo, Tsin W.
Lampah, Daniel A.
Kenangalem, Enny
Tjitra, Emiliana
Price, Ric N.
Weinberg, J. Brice
Hyland, Keith
Granger, Donald L.
Anstey, Nicholas M.
Journal Name PLoS Pathogens
Publication Date 2015
Volume Number 11
Issue Number 3 - Article No. e1004667
ISSN 1553-7374   (check CDU catalogue  open catalogue search in new window)
Scopus ID 2-s2.0-84926453577
Total Pages 13
Place of Publication United States of America
Publisher Public Library of Science
HERDC Category C1 - Journal Article (DIISR)
Abstract Tetrahydrobiopterin (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.
DOI http://dx.doi.org/10.1371/journal.ppat.1004667   (check subscription with CDU E-Gateway service for CDU Staff and Students  check subscription with CDU E-Gateway in new window)
Additional Notes The person who associated a work with this deed has dedicated the work to the public domain by waiving all of his or her rights to the work worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law. You can copy, modify, distribute and perform the work, even for commercial purposes, all without asking permission.
Description for Link Link to CC Attribution 1.0 License
URL https://creativecommons.org/publicdomain/zero/1.0/


© copyright

Every reasonable effort has been made to ensure that permission has been obtained for items included in CDU eSpace. If you believe that your rights have been infringed by this repository, please contact digitisation@cdu.edu.au.

 
Versions
Version Filter Type
Access Statistics: 13 Abstract Views, 10 File Downloads  -  Detailed Statistics
Created: Tue, 26 Jul 2016, 13:03:12 CST