Tetrahydrobiopterin Supplementation Improves Phenylalanine Metabolism in a Murine Model of Severe Malaria

Abstract

Tetrahydrobiopterin (BH4) is an essential cofactor for both phenylalanine hydroxylase and nitric oxide synthase. Patients with severe malaria have low urinary BH4, elevated plasma phenylalanine, and impaired endothelium-dependent vasodilation, suggesting that BH4 depletion may limit phenylalanine metabolism and nitric oxide synthesis. We infected C57BL/6 mice with Plasmodium berghei ANKA to characterize BH4 availability and to investigate the effects of BH4 supplementation. P. berghei ANKA infection lowered BH4 in plasma, erythrocytes, and brain tissue but raised it in aorta and liver tissue. The ratio of BH4 to 7,8-BH2 (the major product of BH4 oxidation) was decreased in plasma, erythrocytes, and brain tissue, suggesting that oxidation contributes to BH4 depletion. The continuous infusion of sepiapterin (a BH4 precursor) and citrulline (an arginine precursor) raised the concentrations of BH4 and arginine in both blood and tissue compartments. The restoration of systemic BH4 and arginine availability in infected mice produced only a minor improvement in whole blood nitrite concentrations, a biomarker of NO synthesis, and failed to prevent the onset of severe disease symptoms. However, sepiapterin and citrulline infusion reduced the ratio of phenylalanine to tyrosine in plasma, aortic tissue, and brain tissue. In summary, BH4 depletion in P. berghei infection may compromise both nitric oxide synthesis and phenylalanine metabolism; however, these findings require further investigation in human patients with severe malaria.

Role of Dietary Antioxidants in the Preservation of Vascular Function and the Modulation of Health and Disease

“…Furthermore, it has been shown that eNOS S -glutathionylation can trigger BH 4 depletion resulting in further eNOS uncoupling with loss of NO production and enhanced superoxide generation. BH 4 depletion has been shown to occur in a variety of animal and human disease models ( 45 , 46 ), although human studies of oral BH 4 replacement therapy have yielded mixed results ( 47 ). Interestingly, BH 4 supplementation (10 mg/kg/day) significantly decreased various types of congenital heart defects in the embryos of pregestational diabetic mice ( 42 ), suggesting the importance of sufficient antioxidant and anti-inflammatory compounds during pregnancy.…”

Dissecting Efficacy and Metabolic Characteristic Mechanism of Taxifolin on Renal Fibrosis by Multivariate Approach and Ultra-Performance Liquid Chromatography Coupled With Mass Spectrometry-Based Metabolomics Strategy

“…Under normal circumstances, about 50% of the PA consumed is used to synthesize proteins of various components, and the rest is converted to tyrosine under the action of PA hydroxylase and then converted into dopamine, epinephrine, norepinephrine, and melanin. When PA hydroxylase is lacking, these metabolites reach abnormally high levels and accumulate in tissues, plasma, and cerebrospinal fluid, which are excreted in large quantities from the urine ( Alkaitis and Ackerman, 2016 ). PA level in blood sample was decreased after TFN treatment involved in PA, tyrosine, and tryptophan biosynthesis and PA metabolism.…”

Functional Metabolomics Analysis Elucidating the Metabolic Biomarker and Key Pathway Change Associated With the Chronic Glomerulonephritis and Revealing Action Mechanism of Rhein

“…Under normal circumstances, about 50% of the PA consumed is used to synthesize proteins of various components, and the rest is converted to tyrosine under the action of phenylalanine hydroxylase, and then converted into dopamine, epinephrine, norepinephrine, and melanin. When PA hydroxylase is lacking, these metabolites reach abnormally high levels and accumulate in tissues, plasma, and cerebrospinal fluid, which are excreted in large quantities from the urine (Alkaitis and Ackerman, 2016). Taurocholic acid can reduce capillary permeability of inflammatory tissues, inhibit inflammatory swelling, and restrain the production of inflammatory mediators such as NO, PGE2, and histamine.…”