title: Intestinal microbiota as a tetrahydrobiopterin exogenous source in hph-1 mice.
abstract: Tetrahydrobiopterin (BH4) is a cofactor of a number of regulatory enzymes. Although there are no known BH4 exogenous sources, the tissue content of this biopterin increases with age in GTP cyclohydrolase 1-deficient hyperphenylalaninemia-1 (hph-1) mice. Since certain bacteria are known to generate BH4, we hypothesize that generation of this biopterin by the intestinal microbiota contributes to its tissue increase in hph-1 adult mice. The goal of this study was to comparatively evaluate hph-1 mice and wild-type C57Bl/6 controls for the presence of intestinal BH4-producing bacteria. Newborn and adult mice fecal material was screened for 6-pyruvoyltetrahydropterin synthase (PTPS-2) an enzyme only present in BH4-generating bacteria. Adult, but not newborn, wild-type control and hph-1 mouse fecal material contained PTPS-2 mRNA indicative of the presence of BH4-generating bacteria. Utilizing chemostat-cultured human fecal bacteria, we identified the PTPS-2-producing bacteria as belonging to the Actinobacteria phylum. We further confirmed that at least two PTPS-2-producing species, Aldercreutzia equolifaciens and Microbacterium schleiferi, generate BH4 and are present in hph-1 fecal material. In conclusion, intestinal Actinobacteria generate BH4. This finding has important translational significance, since manipulation of the intestinal flora in individuals with congenital biopterin deficiency may allow for an increase in total body BH4 content.
authors.affiliation: Physiology &Experimental Medicine Program, The Hospital for Sick Children Research Institute, Toronto, Ontario M5G 1X8, Canada.|Department of Paediatrics and Physiology, University of Toronto, Toronto, Ontario, M5G 1X8 Canada.
authors.forename: Jaques
authors.initials: J
authors.lastname: Belik
authors.affiliation: Physiology &Experimental Medicine Program, The Hospital for Sick Children Research Institute, Toronto, Ontario M5G 1X8, Canada.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Shifrin
authors.affiliation: Baylor Research Institute, Institute of Metabolic Disease, Dallas, TX, 75226, USA.
authors.forename: Erland
authors.initials: E
authors.lastname: Arning
authors.affiliation: Baylor Research Institute, Institute of Metabolic Disease, Dallas, TX, 75226, USA.
authors.forename: Teodoro
authors.initials: T
authors.lastname: Bottiglieri
authors.affiliation: Physiology &Experimental Medicine Program, The Hospital for Sick Children Research Institute, Toronto, Ontario M5G 1X8, Canada.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Pan
authors.affiliation: Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, N1G 2W1 Canada.
authors.forename: Michelle C
authors.initials: MC
authors.lastname: Daigneault
authors.affiliation: Molecular and Cellular Biology, University of Guelph, Guelph, Ontario, N1G 2W1 Canada.
authors.forename: Emma
authors.initials: E
authors.lastname: Allen-Vercoe
mesh_terms: D039903:Actinobacteria / Q000502:physiology*; D000818:Animals; D000831:Animals, Newborn; D001708:Biopterins / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004421:Dystonia / Q000188:drug therapy*; D005243:Feces / Q000382:microbiology*; D000069196:Gastrointestinal Microbiome; D006801:Humans; D008661:Metabolism, Inborn Errors / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000378:metabolism; D019761:Phosphorus-Oxygen Lyases / Q000378:metabolism; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism*; D011596:Psychomotor Disorders / Q000188:drug therapy*
chemical_list: C103827:Phc1 protein, mouse; D001708:Biopterins; D019001:Nitric Oxide Synthase; D063150:Polycomb Repressive Complex 1; D019761:Phosphorus-Oxygen Lyases; C043497:6-pyruvoyltetrahydropterin synthase; C003402:sapropterin