Blau, Nenad

Thöny, Beat

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EDITORIALTetrahydrobiopterin in biomedical researchNenad Blau & Beat Tho¨nyPublished online: 27 January 2009# SSIEM and Springer 2009Tetrahydrobiopterin (BH4) is an endogenously synthe-sized cofactor, required for various enzyme activitiesand for some less well-defined functions. It is alsorequired at the cellular level. The known enzymesthat depend on BH4 are phenylalanine hydroxylase(PAH), tyrosine hydroxylase, tryptophan hydroxylases1 and 2, all three types of nitric oxide (NO) synthases(NOS), and glyceryl-ether monooxygenase (GEMO).At the cellular level, BH4 was found to be a growth orproliferation factor for Crithidia fasciculata and acontrol factor for infectivity of Leishmania major. Inthe nervous system, BH4 is a self-protecting factor forNO or a general neuroprotecting factor via the NOSpathway, and has dopamine-releasing function. Themajor controlling point of BH4 biosynthesis is GTPcyclohydrolase I (GTPCH) whose expression may beunder control of cytokine induction, and at least inliver, GTPCH activity is inhibited by BH4 (andstimulated by phenylalanine) through the GTPCHfeedback regulatory protein (GFRP). With regard tohuman disease, BH4 deficiency (Fatypical PKU_) dueto autosomal recessive mutations in all cofactor-metabolizing enzymes (except sepiapterin reductase)is described as a cause of hyperphenylalaninaemia(HPA). Under normal conditions the intracellular BH4level is thought to play a pivotal role in not only theregulation of tyrosine and tryptophan hydroxylases,but also in the initial and rate-limiting steps in thebiosynthesis of the catecholamines and serotonin.Thus, alterations in BH4 levels result in a disturbanceof biogenic amine metabolism which has been impli-cated as an aetiological factor in a variety of neuro-logical disorders. Mutations in the gene for GTPCHare closely related to Dopa-responsive dystonia(Segawa disease). This evidence strongly supports theimportance of BH4 and dopaminergic transmission indystonia. Alterations in BH4 metabolism have beenobserved in several neuropsychiatric diseases, such asParkinson disease, familial dystonia, and endogenousdepression, as well as in endothelial dysfunction,vitiligo, and more recently in pain perception. Asubtype of PAH deficiency has been associated withBH4-responsiveness and mild or moderate phenyl-ketonuria (PKU) due to specific mutations in thePAH gene, offering potential pharmacological treat-ment with BH4 (sapropterine; KuvanR). Biomedicalresearch on BH4 expanded from the initial investiga-tions in Fatypical PKU_ patients to neurodegeneration,pain, vascular-endothelial, and epidermal dysfunctionincluding diabetes, and other disciplines. Regardingtreatment approaches, the field has been extendedfrom BH4-cofactor and pharmachaperon treatment toenzyme replacement and experimental gene therapy.The International Conference on Tetrahydrobio-pterin, Phenylketonuria, and Nitric Oxide Synthasewas organized in St. Moritz/Champe´r in Switzerland,on March 23–28, 2008, and hosted approximately 90scientists from 15 different countries. More than 50oral presentations were given and organized invarious sessions including BGenetics and biochemistryof BH4 metabolism^, BBH4 metabolism and defi-ciency^, BBH4, GEMO, NOS and endothelial dys-function^, BPAH, PAH as misfolding disease, andBH4-responsive PKU/PAH^, and BPKU (and new)J Inherit Metab Dis (2009) 32:1–2DOI 10.1007/s10545-009-9967-8N. Blau (*) :B. Tho¨nyDivision of Clinical Chemistry and Biochemistry,University Children_s Hospital,Zu¨rich, Switzerlande-mail: nenad.blau@kispi.uzh.chtreatment^. The conference was sponsored by Bio-marin Pharmaceutical Inc., Asubio Pharma Co., andMerck Serono SA. Generous sponsor support provid-ed travelling awards for younger scientists and aspecial prize for the best presentation dedicated tothe memory of Professor John Wood who died in 2008.In addition to the scientific highlights, one of the socialemphases of the program was the traditional PteridinesCup which took place on the slopes of Corviglia in theAlps surrounding St. Moritz (see picture). The nextInternational Symposium on Pteridines and Folateswill take place from June 7 to 12, 2009, in Jeju, Korea(http://www.biopku.org/bh42009/).This issue of JIMD includes selected articles fromthe St. Moritz conference.2 J Inherit Metab Dis (2009) 32:1–2

Tetrahydrobiopterin in biomedical research

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Tetrahydrobiopterin in biomedical research

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