{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T08:31:35Z","timestamp":1789201895937,"version":"build-2803163510"},"reference-count":34,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2001,4,1]],"date-time":"2001-04-01T00:00:00Z","timestamp":986083200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2001,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Deficiencies in the human enzyme phenylalanine hydroxylase (PAH) due to mutations in the PAH gene (<jats:italic>PAH<\/jats:italic>) result in the inborn error of metabolism phenylketonuria (PKU). The clinical symptom of this disease is an elevated concentration of L\u2010phenylalanine (L\u2010Phe) in blood serum. To prevent mental retardation due to the buildup of neurotoxic metabolites of L\u2010Phe, patients with severe PKU must be treated with a low\u2010L\u2010Phe diet starting early in their life. Owing to extensive newborn screening programmes and genotyping efforts, more than 400 different mutations have been identified in the <jats:italic>PAH<\/jats:italic> gene. Recently, there have been several reports of PKU patients showing a normalization of their L\u2010Phe concentrations upon oral administration of the natural cofactor to PAH, (6<jats:italic>R<\/jats:italic>)\u2010L\u2010<jats:italic>erythro<\/jats:italic>\u20105,6,7,8\u2010tetrahydrobiopterin (BH<jats:sub>4<\/jats:sub>). In an attempt to correlate the clinical responsiveness to BH<jats:sub>4<\/jats:sub> administration with PKU genotype, we propose specific structural consequences for this subset of PAH mutations. Based on the location and proximity of this subset of mutations to the cofactor\u2010binding site in the three\u2010dimensional structure of PAH, a hypothesis for BH<jats:sub>4<\/jats:sub> responsiveness in PKU patients is presented. It is believed that some of these mutations result in expressed mutant enzymes that are <jats:italic>K<\/jats:italic><jats:sub>m<\/jats:sub> variants (with a lower binding affinity for BH<jats:sub>4<\/jats:sub>) of the standard PAH enzyme phenotype. Oral administration of excess BH<jats:sub>4<\/jats:sub> thus makes it possible for these mutant enzymes to suppress their low binding affinity for BH<jats:sub>4<\/jats:sub>, enabling this subset of <jats:italic>PAH<\/jats:italic> mutations to perform the L\u2010Phe hydroxylation reaction. Most of the BH<jats:sub>4<\/jats:sub>\u2010responsive <jats:italic>PAH<\/jats:italic> mutations map to the catalytic domain of PAH in either of two categories. Residues are located in cofactor\u2010binding regions or in regions that interact with the secondary structural elements involved in cofactor binding. Based on the series of known mutations that have been found to be responsive to BH<jats:sub>4<\/jats:sub>, we propose that other subsets of <jats:italic>PAH<\/jats:italic> mutations will have a high likelihood of being responsive to oral BH<jats:sub>4<\/jats:sub> administration.<\/jats:p>","DOI":"10.1023\/a:1010371002631","type":"journal-article","created":{"date-parts":[[2002,12,23]],"date-time":"2002-12-23T17:41:19Z","timestamp":1040665279000},"page":"213-230","source":"Crossref","is-referenced-by-count":65,"title":["A structural hypothesis for BH4 responsiveness in patients with mild forms of hyperphenylalaninaemia and phenylketonuria"],"prefix":"10.1002","volume":"24","author":[{"given":"H.","family":"Erlandsen","sequence":"first","affiliation":[{"name":"Department of Molecular Biology and Institute for Childhood and Neglected Diseases, La Jolla The Scripps Research Institute  CA 92037 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. 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