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Anabolic function of phenylalanine hydroxylase in Caenorhabditis elegans
Author(s) -
Calvo Ana C.,
Pey Angel L.,
Ying Ming,
Loer Curtis M.,
Martinez Aurora
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.08-108522
Subject(s) - caenorhabditis elegans , phenylalanine hydroxylase , chemistry , biochemistry , superoxide dismutase , mutant , phenylalanine , enzyme , melanin , cuticle (hair) , tetrahydrobiopterin , microbiology and biotechnology , biology , gene , genetics , cofactor , amino acid
In humans, liver phenylalanine hydroxylase (PAH) has an established catabolic function, and mutations in PAH cause phenylketonuria, a genetic disease characterized by neurological damage, if not treated. To obtain novel evolutionary insights and information on molecular mechanisms operating in phenylketonuria, we investigated PAH in the nematode Caenorhabditis elegans (cePAH), where the enzyme is coded by the pah‐1 gene, expressed in the hypodermis. CePAH presents similar molecular and kinetic properties to human PAH [ S 0.5 (L‐Phe)~150 μΜ; Κ m for tetrahydrobiopterin (BH 4 )~35 μΜ and comparable V max ], but cePAH is devoid of positive cooperativity for L‐Phe, an important regulatory mechanism of mammalian PAH that protects the nervous system from excess L‐Phe. Pah‐1 knockout worms show no obvious neurological defects, but in combination with a second cuticle synthesis mutation, they display serious cuticle abnormalities. We found that pah‐1 knockouts lack a yelloworange pigment in the cuticle, identified as melanin by spectroscopic techniques, and which is detected in C. elegans for the first time. Pah‐1 mutants show stimulation of superoxide dismutase activity, suggesting that cuticle melanin functions as oxygen radical scavenger. Our results uncover both an important anabolic function of PAH and the change in regulation of the enzyme along evolution.—Calvo, A. C., Pey, A. L., Ying, M., Loer, C. M., Martinez, A. Anabolic function of phenylalanine hydroxylase in Caenorhabditis elegans. FASEB J. 22, 3046–3058 (2008)