RRC ID 4215
Author Calvo AC, Pey AL, Ying M, Loer CM, Martinez A.
Title Anabolic function of phenylalanine hydroxylase in Caenorhabditis elegans.
Journal FASEB J.
Abstract 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) approximately 150 microM; K(m) for tetrahydrobiopterin (BH(4)) approximately 35 microM 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 yellow-orange 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.
Volume 22(8)
Pages 3046-58
Published 2008-8
DOI 10.1096/fj.08-108522
PII fj.08-108522
PMID 18460651
MeSH Anabolic Agents / metabolism Animals Biological Evolution Caenorhabditis elegans / enzymology* Caenorhabditis elegans / genetics Caenorhabditis elegans / growth & development Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism Free Radical Scavengers / metabolism Gene Deletion Genes, Helminth Kinetics Melanins / metabolism Osmotic Pressure Oxidative Stress Phenotype Phenylalanine Hydroxylase / chemistry Phenylalanine Hydroxylase / deficiency Phenylalanine Hydroxylase / genetics Phenylalanine Hydroxylase / metabolism* Protein Conformation Substrate Specificity Subtilisins / genetics Subtilisins / metabolism
IF 5.391
Times Cited 16
C.elegans tm520 tm987