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J. Biol. Chem., Vol. 283, Issue 14, 9127-9135, April 4, 2008
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1
2
From the
Department of Medicine, Division of Geriatric Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15213 and the
Buck Institute, Novato, California 94945
In eukaryotes and many bacteria, tyrosine is degraded to produce energy via a five-step tyrosine degradation pathway. Mutations affecting the tyrosine degradation pathway are also of medical importance as mutations affecting enzymes in the pathway are responsible for type I, type II, and type III tyrosinemia. The most severe of these is type I tyrosinemia, which is caused by mutations affecting the last enzyme in the pathway, fumarylacetoacetate hydrolase (FAH). So far, tyrosine degradation in the nematode Caenorhabditis elegans has not been studied; however, genes predicted to encode enzymes in this pathway have been identified in several microarray, proteomic, and RNA interference (RNAi) screens as perhaps being involved in aging and the control of protein folding. We sought to identify and characterize the genes in the worm tyrosine degradation pathway as an initial step in understanding these findings. Here we describe the characterization of the K10C2.4, which encodes a homolog of FAH. RNAi directed against K10C2.4 produces a lethal phenotype consisting of death in young adulthood, extensive damage to the intestine, impaired fertility, and activation of oxidative stress and endoplasmic stress response pathways. This phenotype is due to alterations in tyrosine metabolism as increases in dietary tyrosine enhance it, and inhibition of upstream enzymes in tyrosine degradation with RNAi or genetic mutations reduces the phenotype. We also use our model to identify genes that suppress the damage produced by K10C2.4 RNAi in a pilot genetic screen. Our results establish worms as a model for the study of type I tyrosinemia.
Received for publication, October 9, 2007 , and in revised form, January 25, 2008.
* This work was supported in part by National Institutes of Health Grant K08 AG028977 (to A. F.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S4.
2 Supported by an Ellison Senior Scholar award, R01 AG21069, and R01 AG022868.
1 To whom correspondence should be addressed: 3471 5th Ave., Suite 500, Pittsburgh, PA 15260. Fax: 412-692-2370; E-mail: fishera{at}dom.pitt.edu.
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