Cuticle integrity and biogenic amine synthesis in Caenorhabditis elegans require the cofactor tetrahydrobiopterin (BH4).

Autor:	Loer CM; Department of Biology, University of San Diego, San Diego, California, 92110 cloer@sandiego.edu., Calvo AC; Department of Biomedicine, University of Bergen, 5009 Bergen, Norway., Watschinger K; Division of Biological Chemistry, Biocenter, Innsbruck Medical University, A-6020 Innsbruck, Austria., Werner-Felmayer G; Division of Biological Chemistry, Biocenter, Innsbruck Medical University, A-6020 Innsbruck, Austria., O'Rourke D; Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom., Stroud D; Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom., Tong A; Division of Biological Sciences, University of California, San Diego, California 92093., Gotenstein JR; Division of Biological Sciences, University of California, San Diego, California 92093., Chisholm AD; Division of Biological Sciences, University of California, San Diego, California 92093., Hodgkin J; Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom., Werner ER; Division of Biological Chemistry, Biocenter, Innsbruck Medical University, A-6020 Innsbruck, Austria., Martinez A; Department of Biomedicine, University of Bergen, 5009 Bergen, Norway.
Jazyk:	angličtina
Zdroj:	Genetics [Genetics] 2015 May; Vol. 200 (1), pp. 237-53. Date of Electronic Publication: 2015 Mar 24.
DOI:	10.1534/genetics.114.174110
Abstrakt:	Tetrahydrobiopterin (BH4) is the natural cofactor of several enzymes widely distributed among eukaryotes, including aromatic amino acid hydroxylases (AAAHs), nitric oxide synthases (NOSs), and alkylglycerol monooxygenase (AGMO). We show here that the nematode Caenorhabditis elegans, which has three AAAH genes and one AGMO gene, contains BH4 and has genes that function in BH4 synthesis and regeneration. Knockout mutants for putative BH4 synthetic enzyme genes lack the predicted enzymatic activities, synthesize no BH4, and have indistinguishable behavioral and neurotransmitter phenotypes, including serotonin and dopamine deficiency. The BH4 regeneration enzymes are not required for steady-state levels of biogenic amines, but become rate limiting in conditions of reduced BH4 synthesis. BH4-deficient mutants also have a fragile cuticle and are generally hypersensitive to exogenous agents, a phenotype that is not due to AAAH deficiency, but rather to dysfunction in the lipid metabolic enzyme AGMO, which is expressed in the epidermis. Loss of AGMO or BH4 synthesis also specifically alters the sensitivity of C. elegans to bacterial pathogens, revealing a cuticular function for AGMO-dependent lipid metabolism in host-pathogen interactions. (Copyright © 2015 by the Genetics Society of America.)
Databáze:	MEDLINE
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