title: Cuticle integrity and biogenic amine synthesis in Caenorhabditis elegans require the cofactor tetrahydrobiopterin (BH4).
abstract: 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.
authors: Department of Biology, University of San Diego, San Diego, California, 92110 cloer@sandiego.edu.
authors: Curtis M
authors: CM
authors: Loer
authors: Department of Biomedicine, University of Bergen, 5009 Bergen, Norway.
authors: Ana C
authors: AC
authors: Calvo
authors: Division of Biological Chemistry, Biocenter, Innsbruck Medical University, A-6020 Innsbruck, Austria.
authors: Katrin
authors: K
authors: Watschinger
authors: Division of Biological Chemistry, Biocenter, Innsbruck Medical University, A-6020 Innsbruck, Austria.
authors: Gabriele
authors: G
authors: Werner-Felmayer
authors: Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom.
authors: Delia
authors: D
authors: O'Rourke
authors: Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom.
authors: Dave
authors: D
authors: Stroud
authors: Division of Biological Sciences, University of California, San Diego, California 92093.
authors: Amy
authors: A
authors: Tong
authors: Division of Biological Sciences, University of California, San Diego, California 92093.
authors: Jennifer R
authors: JR
authors: Gotenstein
authors: Division of Biological Sciences, University of California, San Diego, California 92093.
authors: Andrew D
authors: AD
authors: Chisholm
authors: Department of Biochemistry, University of Oxford, Oxford OX1 3QU, United Kingdom.
authors: Jonathan
authors: J
authors: Hodgkin
authors: Division of Biological Chemistry, Biocenter, Innsbruck Medical University, A-6020 Innsbruck, Austria.
authors: Ernst R
authors: ER
authors: Werner
authors: Department of Biomedicine, University of Bergen, 5009 Bergen, Norway.
authors: Aurora
authors: A
authors: Martinez
mesh_terms: D000818:Animals; D001679:Biogenic Amines / Q000096:biosynthesis*; D001708:Biopterins / Q000031:analogs & derivatives* / Q000235:genetics / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004817:Epidermis / Q000378:metabolism*; D006136:GTP Cyclohydrolase / Q000235:genetics / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000235:genetics / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism
chemical_list: D001679:Biogenic Amines; D029742:Caenorhabditis elegans Proteins; D001708:Biopterins; D012701:Serotonin; D006899:Mixed Function Oxygenases; C020678:glyceryl-ether monooxygenase; D006136:GTP Cyclohydrolase; C003402:sapropterin; D004298:Dopamine
keywords: AGMO; GTPCH; alkylglycerol monooxygenase; biopterin; dopamine; epidermis; serotonin