RRC ID 45597
Author Loer CM, Calvo AC, Watschinger K, Werner-Felmayer G, O'Rourke D, Stroud D, Tong A, Gotenstein JR, Chisholm AD, Hodgkin J, Werner ER, Martinez A.
Title Cuticle integrity and biogenic amine synthesis in Caenorhabditis elegans require the cofactor tetrahydrobiopterin (BH4).
Journal Genetics
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.
Volume 200(1)
Pages 237-53
Published 2015-5
DOI 10.1534/genetics.114.174110
PII genetics.114.174110
PMID 25808955
PMC PMC4423366
MeSH Animals Biogenic Amines / biosynthesis* Biopterin / analogs & derivatives* Biopterin / genetics Biopterin / metabolism Caenorhabditis elegans / enzymology Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism Dopamine / metabolism Epidermis / metabolism* GTP Cyclohydrolase / genetics GTP Cyclohydrolase / metabolism Mixed Function Oxygenases / genetics Mixed Function Oxygenases / metabolism Serotonin / metabolism
IF 4.075
Times Cited 3
C.elegans tm773 tm1984 tm5924 tm2373 tm520 tm2337