Journal
GENETICS
Volume 200, Issue 1, Pages 237-U457Publisher
GENETICS SOCIETY AMERICA
DOI: 10.1534/genetics.114.174110
Keywords
biopterin; epidermis; serotonin; dopamine; GTPCH; alkylglycerol monooxygenase; AGMO
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Funding
- Summer Undergraduate Research Experience (SURE) grants
- National Institutes of Health (NIH) Office of Research Infrastructure Programs [P40 OD010440]
- Fletcher Jones Foundation
- National Institute of General Medical Sciences AREA grant [R15 GM60203]
- USD Faculty Research and International Opportunity grants
- National Science Foundation Major Research Instrumentation award [1229443]
- Research Council of Norway
- Kristian Gerhard Jebsen Foundation
- Western Norway Health Authorities
- Austrian Science Fund [P22406]
- NIH [R01 GM054657]
- Medical Research Council (MRC) (United Kingdom) [MR/J001309/1]
- Wellcome Trust [090532/Z/09/Z]
- MRC Hub grant [G0900747 91070]
- MRC [MR/J001309/1] Funding Source: UKRI
- Austrian Science Fund (FWF) [P 22406] Funding Source: researchfish
- Medical Research Council [MR/J001309/1] Funding Source: researchfish
- Div Of Biological Infrastructure
- Direct For Biological Sciences [1229443] Funding Source: National Science Foundation
- Austrian Science Fund (FWF) [P22406] Funding Source: Austrian Science Fund (FWF)
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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.
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