Latzer, Joachim et al. (2015) International Worm Meeting "Completing the de novo synthesis pathway for the coenzyme tetrahydrobiopterin (BH4) in C. elegans by structural modeling and mutant screening."

Latzer, Joachim, Knapp, Alec, Vitomirov, Aleks, Loer, Curtis

[International Worm Meeting, 2015]

The small molecule coenzyme tetrahydrobiopterin (BH4) is required in animals for the function of three enzymes that metabolize aromatic amino acids and another that breaks down ether lipids. BH4-deficient worms lack the neurotransmitters dopamine and serotonin, derived from Trp and Tyr, and have leaky, fragile cuticles caused by aberrant lipid metabolism in the hypodermis. The defective cuticle in BH4-deficient worms also alters a worm's susceptibility to bacterial pathogens (Loer et al., 2015, Genetics 200: in press). The first two steps of BH4 synthesis are performed by GTP Cyclohydrolase I (GTPCH1, gene cat-4) and 6-Pyruvoyl Tetrahydrobiopterin Synthetase (PTPS, gene ptps-1). The final two synthetic steps are typically carried out in animals by Sepiapterin Reductase (SR), although other reductases can perform the function in some cases. C. elegans lacks an SR ortholog, but has over 100 reductase/dehydrogenase genes with weak homology to known SRs. We are using computational methods to predict which reductase enzymes in C. elegans might be able to bind BH4-related molecules, generating structural homology models with I-TASSER, followed by docking a biopterin substrate with Chimera Autodock Vina. Using AMBER, binding free energies of BH4 bound to candidate protein structures are compared with those of a reference BH4-bound structure. At the same time, we are screening all available mutants in candidate reductase genes for dopamine and serotonin synthesis and cuticle strength to try to identify the genes(s) required for the final synthesis steps of BH4 in C. elegans..