Analysis of pyrimidine catabolism in Drosophila melanogaster using epistatic interactions with mutations of pyrimidine biosynthesis and beta-alanine metabolism.
The biochemical pathway for pyrimidine catabolism links the pathways for pyrimidine biosynthesis and salvage with beta-alanine metabolism, providing an array of epistatic interactions with which to analyze mutations of these pathways. Loss-of-function mutations have been identified and characterized for each of the enzymes for pyrimidine catabolism: dihydropyrimidine dehydrogenase (DPD), su(r) mutants; dihydropyrimidinase (DHP), CRMP mutants; beta-alanine synthase (betaAS), pyd3 mutants. For all three genes, mutants are viable and fertile and manifest no obvious phenotypes, aside from a variety of epistatic interactions. Mutations of all three genes disrupt suppression by the rudimentary gain-of-function mutation (r(Su(b))) of the dark cuticle phenotype of black mutants in which beta-alanine pools are diminished; these results confirm that pyrimidines are the major source of beta-alanine in cuticle pigmentation. The truncated wing phenotype of rudimentary mutants is suppressed completely by su(r) mutations and partially by CRMP mutations; however, no suppression is exhibited by pyd3 mutations. Similarly, su(r) mutants are hypersensitive to dietary 5-fluorouracil, CRMP mutants are less sensitive, and pyd3 mutants exhibit wild-type sensitivity. These results are discussed in the context of similar consequences of 5-fluoropyrimidine toxicity and pyrimidine catabolism mutations in humans.
Rawls
John M
JM
Molecular and Cellular Biology Group, Department of Biology, University of Kentucky, Lexington, Kentucky 40506, USA. jrawls@uky.edu
D000581:Amidohydrolases / Q000235:genetics*; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D017124:Conserved Sequence; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000235:genetics*; D004331:Drosophila melanogaster / Q000196:embryology / Q000201:enzymology* / Q000235:genetics; D004843:Epistasis, Genetic; D005260:Female; D005472:Fluorouracil / Q000378:metabolism; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics; D011743:Pyrimidines / Q000096:biosynthesis / Q000378:metabolism*; D062826:Zonula Occludens-1 Protein; D015091:beta-Alanine / Q000235:genetics / Q000378:metabolism*
D008565:Membrane Proteins; D010750:Phosphoproteins; D011743:Pyrimidines; C569042:TJP1 protein, human; D062826:Zonula Occludens-1 Protein; D015091:beta-Alanine; D042943:Dihydrouracil Dehydrogenase (NADP); D000581:Amidohydrolases; C021590:beta-ureidopropionase; C020047:dihydropyrimidinase; D005472:Fluorouracil