Identification of the human methylmalonyl-CoA racemase gene based on the analysis of prokaryotic gene arrangements. Implications for decoding the human genome.
In this report, we identify the human DL-methylmalonyl-CoA racemase gene by analyzing prokaryotic gene arrangements and extrapolating the information obtained to human genes by homology searches. Sequence similarity searches were used to identify two groups of homologues that were frequently arranged with prokaryotic methylmalonyl-CoA mutase genes, and that were of unknown function. Both gene groups had homologues in the human genome. Because methylmalonyl-CoA mutases are involved in the metabolism of propionyl-CoA, we inferred that conserved neighbors of methylmalonyl-CoA mutase genes and their human homologues were also involved in this process. Subsequent biochemical studies confirmed this inference by showing that the prokaryotic gene PH0272 and its human homologue both encode DL-methylmalonyl-CoA racemases. To our knowledge this is the first report in which the function of a eukaryotic gene was determined based on the analysis of prokaryotic gene arrangements. Importantly, such analyses are rapid and may be generally applicable for the identification of human genes that lack homologues of known function or that have been misidentified on the basis of sequence similarity searches.
Bobik
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Department of Microbiology and Cell Science, University of Florida, Gainesville, Florida 32611, USA. bobik@ufl.edu
Rasche
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D000214:Acyl Coenzyme A / Q000378:metabolism; D000595:Amino Acid Sequence; D019843:Archaeal Proteins / Q000235:genetics; D003001:Cloning, Molecular; D017124:Conserved Sequence; D004265:DNA Helicases / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D023061:Gene Order; D006801:Humans; D008969:Molecular Sequence Data; D019998:Racemases and Epimerases / Q000235:genetics* / Q000378:metabolism; D017385:Sequence Homology; D017386:Sequence Homology, Amino Acid
D000214:Acyl Coenzyme A; D019843:Archaeal Proteins; D018076:DNA, Complementary; C009061:propionyl-coenzyme A; D004265:DNA Helicases; D019998:Racemases and Epimerases; C021581:methylmalonyl-coenzyme A racemase; C403162:MCM protein, Methanobacterium thermoautotrophicum