The methylator meets the terminator

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Abstract
In the preproteomic age, one of the best approaches for deciphering the physiological role of an unknown gene product was to examine the phenotype of mutant strains and take educated guesses for its function that would guide biochemical experimentation. Such a process could take months to years to accomplish. In the proteomic age, the best initial approach is to use a computer to compare the deduced amino acid sequence of the gene product with those of proteins of known function, and with luck, one might get to the same place in seconds to minutes! But what happens when the results of these two approaches don't appear to make any sense with each other? This issue of PNAS presents an article by Nakahigashi et al. (1) that shows how a gene product originally identified by its mutant phenotype as an enzyme of heme biosynthesis and then by sequence similarity as a possible DNA adenine- N- 6-methyltransferase actually functions as a protein glutamine methyltransferase modulating the termination activity of release factors (RFs) in ribosomal protein synthesis! It provides a nice case study for why one can't rest until the biochemistry is done. The hemK gene of Escherichia coli originally was described in 1995 from a genetic screen designed to reveal new types of heme synthesis mutants (2). Here, one mutation in a light-resistant revertant of a light-sensitive hemH − porphyrin-deficient strain was mapped to a locus in an operon consisting of the hemA gene encoding glutamyl-tRNA reductase, catalyzing the first committed step of the heme synthesis pathway, and the apparently unrelated prfA gene encoding peptidyl RF1, with a transcriptional order of hemA-prfA-hemK (2, 3). HemK mutant cells were found to be unable to make heme from 5-aminolevulinate (2). The presence of 5-aminolevulinate dehydratase and porphobilinogen deaminase activities in the mutant, as …