Regulation of methionine synthesis in Salmonella typhimurium: mutants resistant to inhibition by analogues of methionine.

BIOCHEMICAL and genetical experiments with methionine auxothrophs of Salmonella typhimurium (SMITH 1961 ; SMITH and CHILDS 1966; CHILDS and SMITH unpublished) have resulted in the recognition of six structural genes ( m t A , B, C, E, F and H ) concerned with well defined sequential steps in the biosynthesis of methionine (Figure 1) . Mutants of another gene (metG) do not have a specific enzyme deficiency: they are leaky due to a low level of activity of all the methimine enzymes. Methionine inhibits the activity of homoserine O-transsuccinylase (metA) and represses the synthesis of all the enzymes of the pathway (ROWBURY 1964). Two pairs of genes (metA and H and metB and F ) are linked closely enough to be co-transducible whereas the mete, E and G genes are each located in well separated regions of the circular bacterial genome (Figure 3). On the basis of this partial clustering of genes concerned with related functions, it seemed likely that the mode of regulation of methionine synthesis in this organism would be sufficiently different from that of the control of lactose (BECKWITH 1967) and arabinose fermentation (ENGLESBERG et al. 1965) in EScherichia coli, histidine (AMES et al. 1967) and leucine (BURNS et al. 1966) synthesis in S. typhimurium and tryptophan synthesis in both organisms (BLUME and BALBINDER 1966; YANOFSKY and LENNOX 1959) to justify further investigation. Mutants of bacteria resistant to inhibition by analogues of metabolic end products have often been shown to be abnormal in regulation of the biosynthesis of the normal end product ( COHEN and JACOB 1959) and to be readily amenable to both biochemical and genetic analyses. The methionine analogues a-DL-methyl methionine, DL-ethionine and DL-norleucine were found to be inhibitory and this paper is concerned with the isolation, phenotypic characterisation, enzymic abnormalities and mapping of mutants resistant to these analogues. Preliminary results (SMITH and LAWRENCE 1966) suggested that the regulation of methionine synthesis in S . typhimurium possesses some unique features.