Control of Methionine Synthesis and Uptake by MetR and Homocysteine in Streptococcus mutans

Abstract

thermophilus. These data suggest a common mechanism for the regulation of the methionine supply in streptococci. However, some streptococcal species are unable to synthesize the homocysteine coeffector. This intriguing feature is discussed in the light of comparative genomics and streptococcal ecology.The sulfur-containing amino acid methionine is of major importance in the cellular metabolism of all living organisms. Methionine is the universal initiator of protein synthesis, and its derivative S-adenosylmethionine (SAM) and autoinducer-2 (AI-2) (see Fig. 1) are involved in a variety of cellular processes. SAM serves as the major biological methyl donor in methylation reactions, which are essential for the biosynthesis of phospholipids, proteins, DNA, and RNA (11), and the signaling molecule AI-2 is involved in interspecies communication and gene regulation in both gram-negative and grampositive bacteria (7,21,46). Methionine availability is limiting for the growth of several lactic acid bacteria (4) and group B streptococci (39), and methionine biosynthetic genes are essential for the virulence of Brucella melitensis (28), Haemophilus parasuis (22), and Salmonella enterica (9).Methionine can be either supplied from the environment by the cell or synthesized de novo (see Fig. 1). Two methionine transport systems in microorganisms have been described previously: an ABC transporter that belongs to the methionine uptake transporter (MUT) family (23,33,48) and BcaP of the permease transporter family (8). Methionine can be produced directly by the methylation of homocysteine by a methionine synthase (MetE) in conjunction with a methylenetetrahydrofolate reductase (MetF) (see Fig. 1) (16,27). Homocysteine can be synthesized from (i) cysteine by the transsulfuration pathway (MetA, MetB, and MetC), (ii) sulfide by the sulfhydrylation pathway (MetA and CysD), and (iii) methionine by the SAM recycling pathway (MetK, Pfs, and LuxS). Both the transsulfuration and sulfhydrylation pathways start with O-acylhomoserine, synthesized by the acylation of homoserine by homoserine acyltransferase (MetA). In the transsulfuration pathway, homocysteine is formed from O-acylhomoserine and cysteine in two steps, with the intermediary formation of cystathionine. This process requires the sequential action of a cystathionine ␥-synthase (MetB) and a cystathionine ␤-lyase (MetC). In the sulfhydrylation pathway, homocysteine is directly synthesized from O-acylhomoserine and sulfide by Oacylhomoserine sulfhydrylase (CysD). Finally, in the SAM recycling pathway, methionine serves as a substrate for the synthesis of homocysteine, after its activation by ATP to form SAM. The utilization of SAM as a methyl donor results in the formation of S-adenosylhomocysteine, which is degraded into AI-2 and homocysteine by the successive action of an S-adenosylhomocysteine nucleosidase (Pfs) and an S-ribosylhomocysteinase (LuxS) (see Fig. 1).While methionine biosynthetic enzymes and metabolic pathways are well conserved among bacteria, the regulation of methi...

Comparative genomic analysis of T-box regulatory systems in bacteria

“…Similarly, the loss of the S-box riboswitch regulating methionine biosynthesis in the Lactobacillales has lead to the expansion of MET-T-boxes in the Lactobacillaceae lineage (whereas in the Streptococcus spp. these genes are regulated by a new transcription factor, MtaR/MetR) Kovaleva and Gelfand 2007;Sperandio et al 2007).…”

Structure and function of the LysR-type transcriptional regulator (LTTR) family proteins

“…The conservation of LTTRs within the genomes of extremely diverse bacteria means that they have evolved a regulatory role over genes with similarly diverse functions, whose products can be involved in metabolism, cell division, quorum sensing, virulence, motility, nitrogen fixation, oxidative stress responses, toxin production, attachment and secretion, to name a few (Table 1) (Kovacikova & Skorupski, 1999;Deghmane et al, 2000Deghmane et al, , 2002Cao et al, 2001;Kim et al, 2004;Russell et al, 2004;Byrne et al, 2007;Lu et al, 2007;Sperandio et al, 2007). This review aims to bring together the increasing body of knowledge concerning the structure, functions and molecular genetics that is helping to unravel the paradigm of the largest group of transcriptional regulators identified within the prokaryotic kingdom.…”

Computational Analysis of Cysteine and Methionine Metabolism and Its Regulation in Dairy Starter and Related Bacteria

“…identified as being important regulators of the genes related to cysteine and methionine metabolism in streptococci (25,68,69). They belong to the LysR family of transcription regulators.…”

“…For instance, Hullo et al (30) reported on the regulatory mechanisms related to cysteine and methionine conversions in Bacillus subtilis. Sperandio et al described these relations for Lactococcus lactis (70) and Streptococcus mutans (68,69). Rodionov et al (59) and Kovaleva and Gelfand (36) performed a comprehensive comparative in silico study for the…”

“…The transcription of genes encoding the proteins that are involved in cysteine and methionine metabolism in lactic acid bacteria and other Lactobacillales is controlled by both regulator-binding and RNA structural switches. In various Streptococcaceae, the LysR-family transcription regulators MtaR and CmbR have been shown to be involved in activation as well as repression of genes such as cysD, cysK, metA, metC, metE, and metF (e.g., for Lactococcus lactis [25,70] and Streptococcus mutans [36,68]). The transcription regulator HomR was reported to control the expression of metB in S. mutans and Streptococcus thermophilus (69).…”