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

Brice Sperandio,^1, Céline Gautier,¹ Stephen McGovern,¹ Dusko S. Ehrlich,¹ Pierre Renault,¹ Isabelle Martin-Verstraete,² and Eric Guédon^1*

Laboratoire de Génétique Microbienne, Institut National de la Recherche Agronomique, 78352 Jouy-en-Josas Cedex,¹ Unité de Génétique des Génomes Bactériens, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris Cedex 15, and UFR de Biochimie, Université Paris 7, 2 Place Jussieu, 75251 Paris, France²

Received 3 May 2007/ Accepted 25 July 2007

MetR (formerly Smu.1225), a regulator of the LysR family, controls key genes for methionine supply in Streptococcus mutans. An S. mutans metR mutant is unable to transport L-methionine and to grow in the absence of this amino acid. Accordingly, MetR activates transcription by binding to the promoter regions of two gene clusters and smu.1487, whose products are involved in methionine biosynthesis (MetEF and Smu.1487) and uptake (AtmBDE). Transcriptional activation by MetR requires the presence of a 17-bp palindromic sequence, the Met box. Base substitutions in the Met box hinder the formation of a MetR-DNA complex and abolish MetR-dependent activation, showing that Met boxes correspond to MetR recognition sites. Activation by MetR occurs in methionine-depleted medium and is rapidly triggered under nonactivating conditions by the addition of homocysteine. This intermediate of methionine biosynthesis increases the affinity of MetR for DNA in vitro and appears to be the MetR coeffector in vivo. Homocysteine plays a crucial role in methionine metabolic gene regulation by controlling MetR activity. A similar mechanism of homocysteine- and MetR-dependent control of methionine biosynthetic genes operates in S. 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.

Published ahead of print on 3 August 2007.

Present address: Unité de Pathogénie Microbienne Moléculaire, Unité INSERM 786, Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris, France.

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