Role of the Transcriptional Regulator RamB (Rv0465c) in the Control of the Glyoxylate Cycle in Mycobacterium tuberculosis

Mycobacterium tuberculosis generally is assumed to depend on lipids as a major carbon and energy source when persisting within the host. The utilization of fatty acids requires a functional glyoxylate cycle with the key enzymes isocitrate lyase (Icl) and malate synthase. The open reading frame Rv0465c of M. tuberculosis H37Rv encodes a protein with significant sequence similarity to the transcriptional regulator RamB, which in Corynebacterium glutamicum controls the expression of several genes involved in acetate metabolism, i.e., those encoding enzymes of acetate activation and the glyoxylate cycle. We show here that the M. tuberculosis Rv0465c protein can functionally complement RamB in C. glutamicum and that it binds to the promoter regions of M. tuberculosis icl1 and Rv0465c. Construction and subsequent transcriptional and enzymatic analysis of a defined Rv0465c deletion mutant in M. tuberculosis revealed that the Rv0465c protein, now designated RamB, represses icl1 expression during growth with glucose and negatively autoregulates the expression of its own operon. Whole-genome microarray analysis of the M. tuberculosis ramB (ramB(MT)) mutant and the wild type furthermore showed that apart from icl1 and the ramB(MT) operon, the expression of all other M. tuberculosis genes involved in acetate metabolism remain unchanged in the mutant. Thus, RamB(MT) has a more specific regulatory function as RamB from C. glutamicum and is confined to expression control of icl1 and the ramB(MT) operon.