Figure 6.

Proposed schematic model illustrating the contribution of TpxD and CodY to the pneumococcal global transcriptional response to H₂O₂. Under oxidative stress conditions H₂O₂ activates directly or indirectly a cascade of genes and transcription factors (TF), among them CodY (1). We speculate that CodY activation by H₂O₂ is due to a conformational change originating from specific cysteine oxidation (2). As a result, CodY binding to tpxD regulatory sequence is enhanced, leading to TpxD up-regulation (3), thereby preventing the accumulation of high H₂O₂ levels. BCAA are known to enhance CodY binding to DNA (4), thereby inducing tpxD expression (3). Under oxidative stress conditions, CodY modulates the intracellular level of BCAA through the up-regulation of the BCAA transporter, brnQ (5) and down-regulation of the BCAA biosynthetic machinery (ilv) (6). Consequently, the need for pyruvate, which is the central precursor in BCAA biosynthesis, is expected to decrease (7) leading to a shift in glucose catabolism toward the pentose phosphate pathway (PPP). This metabolic shift will result in increased NADPH formation (8), thus enhancing TpxD recycling by the thioredoxin-thioredoxin reductase system.