Gene regulation in Streptococcus pneumoniae - RePub - Erasmus ...
Gene regulation in Streptococcus pneumoniae - RePub - Erasmus ...
Gene regulation in Streptococcus pneumoniae - RePub - Erasmus ...
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makes it possible for the pneumococcus to adequately react to external signals. The specific<br />
signals pneumococcal CodY recognizes are the branched-cha<strong>in</strong> am<strong>in</strong>o acids (BCAA)<br />
isoleuc<strong>in</strong>e, leuc<strong>in</strong>e, and val<strong>in</strong>e, lead<strong>in</strong>g to an orchestrated change <strong>in</strong> gene expression <strong>in</strong><br />
anticipation of a chang<strong>in</strong>g environment (Figure 1).<br />
CodY was first described <strong>in</strong> B. subtilis (44), and has been studied extensively <strong>in</strong> this<br />
organism. B. subtilis CodY regulates the expression of over a hundred genes, vary<strong>in</strong>g from<br />
genes <strong>in</strong>volved <strong>in</strong> sporulation, genetic competence, motility, and chemotaxis, but its role is<br />
most pronounced <strong>in</strong> nitrogen metabolism (32). In B. subtilis, CodY reacts on <strong>in</strong>tracellular<br />
GTP concentrations and on branched-cha<strong>in</strong> am<strong>in</strong>o acids, and these molecules enhance b<strong>in</strong>d<strong>in</strong>g<br />
of CodY to its DNA-b<strong>in</strong>d<strong>in</strong>g box (38, 42). B. subtilis CodY carries a helix-turn-helix and a<br />
GTP-b<strong>in</strong>d<strong>in</strong>g motif at the carboxy-term<strong>in</strong>al half of the prote<strong>in</strong>. Strik<strong>in</strong>gly, <strong>in</strong> L. lactis,<br />
<strong>Streptococcus</strong> mutants and S. <strong>pneumoniae</strong>, the GTP-b<strong>in</strong>d<strong>in</strong>g motif is present, but CodY did<br />
not seem to respond to GTP, as <strong>in</strong> vitro b<strong>in</strong>d<strong>in</strong>g assays did not show any enhancement of<br />
prote<strong>in</strong>-DNA <strong>in</strong>teractions (8, 17, 28). The GTP-b<strong>in</strong>d<strong>in</strong>g motifs of L. lactis, S. mutants and S.<br />
<strong>pneumoniae</strong> do show multiple am<strong>in</strong>o acid residue substitutions, which may expla<strong>in</strong> the<br />
observed unresponsiveness to GTP (38, 44). The difference of CodY-mediated repression <strong>in</strong><br />
response to GTP between this group of bacteria and B. subtilis might reflect the importance of<br />
GTP-sens<strong>in</strong>g <strong>in</strong> B. subtilis: GTP plays a crucial role <strong>in</strong> the physiology of B. subtilis, as pivotal<br />
species-specific processes such as sporulation take place when the cellular levels of GTP<br />
decrease (29, 33). In contrast, L. lactis, S. mutants, and S. <strong>pneumoniae</strong> lack a functional<br />
sporulation mach<strong>in</strong>ery.<br />
Str<strong>in</strong>gent response and CodY<br />
<strong>Gene</strong> <strong>regulation</strong> and metabolism <strong>in</strong> S. <strong>pneumoniae</strong><br />
In B. subtilis, CodY is clearly l<strong>in</strong>ked to the so-called str<strong>in</strong>gent response. The str<strong>in</strong>gent<br />
response is a reaction dur<strong>in</strong>g am<strong>in</strong>o acid limitation <strong>in</strong> which ribosomal RNA synthesis is shut<br />
down and a ribosome-bound prote<strong>in</strong> called RelA is activated. RelA is a GTP<br />
pyrophosphok<strong>in</strong>ase that converts GTP to (p)ppGpp, a molecule which is often referred to as<br />
the alarmone (for review see 22, 37). Dur<strong>in</strong>g the str<strong>in</strong>gent response the GTP concentration is<br />
lowered by two processes: production of (p)ppGpp out of GTP, and the <strong>in</strong>hibition of IMP<br />
dehydrogenase (20, 33). Recently, Lemos et al. have shown that <strong>in</strong> S. mutants, CodY-<br />
<strong>regulation</strong> and the str<strong>in</strong>gent response (and the effect of RelA activation) are closely l<strong>in</strong>ked<br />
(28). The <strong>in</strong>troduction of an additional codY mutation <strong>in</strong> S. mutans ΔrelAPQ fully restored<br />
growth <strong>in</strong> medium lack<strong>in</strong>g leuc<strong>in</strong>e or val<strong>in</strong>e, demonstrat<strong>in</strong>g that the growth-defective<br />
phenotype of ΔrelAPQ was directly l<strong>in</strong>ked to CodY. Moreover, artificially lower<strong>in</strong>g GTP<br />
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