One of the grad students has new data showing that the active form of the regulatory protein CRP is needed not only for expression of the CRP-S genes coregulated by the Sxy protein, but for expression of Sxy itself. This has reminded me of a puzzle in our understanding of how cyclic AMP (cAMP), the activator of CRP, depends on sugar uptake.
Many bacteria have evolved to use cAMP as a signal that supplies of energy and carbon are running low, and the concentration of cAMP in the cell is controlled mainly by a sugar-uptake pathway called the phosphotransferase system (PTS). This is a cluster of membrane-associated proteins that bind specific sugars in the cell's environment, bring them across the membrane, and stick a phosphate group onto them so they can't leak back out. Each kind of PTS sugar (glucose, fructose etc.) has one or two specialized proteins to take it up, in addition to the generalist proteins that bring in the phosphate and set the stage. (Some other sugars don't use the PTS at all - these are usually less common sugars.)
The PTS uses the availability of its sugars to control the synthesis of cAMP. If lots of sugar is being transported, no cAMP is made. But if sugar supply runs out, the PTS stimulates synthesis of cAMP. This in turn activates CRP to turn on genes for using other (non-PTS) sugars and for conserving other energy resources. Bacteria differ in the sugars their PTS systems can handle, depending on the environment they're adapted to. E. coli, for example, has PTS uptake proteins for many different sugars, because it lives in the gut.
When the H. influenzae genome sequence first became available, we checked it for genes encoding PTS transport proteins. We were a bit surprised to find only proteins for transporting one sugar, and more surprised that this sugar was fructose, not glucose. Because we had shown that H. influenzae uses its PTS to control cAMP levels and thus to control the activity CRP, this meant that the availability of fructose was a major factor in the cell's decision to take up DNA.
This was surprising because I had assumed that glucose was the primary sugar in human bodily fluids, including respiratory mucus (H. influenzae's environment). I was told that in fact fructose might have evolutionarily precedents - the ancestral PTS may have transported fructose. And I found out that there was significant fructose in at least some bodily fluids, though not much in our blood unless we'd been consuming sugar (sucrose is a glucose+fructose dimer ). Nevertheless fructose seemed an odd choice for the sugar regulating CRP activity, and I kept wondering whether the absence of a glucose PTS uptake protein was a peculiarity of the lab strain of H. influenzae rather than a general property of the species.
That was 11 years ago, and now we have genome sequences of several H. influenzae strains and of 8 or 9 other Pasteurellacean species. So I did some searching for the glucose and fructose transporters, and found that I was wrong. None of the other H. influenzae strains have genes for glucose PTS proteins, and neither do about half of the other species in H. influenzae's family. Nor do they all have genes for fructose PTS proteins. The distributions of these genes doesn't perfectly match the phylogenetic relationships of the species, suggesting that genes may have been lost (or gained) several times. (Ravi Barabote and Milton Saier review the PTS genes in all bacteria: (2005) MMBR 69:608-634.)
So I'm still perplexed. CRP regulates a large number of genes in H. influenzae, and I would think there would be strong selection to optimize the regulatory machinery that decides when these genes should be turned on. But these bacteria seem to have been very cavalier (careless) in looking after the PTS genes that control this decision. This might mean that PTS regulation of cAMP isn't really such a big deal, or it might mean that the bacteria know things I don't about how glucose and fructose levels vary in their environments.
Philosophy begins where physics ends, and physics begins where philosophy ends
7 hours ago in The Curious Wavefunction