Tuesday, July 3, 2012

One more '-omics' analysis of the stringent response: BIBLIOMICS

The stringent response is confusing, no doubt about that. I personally get exceedingly confused when I read in vivo papers from the 80s. I somehow hope that there should be hidden gems there, and it is just my stupidity that stops me from discovering these.... so I try... and I get confused. In vivo data confuse me, and in vivo data from the 80s.... I am lost.

Importantly, I always try to read one paper at a time, maximum ten, rarely more then twenty. Imagine what happens if one would read them all? And how, I wonder, how would one call this sort of thing? Wonder no more; enter Carneiro and colleagues. What they did, they collected the whole bibliome about the E. coli stringent response and analyzed it in attempt to gain a birds-eye view, providing 'a more systematic understanding of this cellular response'. 

They summarize the nitty-gritty of the stringent response in the magnificent Figure 1.

 The sheer number of mistakes they make is owe-inspiring and truly shows the power of the high-throughput learning. It is OK that tRNAs have their anticodons on one the 3' (or is it 5'?) end and amino acids are attached where the anticodons should be. Fine, that the amino acid moieties are outside of the ribosome when the tRNAs are attached. Fine, that there is no way in hell one can figure out there are the A- , P- and E-sites of their ribosomes, and, surely, it would be nice to be able to know position of at least the A-site when we are talking about the stringent response. But what is truly fabulous, is that the ribosomal protein L11 is part of the small ribosomal subunit (L... the letter L is giving us a hint... large, maybe?...). Since RelA is interacting with L11, so this causes a bit of a trouble, and RelA ends up on the small subunit as well (ah, never mind this paper). In this awkward position RelA has no chances of inspecting the CCA of the A-site tRNA, but maybe it is for the best, given how messed up the tRNA already is and that we have no idea where the A-site could be...

The bird-eye view allows Carneiro and collegues to make some information-packed generalizations. I am not sure what we learn this way, but the figures speak for themselves:

Rrrright, the dashed line overtook the solid one and they never crossed, therefore the ratios between the blue and red bars changed with time... I want some error-bars, then it will be really, really nice and scientific.

But it is not only the figures that are great. The text is awesome as well. 'Later, in 1980, the ppGpp level was found to be controlled by the SpoT enzyme via GTP hydrolysis activity (PMID: 6159345)'. GTP hydrolysis! By SpoT! Yay! 'The 50S ribosomal subunit protein L11 has been indirectly implicated in the feedback inhibition of (p)ppGpp, because ribosomes lacking this protein are unable to stimulate the synthesis of these nucleotides (PMID:11673421; PMID:17095013) [39,61].' Feedback inhibition! This redefines the meaning of feedback... Wow! No wonder L11 migrated on the large subunit... 

Being subjected to such a monumental degree of confusion, the authors started expressing themselves in a most peculiar way; for the lack of a better word I would call it 'cautious': 'As a result, it was possible to perceive the relevance of specific translation GTPases known to be inhibited by (p)ppGpp nucleotides'. 'Studies showed that (p)ppGpp inhibits translation by repressing the expression of ribosomal proteins and also potentially inhibiting the activity of the particular proteins'. 

I certainly hope that soon the authors should take on the mighty ribosome. There are many more papers in the ribosomal bibliome, and the level of confusion might be even higher. I would also recommend some 3D plots!


Carneiro, S., Lourenço, A., Ferreira, E. C., & Rocha, I. (2011). Stringent response of Escherichia coli: revisiting the bibliome using literature mining. Microbial informatics and experimentation, 1(1), 14. doi:10.1186/2042-5783-1-14 PIMD: 22587779

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