On the Origins of Life and The RNA World

On The Panda’s Thumb, Ian Musgrave has an interesting entry on the origins of life and the RNA World – it traces back to this ScienceBlogs essay.  Apropos of this, a nice publication came across my RSS feed late last week.  This study reveals that one of the chemical functionalities that catalyzes the charging of a tRNA is provided by the tRNA substrate itself.  The abstract, and brief commentary, are after the fold.  As always, enjoy.

Aminoacyl-tRNA synthetases (aaRSs) join amino acids to 1 of 2 terminal hydroxyl groups of their cognate tRNAs, thereby contributing to the overall fidelity of protein synthesis. In class II histidyltRNA synthetase (HisRS) the nonbridging Sp-oxygen of the adenylate is a potential general base for aminoacyl transfer. To test for conservation of this mechanism in other aaRSs and the role of terminal hydroxyls of tRNA in aminoacyl transfer, we investigated the class II Escherichia coli threonyl-tRNA synthetase (ThrRS). As with other class II aaRSs, the rate-determining step for ThrRS is amino acid activation. In ThrRS, however, the 2′-OH of A76 of tRNAThr and a conserved active-site histidine (His-309) collaborate to catalyze aminoacyl transfer by a mechanism distinct from HisRS. Conserved residues in the ThrRS active site were replaced with alanine, and then the resulting mutant proteins were analyzed by steady-state and rapid kinetics. Nearly all mutants preferentially affected the amino acid activation step, with only a modest effect on aminoacyl transfer. By contrast, H309A ThrRS decreased transfer 242-fold and imposed a kinetic block to CCA accommodation. His-309 hydrogen bonds to the 2′-OH of A76, and substitution of the latter by hydrogen or fluorine decreased aminoacyl transfer by 763- and 94-fold, respectively. The proton relay mechanism suggested by these data to promote aminoacylation is reminiscent of the NAD -dependent mechanisms of alcohol dehydrogenases and sirtuins and the RNA-mediated catalysis of the ribosomal peptidyl transferase center.

The last paragraph of the paper:

The 10^2 to 10^3 rate enhancement provided by the 2’-OH of A76 to the aminoacylation of tRNAThr is several orders of magnitude less than the contribution of tRNA-assisted catalysis to peptidyl transferase (18). Both systems, however, illustrate how catalytic features of primordial RNA-based aminoacylating enzymes (38 ) may have been partially retained to enhance protein-based catalysis. As part of the evolution of a modern translation apparatus with greater speed and accuracy, genetic selection might have driven early RNA-based aminoacylation catalysts to partner with simple protein-based enzymes, with functional groups on both partners contributing to the overall catalytic mechanism. Such a model could explain why in the case of the ribosome and the aaRSs, obvious protein-derived general acid/general base catalysts are missing and why the catalytic contribution of ionizable ribose groups is still significant. Along these lines, the parallel roles of the 2’-OH in tRNAThr and the 2’-OH of the NAD cofactor of ADH in their respective proton relay mechanisms is striking and recalls the early proposal from H. B. White (39) that contemporary coenzymes may share an evolutionary history with catalytic RNAs.

The last sentence is exciting, and speaks to the broader issue that is the topic of Ian’s post.  However, even if the study I mention here is not reflective of a deep-rooted conservation of chemical mechanism (this remains a viable alternative perspective, IMO), and is instead an instance in which RNA has supplanted protein in providing chemical functionality, it is clear that RNA can insinuate itself at many different levels in the workings of cells.

The citation:

Minajig A, Francklyn CS. 2008. RNA-assisted catalysis in a protein enzyme: The 2′-hydroxyl of tRNAThr A76 promotes aminoacylation by threonyl-tRNA synthetase. Proc. Natl. Acad. Sci.

Reference 39 from this study (for those interested in the history of these concepts):

39. White HB, III (1976) Coenzymes as fossils of an earlier metabolic state. J Mol Evol 7:101–104.

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