Ligand-pKa shifts through metals: potential relevance to ribozyme chemistry

Functional and crystallographic analyses of catalytically active RNA molecules ('ribozymes') have revealed a multitude of different routes by which nature accomplishes cleavage reactions of the RNA sugar-phosphate backbone. While there is agreement that these reactions involve general acid-base chemistry, the choice of 'acid' and of 'base' appears to be quite versatile. Among the numerous surprises that have emerged from these studies in recent years is the phenomenon of 'shifted pK(a) values' of nucleobases, hence, the fact that pK(a) values of isolated nucleobases in H(2)O can be shifted in either direction--upward or downward--into the physiological pH range, and that consequently allows these nucleobases to function as 'acids' or 'bases'. Another change in paradigm in recent years relates to the role of divalent metal ions in these catalytic reactions, which points to the possibility of an indirect involvement in the catalytic cycle rather than necessarily to a direct participation, as in the case with the hepatitis delta virus ribozyme. In this review, basic features of nucleobases and/or aqua ligand pK(a) shifts caused by metal coordination and H-bonding are discussed.