Biological Information Transfer Beyond the Genetic Code The Sugar Code

Hans-Joachim Gabius

Abstract In the era of genetic engineering, cloning, and genome sequencing, the focus of research on the genetic code has received an even further accentuation in the public eye. When, however, aspiring to understand intra- and intercellular recognition processes comprehensively, the two biochemical dimensions established by nucleic acids and proteins are not sufficient to satisfactorily explain all molecular events in, e.g. cell adhesion or routing. To bridge this gap consideration of further code systems is essential. A third biochemical alphabet forming code words with an information storage capacity second to no other substance class in rather small units (words, sentences) is established by monosaccharides (letters). As hardware oligosaccharides surpass peptides by more than seven orders of magnitude in the theoretical ability to build isomers, then the total of conceivable hexamers is calculated. Beyond the sequence complexity application of nuclear magnetic resonance (NMR) spectroscopy and molecular modeling have been instrumental to discover that even small glycans can often reside in not only one but several distinct low-energy conformations (keys). Intriguingly, conformers can display notably different capacities to fit snugly into the binding site of nonhomologous receptors (locks). This process, experimentally verified for two classes of lectins, is termed "differential conformer selection." It adds potential for shifts of the conformer equilibrium to modulate ligand properties dynamically and reversibly to the well-known changes of sequence (including anomeric positioning and linkage points) and of pattern of substitution, e.g. by sulfation. In the intimate interplay with sugar receptors (lectins, enzymes, and antibodies) the message of coding units of the sugar code is deciphered. This communication will trigger postbinding signaling and the intended biological response. Knowledge about the driving forces for the molecular rendezvous, that is, contributions of bidentate or cooperative hydrogen bonds, dispersion forces, stacking and solvent rearrangement, will enable the design

* Reprinted with permission from Naturwissenschaften, Vol. 87 (2000), pp. 108-121. Institut für Physiologische Chemie, Tierärztliche Fakultät, Ludwig-Maximilians- Universität München, Veterinärstr. 13, D-80539 München, Germany, e-mail: [email protected]

M. Barbieri (ed.), The Codes of Life: The Rules of Macroevolution. © Springer 2008

of high-affinity ligands or mimetics thereof. They embody clinical applications reaching from receptor localization in diagnostic pathology to cell-type-selective targeting of drugs and inhibition of undesired cell adhesion in bacterial/viral infections, inflammation, or metastasis.

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