Sweet mysteries of nature: computer simulations unravel how carbohydrates form
Fifty per cent of our daily calorie intake comes from carbohydrates, our "biological fuel". Moreover, carbohydrates influence cell-to-cell communication, the functioning of the immune system, the ability of various infectious agents to make us sick, and the progression of cancer.
One of the most important reactions in the metabolism of carbohydrates is the formation of the glycosidic bond, i.e. the covalent linkage between simple monosacharides (monomers) to build polysaccharides such as glucogen, starch or celulose (polymers).
Most glycosidic bonds are synthesized in nature from sugars that are activated by a cofactor (mostly, a nucleotide). The enzymes responsible for this action are glycosyltransferases (GTs), which form the glycosidic bond by transferring a sugar molecule from a donor molecule (an activated sugar) to an acceptor molecule (typically another sugar). These enzymes can operate with retention or inversion of the configuration of the carbon atom of the glycosidic bond they form. The mechanism of inverting GTs is well known, but the mechanism of retaining GTs has remained one of the most puzzling aspects in the field of glycobiology.
It had been proposed that the enzyme helps the reaction by binding to the donor molecule. Still, the lack of clear experimental evidence led scientists to think of an extremely unusual "front-face" type mechanism, in which the reaction takes place on a single "face" of the sugar. This mechanism has been surrounded by much controversy, since in principle it implies that two covalent bonds are forming and breaking, respectively, in the same region of space.
By means of ab initio molecular dynamics techniques and the use supercomputers (BSC), the PCB researchers demonstrated that the "front-face" type mechanism is feasible thanks to the formation of a positively-charged species (a carbocation) with an extremely short half-life that moves quickly from the donor to the acceptor.
The modelled enzyme is glycosyltransferase trehalose-6-phosphate synthase (OtsA), which participates in the final synthesis of trehalose, a disaccharide of great importance in nature. Given their absence in mammalian biology, trehalose synthesising and processing enzymes offer attractive inhibition targets.
Glycosyltransferases are responsible for the structure of many carbohydrates and, therefore, the knowledge of their mechanism of action will help to modify their function, thereby improving the synthesis of known carbohydrates and new structures. It will also contribute to th