XXII. BIOCHEMICKÝ ZJAZD - Jesseniova lekárska fakulta

Lectures
MOLECULar MODELING INSIGHT INTO CATALYTIC MECHANISMS OF
GLYCOSYLTraNSFEraSES
Igor Tvaroška
Institute of Chemistry, Slovak Academy of Sciences, 845 38 Bratislava, Slovakia
N- and O-linked oligosaccharide chains of glycoproteins play a crucial role in a number
of biological processes. These compounds are found throughout biological systems and
have been implicated in molecular recognition events such as bacterial, viral, and cellcell
adhesion, inflammation, and tumor invasion. Numerous glycosyltransferases, that
catalyze the addition of a specific glycosyl residue from sugar nucleotide to an acceptor
substrate, were validated as prime targets for therapeutic intervention in human diseases.
Effective inhibitors of these enzymes are not yet available and development of inhibitors
for a specific glycosyltransferase is, therefore, of great interest. Though transition state
analogs are valued tools for drug discovery as potent and specific inhibitors of enzymes,
up to date, the ability to generate transition state analogs of glycosyltransferases has
lagged behind. A transition state analog is a stable compound that structurally resembles
the three-dimensional structure and charge distribution of a substrate(s) portion of
the unstable transition state of an enzymatic reaction. Knowledge of the geometry and
charge distribution of transition state provides blueprint for the design of the transition
state analog inhibitors. It is obvious, that design of transition state analog inhibitors of
an enzyme requires knowledge of the mechanism of the enzymatic reaction and the
structure of transition state. Therefore, we have investigated the catalytic mechanism for
inverting and retaining glycosyltransferases employing high level ab initio, DFT, and hybrid
QM/MM calculations [1-6]. These results provided detailed insight into the mechanism
of the monosaccharide transfer catalyzed by glycosyltransferases and revealed the main
structural features of the transition states. The purpose of this paper is to summarize
the structural insights into the catalytic mechanism of glycosyltransferases inferred from
these calculations.
Acknowledgements: This work was supported by the grants from the Slovak Research
and Development Agency No. APVV-0607-07 and the Slovak Grant Agency VEGA No.
2/0128/08.
XXII. Biochemistry Congress, Martin
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