Mark W. Peczuh

Bioorganic Chemistry

Associate Professor (b. 1971)
NIH Postdoctoral Fellow, Princeton Universtiy 1999-2001
Ph.D., Yale University, 1999
M.S., University of Pittsburgh, 1997
B.S., Boston College, 1993

Phone: 860-486-1605
Email : mark.peczuh@uconn.edu

Peczuh Group Home Page

Peczuh Research Group  -  Summary

The major research theme in the Peczuh Group is the design and preparation of new carbohydrate compounds and the analysis of their interactions with proteins.  Our investigation of protein-carbohydrate molecular recognition events is from the perspective of bioorganic chemistry.  That is, we use a full complement of assay techniques and spectroscopies to investigate how incremental changes in carbohydrate structure can effect binding to target proteins.  The synthesis and conformational analysis of unnatural carbohydrate structures is considered the foundation of our current and future research investigations. 

1)  Synthesis of Septanose Carbohydrates

Homologated, or expanded, analogs of natural biopolymer building blocks are a new class of molecules that often have interesting structures and biological functions.  We are interested in developing synthetic methods for the preparation of septanose sugars; these are seven membered ring homologs of natural pyranoses.  We have developed synthetic routes to a number of septanose monosaccharide building blocks such as oxepines (seven membered ring cyclic enol ethers) and thiophenyl septanosides which are amenable to further glycosylation reactions.  Our approaches have utilized carbohydrate based oxepines prepared by ring closing metathesis (RCM) or cyclization/elimination routes.  The resulting oxepines have been used to prepare 1,2-anhydrosugar donors via epoxidation, or have been carried on to thioglycoside type donors.    Both types of glycosyl donors efficiently provide a range of septanoside structures.  Notably, the thiophenyl septanosid has been used to prepare a disaccharide that contains a septanose residue at both (reducing and non-reducing) ends of the molecule.   

2)  Conformational Analysis of Septanose Carbohydrates

The analysis of conformational preferences for the unnatural septanosides that have been synthesized is critical to their utilization in protein-septanose interactions.  Our approach to conformational analysis has taken two major veins.  The first is a comparison of calculated  (and their corresponding coupling constant values) to spectroscopically observed structures.  A calculated Boltzmann distribution of conformers is used to generate predicted ³J_H,H coupling constant values which is then compared to the ³J_H,H values observed in ¹H NMR spectra.  To date, good agreement between the calculated and observed ring conformations has been noted for simple methyl septanosides.  Remarkably, the methyl septanosides take up primarily one (>80% population) twist-chair (TC) conformation.  The second method for describing septanoside conformations has been through X-ray crystallography.  The agreement between the solid state (shown above) and solution data indicate that: i) the calculation/spectroscopy method is valid and ii) solid state conformations are representative of solution conformations. 

3)  Protein-Septanose Interactions

            Two separate projects aimed at understanding and/or influencing protein-carbohydrate interactions.  Septanose-Lectin Interactions - Here, the simple question “Can natural lectins bind septanose carbohydrates?” is being asked.  Toward this end, we are currently investigating the interaction between a family of methyl septanoside structures and their ability to be bound by the natural lectin Concanavalin A from the jack bean.  This model system is attractive because the binding of pyranose (natural) monosaccharides has been thoroughly described both thermodynamically and structurally.  We have measured binding using Isothermal Titration Calorimetry (ITC) and observed that b- rather than a-septanosides are bound by ConA.  This preference is the opposite of that observed for pyranoses.  We are currently working on NMR based techniques (Saturation Transfer Difference experiments) to describe the protein-septanose interaction more precisely.  Glycosidase Inhbition – A specific class of glycosyl hydrolyase enzymes, the retaining b-glycosidases, have been targetted for inhibition based on the following rationale.  i)  Retaining b-glycosidases such as chitinase are likely responsible for transglycosidation of cell wall components important to the viability of fungi such as C. elegans.  ii)  Based on the mechanism of the hydrolysis reaction, these enzymes must distort the chair conformation of their substrates into a higher energy sofa conformation.  Septanosides should access these conformations with a lower energetic barriers and should be viable inhibitors of the enzyme and therefore potential antibiotics. 

4) Other Projects

            Protein Secondary Structure Mimics - The identification of bona fide non-proteinogenic secondary structure mimics is motivated by their potential for interaction with biologically significant proteins.  Binding to a protein surface may sterically block its interaction with a protein partner in a desirable way.  Affecting the Function of Glycosyltransferase Enzymes - In nature, carbohydrates are built up by a wide array of glycosyltransferases.  Little is known about how substrate specificities are determined by Gtfs.  Evolving glycosyltransferases that perform novel glycosylations from natural proteins can prove to facilitate carbohydrate synthesis.  We are interested in developing enzymes for preparative glycosylations with an aim of generating an enzyme with relaxed glycosyl donor and acceptor specificity.  Such proteins could then be used for carrying out chemically difficult glycosylations.

Recent Publications

•  Carbohydrate Based Oxepines:  Ring Expanded Glycals for the Synthesis of Septanose

   Saccharides  Peczuh, M. W.;  Snyder, N. L.  Tetrahedron Lett. 2003, 44, 4057-4061. 

•  Synthesis, crystal structure and reactivity of a D-xylose based oxepine  Peczuh, M. W.;

   Snyder, N. L.; Fyvie, W. S.   Carbohydr. Res. 2004, 339, 1163-1171. 

•  Synthesis of 2-iodo-2-deoxy septanosides from a D-xylose based oxepine:  intramolecular

   cyclization in the absence of a glycosyl acceptor  Fyvie, W. S.; Morton, M.; Peczuh, M. W.

   Carbohydr. Res. 2004, 339, 2363-2370. 

•  Septanose Carbohydrates:  Synthesis and Conformational Studies of Methyl-a-D-Glycero-D-

   idoseptanoside and Methyl b-D-Glycero-D-guloseptanoside  DeMatteo, M.; Snyder, N. L..;

   Morton, M.; Baldisseri, D. M.; Hadad, C. M.; Peczuh, M. W.  J. Org. Chem.  ASAP. 

•  Sequential Cyclization-Elimination Route to Carbohydrate BasedOxepines Castro, S.;

   Peczuh, M. W.  submitted.