Dr. Roger Sandwick

Associate Professor of Chemistry & Biochemistry
Chemistry & Biochemistry Department
451 McCardell Bicentennial Hall
Middlebury College
Office Phone:   x 3496   
Email: rsandwic@middlebury.edu

Research Interests

My research interest over the past ten years has been concerned with un-catalyzed reactions of phosphate biomolecules. Two recent publications (see CV) describes my research group's efforts in characterizing the role of magnesium and nitrogen bases (specifically imidazole) on the degradation of 5-phosphoribosyl-a-pyrophosphate (PRPP). 31P NMR was used to monitor the degradation process.

My recent efforts have focussed on the molecule 5-phosphoribosamine (PRA). PRA is made in cells from PRPP via the enzyme glutamine phosphoribosylpyrophosphate amidotransferase (GPATase) and is then subsequently used by glycinamide ribonucleotide (GAR) synthetase to make GAR. GAR is then subsequently used in the purine synthesis pathway to ultimately manufacture AMP and GMP.

An interesting aspect of PRA is that it is relatively unstable at physiological conditions. Its half-life at pH = 7.5 is either 38 sec or 13 sec, depending on literature source you want. This short half life brings up the question of how newly synthesized PRA gets transported to the next enzyme in the sequence (i.e. GAR synthetase) at a rate that would correspondingly avoid the high rate of PRA degradation. A proposal has been made that the PRA is channeled from the active site of GPATase to the active site of GAR synthesis in a direct transfer mechanism (i.e. a complex if formed between the two enzymes), however no evidence for an affinity of these enzymes for one another has ever been shown. Our research wishes to determine if a direct transfer mechanism occurs and, if so, how exactly this transfer occurs.

A second research interest regards a chemical transformation termed the Maillard reaction. This reaction, named after the French chemist who discovered it in the early 1900’s, involves the initial linking of sugars to amines followed by a series of subsequent reactions which lead to a complex set of products. The Maillard reaction has received a great deal of interest over the years as the reaction that produces the brown colors during cooking. For example, the brown colors generated on a loaf of bread or on crackers during the baking process and the browning of meats during roasting are Maillard reaction products. These and other Maillard products generate important aromas and flavors that are of great interest to the food industry. Not all of these Maillard products are beneficial, however. Some Maillard products have been shown to be toxic and/or mutagenic. For example, a recent finding has demonstrated the production of the Maillard product acrylamide, a neurotoxin, during the baking or frying of potatoes and some other foods.

A type of Maillard reaction also occurs in the human body. Since cells contain sugars (like glucose) and amines (like amino acids in proteins), the potential for the reaction is present. However, as the reaction proceeds at relatively slow rates at physiological temperatures (as opposed to baking temperatures), the Maillard products are typically not in high concentration since they are effectively eliminated from the body at reasonable rates. In certain situations, however, the reaction does occur. For example, in uncontrolled diabetes, the high glucose levels in the blood encourage fast reaction rates with the amines of proteins and advanced glycation end-products (AGEs) are generated. The most well-known of these products is hemoglobin A1C, a glycated hemoglobin which is today used as a marker for the disease. Other diseases/conditions suspected of generating AGEs include Alzheimer’s disease and the aging process.

Our laboratory is interested in the Maillard reactions of cellular amines and proteins with ribose 5-phosphate (R5P). We have determined that this molecule reacts with amino acids at rates hundreds of times faster than glucose. We have also found that R5P displays some interesting protein cross-linking behavior. The implications of these reactions for the cell are currently unknown. Although R5P reacts faster, it is of lower concentration relatively to other sugars like glucose. In our research, we are attempting to characterize the relative rates of reactions, the products that are formed, and the types of protein groups involved in the cross-linking reaction. We are also interested in whether any of the R5P-derived Maillard products are toxic or mutagenic.