Faculty and Students | Training Program at the Chemistry Biology Interface

2007-2009 Trainees	Home Department	CBI Mentor
Matthew DeSeino Research Description: My research involves the biosynthetic pathway of FR-900098, a phosphonic acid with potential as a novel chemotherapeutic against malaria. Through feeding experiments, mass spectrometry and ³¹P-NMR analysis, the required enzymes for heterologous production of the compound in E. coli can be identified. Once the pathway has been elucidated, protein engineering of these enzymes can create various FR-900098 derivatives and metabolic engineering can be used to overproduce the desired FR-900098.	Chemical & Biomolecular Engineering	Huimin Zhao
Jessica Frisz Research Description:	Chemical & Biomolecular Engineering	Mary L. Kraft
David Knapp Research Description: As a graduate student in the Burke Group, my current project involves the synthesis of a mycosamine sugar building block, as part of the Amphotericin B total synthesis effort. Mycosamine sugars are ubiquitous among polyene macrolide antibiotics, and their efficient attachment to the parent macrocyle is an as-of-yet unsolved problem that has hampered the study of this important class of drugs. The current synthetic plan will also allow access to amphotericin B derivatives, whose potency against yeast fungal cells will offer insight into amphotericin’s mechanism of action. A better understanding of how amphotericin B forms membrane-spanning ion channels will ultimately provide the groundwork for the development of a synthetic ion channel mimic, a potential treatment for currently incurable diseases like cystic fibrosis.	Chemistry	Martin D. Burke
Julia Martin Research Description: The sulfhydryl of cysteine residues may play an important role in the defense against hydrogen peroxide (H₂O₂) stress. The formation of disulfide bonds amongst cysteine residues promotes protein stability and function and assist in redox regulation. Disulfide bonds are rarely observed in cytoplasmic proteins and a minute level of H₂O₂ is found in wild type Escherichia coli cells, suggesting that even at low levels H₂O₂ is harmful. Only two known proteins directly interact with hydrogen peroxide through sulfhydryls: OxyR and AhpC. During H₂O₂ stress, OxyR is activated by the formation of an intramolecular disulfide bond through its interaction with H₂O₂. Oxidized OxyR in return induces the transcription of antioxidant genes (trxC, grxA, gor) involved in the reduction of sulfhydryls. It is unclear why OxyR upregulates these genes and what physiological role these proteins play during H₂O₂ stress. As part of the thioredoxin and glutaredoxin systems, these proteins may play a key role in fixing inappropriate disulfide bond formations or recycling enzymes such as ribonucleotide reductase and phosphoadenosine-phosphosulfate (PAPS) reductase through disulfide bond exchanges. They may also aid in turning off the OxyR response.	Microbiology	James A. Imlay
Matthew Olsen Research Description: My research involves the synthesis of models for the active site of Fe-only hydrogenase. Hydrogenases are remarkable because they reversibly interconvert dihydrogen to protons and electrons using iron. They operate at near thermodynamic efficiency, use an inexpensive metal, and are only reversibly inactivated by CO, making their biomimetic modeling applicable to the design of fuel cells. Furthermore, a hydrogenase-based metabolism supports the pathogen H. pylori, which solely infects the mucosal lining of the human stomach where it gives rise to ulcers and gastric cancer. Therefore, hydrogenase models are also biomedically relevant. A complete mechanistic understanding of hydrogenases can be developed by the study of structural models	Chemistry	Thomas B. Rauchfuss
Quinn Peterson Research Description: Apoptosis is the mechanism by which cells commit suicide in response to intrinsic and extrinsic signals during cell stress or development. The pathways activated in response to these signals involve the activation of a class of cysteine proteases known as caspases. Ultimately caspase-3, an executioner caspase, is activated and in turn proteolyses its cellular substrates resulting apoptosis. Cancer is characterized by the ability of cells to evade apoptosis through mutation and misregulation of key apoptotic proteins including caspases. Counter intuitively cellular levels of procaspase-3 are often elevated in cancer cells. Despite being primed for apoptosis, activation of procaspase-3 does not occur in cancer cells due to upstream mutations in proapoptotic proteins, and aberrant expression levels of certain anti-apoptotic proteins; these alterations prevent apoptotic signals from reaching procaspase-3. A small molecule which directly activates procaspase-3 to caspase-3 could provide the potential for new approaches for cancer therapy. In a screen for small molecule activators of procaspase-3, a novel compound, PAC-1, was identified. This compound was shown to directly activate procaspase-3 to caspase-3 in vitro, kill cancer cells in culture and inhibit tumor growth in mouse xenograft models. Further mechanistic characterization of this compound and the development of more potent derivatives are in progress.	Biochemistry	Paul J. Hergenrother