Assistant Professor

B.S. 1999, Hope College
Ph.D. 2004, Colorado State University
NIH Postdoctoral Fellow 2004-2007, Stanford University

Organic Chemistry
Chemical biology of complex biosynthetic systems.

Department of Chemistry, 701A LGRT
University of Massachusetts
710 North Pleasant Street
Amherst, MA 01003-9336

office: 613 LGRT
tel: 413-545-2294 fax: 413-545-4490

schnarr@chem.umass.edu

Principal Research Interests

Polyketide-derived natural products are an enormously valuable source of biologically active compounds assembled via dedicated protein assemblies known as polyketide synthases (PKSs).  Type I, or modular PKSs, consist of large, multienzyme polypetides arranged in assembly line fashion.  Discreet clusters of covalently-tethered, catalytic domains are responsible for two-carbon elongation of the polyketide backbone and subsequent tailoring of the resultant carbonyl functionality.  Given the modularity and product diversity typical of PKS assemblies, much attention has been focused toward viable engineering strategies for natural product analog generation. 

Although significant strides have been made toward rational reprogramming of these megasynthases, progress has often suffered from low turnover and inherently high specificity for natural recognition partners.  Our lab is primarily interested in developing engineered systems which help us to better understand and potentially curtail these primary hurdles.  Using a variety of chemical and biological techniques, we plan to exploit combinations of existing biosynthetic systems for use as miniature small-molecule factories.  Ultimately, we hope to establish a reliable means of tailoring polyketide structure through simple genetic manipulation of biosynthetic components.

Additionally, our lab is interested in developing novel techniques to analyze small-molecule output in complex PKS assemblies.  More specifically, we will utilize “silent” functionalities with known binding behavior as either permanent or cleavable chemical handles on full-length and intermediate polyketide structures.  Success in this endeavor will provide facile means of simultaneously assaying chemical output and potential barriers to efficient turnover during product assembly.

1. Hicks, L. M.; Mazur, M. T.; Miller, L. M.; Dorrestein, P. C.; Schnarr, N. A.; Khosla, C.; Kelleher, N. L. “Investigating Nonribosomal Peptide and Polyketide Biosynthesis by Direct Detection of Intermediates on >70 kDa Polypeptides by Using Fourier-Transform Mass Spectrometry” ChemBioChem, 2006, 7, 904-907.
2. Chen, A. Y.; Schnarr, N. A.; Kim, C-Y.; Cane, D. E.; Khosla, C.* “Extender Unit and Acyl Carrier Protein Specificity of Ketosynthase Domains of the 6-Deoxyerythronolide B Synthase”  J. Am. Chem. Soc., 2006, 128, 3067-3074.
3. Schnarr, N. A.; Chen, A. Y.; Cane, D.E.; Khosla, C.* "Analysis of Covalently Bound Polyketide Intermediates on 6-Deoxyerythronolide B Synthase by Tandem Proteolysis-Mass Spectrometry" Biochemistry, 2005, 44, 11836-11842.
4. Hartung, I. V.; Rude, M. A.; Schnarr, N. A.; Hunziker, D.; Khosla, C.* "Stereochemical Assignment of Intermediates in the Rifamycin Biosynthetic Pathway by Precusor-Directed Biosynthesis" J. Am. Chem. Soc., 2005, 127, 11202-11203.
5. Schnarr, N. A.; Kennan, A. J.* "pH-Switchable Strand Orientation in Peptide Assemblies" Org. Lett., 2005, 7, 395-398.
6. Schnarr, N. A.; Kennan, A. J.* "Strand Orientation by Steric Matching: a Designed Antiparallel Coiled-Coil Trimer" J. Am. Chem. Soc., 2004, 126, 14447-14451.
7. Schnarr, N. A.; Kennan, A. J.* "Coiled-Coil Surface Presentation: An Efficient HIV gp41 Binding Interface Mimic" J. Am. Chem. Soc., 2004, 126, 10260-10261.
8. Schnarr, N. A.; Kennan, A. J.* "Sequential and Specific Exchange of Multiple Coiled-Coil Components" J. Am. Chem. Soc., 2003, 125, 13046-13051. 
9. Schnarr, N. A.; Kennan, A. J.* "pH Triggered Strand Exchange in Coiled-Coil Heterotrimers"   J. Am. Chem. Soc., 2003, 125, 6364-6365.
10. Schnarr, N. A.; Kennan, A. J.* "Specific Control of Peptide Self-Assembly with Combined Hydrophobic and Hydrophilic Interfaces" J. Am. Chem. Soc., 2003, 125, 667-671.
11. Schnarr, N. A.; Kennan, A. J.* "Peptide Tic-Tac-Toe: Heterotrimeric Coiled-Coil Specifity from Steric Matching of Multiple Hydrophobic Sidechains" J. Am. Chem. Soc., 2002, 124, 9779-9783.
12. Schnarr, N. A.; Kennan, A. J.* "Coiled-Coil Formation Governed by Unnatural Hydrophobic Core   Sidechains" J. Am. Chem. Soc., 2001, 123, 11081-11082.