Some of the more interesting aspects of natural product biosynthesis are the variations on common themes. A case in point is the shikimate pathway. Starting with the condensation of phosphoenolpyruvate with D-erythrose 4-phosphate, the shikimate pathway has been the focus of intense scrutiny. One variant of the shikimate pathway is found in Amycolatopsis mediterranei where 1-imino-1-deoxy-D-erythrose 4-phosphate replaces D-erythrose 4-phosphate as the likely starting point of what has been named the aminoshikimate pathway. The hypothesis that 3-amino-3-deoxy-D-fructose 6-phosphate is the source of 1-imino-1-deoxy-D-erythrose 4-phosphate will be explored. In turn, the biosynthesis of 3-amino-3-deoxy-D-fructose 6-phosphate is to be elaborated. Beyond answering fundamental biosynthetic questions associated with the source of the nitrogen atom utilized by the aminoshikimate pathway, proposed research could ultimately lead to a biocatalytic route to aminoshikimic acid suitable for use in the synthesis of anti-influenza agents. A second variant of the shikimate pathway is to be created in Escherichia coli where phosphoenolpyruvate will be replaced by pyruvate as the three-carbon metabolite condensed with D-erythrose 4-phosphate. This will require recruitment of native and evolved 2-keto-3-deoxy-6-phosphogalactonate aldolase to catalyze the condensation of pyruvate with D-erythrose 4-phosphate. Initiating the shikimate pathway with the condensation of pyruvate with D-erythrose 4-phosphate could substantially improve the yields of pharmaceutically important molecules microbially synthesized by way of this pathway and may serve as a paradigm of shikimate pathway variants employed by microbes under anaerobic growth conditions.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM065541-01
Application #
6465605
Study Section
Special Emphasis Panel (ZRG1-SSS-B (01))
Program Officer
Jones, Warren
Project Start
2002-04-01
Project End
2006-03-31
Budget Start
2002-04-01
Budget End
2003-03-31
Support Year
1
Fiscal Year
2002
Total Cost
$282,257
Indirect Cost
Name
Michigan State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
193247145
City
East Lansing
State
MI
Country
United States
Zip Code
48824