509-335-7291, rketchum@wsu.edu

Assistant Research Professor, Institute of Biological Chemistry

Ph.D. 1991, Colorado State University

Research Interests

Taxol (paclitaxel) is one of the most important anti-cancer drugs to have been developed in the last twenty years.   Its role in the treatment of breast, ovarian, and non-small cell lung cancer and in the treatment of AIDS-related Kaposi’s sarcoma, has been well documented.  More recently, Taxol has shown promising results in drug-eluting coronary artery stents used in the treatment of diseased vasculature.  The original source of Taxol was the bark of the Pacific Yew (Taxus brevifolia), which limited its availability, but current production based upon extraction of the drug or its immediate precursors from cell culture or leaf tissue has helped to relieve some of the supply problem.  However, because total synthesis of Taxol is not cost effective, isolation of the drug and its semisynthetic precursors continue to rely on biological sources.  The low abundance of Taxol and Taxol-precursors in cell cultures and leaf tissue, and the complex purification procedures required, are responsible for the relatively high cost of the drug.  Increasing the yield of Taxol and its precursors that can be obtained from natural sources would result in a more reliable supply of the drug and help to reduce the cost of this vitally important medicine. 

Our research approaches the Taxol supply problem from several different directions.  First, our laboratory uses molecular and biochemical approaches to identify, clone, and express the genes in the complex Taxol biosynthetic pathway (it is believed that 19 distinct enzymatic steps are involved in the biosynthesis of Taxol from the primary metabolic precursor, geranylgeranyl diphosphate). Second, we have developed and continue to refine the use of cell cultures derived from yew seeds to produce Taxol in cell cultures, eliminating the need to harvest material from whole plants for our studies.  Third, metabolic profiling (metabolomics) of taxoids produced in cell culture is enabling us to identify targets for potential metabolic engineering by redirecting pathway flux.  Finally, we have developed and are optimizing a system for the transformation of Taxus cells that will lead to the metabolic engineering of the Taxol biosynthetic pathway.        

Selected Publications

Ketchum, R.E.B, Wherland, L., and Croteau, R.B.  2006.  Stable transformation and long-term maintenance of transgenic Taxus cell suspension cultures.  Plant Cell Rep. (submitted).

Ketchum, R.E.B., Horiguchi, T., Qiu, D., Kim, Y.S., Williams, R.M., and Croteau, R.B.  2006.  Feeding cultured Taxus cells with early precursors reveals a bifurcation in the taxoid biosynthetic pathway.  Phytochemistry (submitted).

Ketchum, R.E.B and Croteau, R.B.  2006.  The taxoid metabolome and the elucidation of the paclitaxel biosynthetic pathway in cell suspension cultures of Taxus.  In Plant Metabolomics, Biotechnology in Agriculture and Forestry , K. Saito, R. Dixon, and L. Willmitzer (Eds.), Vol. 57, pp. 291-309, Springer, Heidelberg.

Croteau, R., Ketchum, R.E.B., Long, R.M., Kaspera, R., Wildung, M.R., 2006.  Taxol® biosynthesis and molecular genetics.  Phytochem. Rev. 5:75-97.

Ketchum, R.E.B., Rithner, C.D., Qiu, D., Kim, Y.S., Williams, R.M., and Croteau, R.B.  2003.  Taxus metabolomics: Methyl jasmonate preferentially induces production of taxoids oxygenated at C-13 in Taxus x media cell cultures.  Phytochemistry 62:901-909.

Kahn, M.L., Para-Colmenaras, A., Ford, C.L., Kaser, F., McCaskill, D., and Ketchum, R.E.  2002.  A mass spectrometry method for measuring 15N incorporation into pheophytin.  Anal. Biochem. 307:219-225

Lange, B.M. and Ketchum, R.E.B. 2002. Functional genomics approaches to unravel essential oil biosynthesis.  In J.T. Romeo and R.A. Dixon (eds.). Phytochemistry in the Genomics and Post-Genomics Eras. Recent advances in Phytochemistry 36, pp. 145-162, Pergamon, Amsterdam.

Lange, B.M., Ketchum, R.E.B. and Croteau, R.  2001. Isoprenoid biosynthesis: metabolite profiling of peppermint oil gland secretory cells and application to herbicide target analysis.  Plant Physiol. 127:305-14.

Wheeler, A.L., Long, R.M., Ketchum, R.E., Rithner, C.D., Williams, R.M., Croteau, R.  2001.  Taxol biosynthesis: differential transformations of taxadien-5 alpha-ol and its acetate ester by cytochrome P450 hydroxylases from Taxus suspension cells. Arch. Biochem Biophys. 390:265-78.

Ketchum, R.E.B., Tandon, M., Begley, T., Croteau, R., Gibson, D.M. and Shuler, M.L. 1999.  Isolation of labeled 9-dihydrobaccatin III and related taxoids from cell cultures of Taxus canadensis elicited with methyl jasmonate. J. Nat. Prod. 62:1395-1398.