Thomas Hemscheidt

Associate Professor

University of Hawaii at Manoa
Department of Chemistry
2545 McCarthy Mall,
Honolulu,HI 96822-2275

Phone: (808) 956-6401
Fax: (808) 956-5908
Email: tomh@gold.chem.hawaii.edu

received his undergraduate education at the Ruhr-Universität Bochum, Germany, and his Ph.D. from the Ludwig-Maximilians-Universität München, Germany, in 1983. After postdoctoral work at McMaster University in Hamilton, Ont., Canada, from 1983 to 1985 he remained at that institution as a Research Associate. In 1991 he moved to the University of Hawaii as an Assistant Researcher and Head of the Enzymology and Molecular Biology Facility in the Natural Products Program in the Department of Chemistry. In 1996 he assumed his current position as Assistant Professor in the Department of Chemistry.

The emphasis of my research program is in the area of natural products chemistry, specifically biosynthesis and the isolation of natural products from plants and fungi.

BIOSYNTHESIS

            From the very beginning when structures of natural products were first established, chemists have been interested in the question how the producing organisms elaborate these fascinating structures. Consequently, over the past 40 years considerable progress has been made in establishing a reasonably accurate picture of these processes. The current interest is mostly focussed firstly on mechanistic questions and secondly on approaches to manipulate these pathways to arrive at new natural products by means of genetic engineering techniques.

				Alkaloids. We have been working over the past several years on a study of the mechanism of formation of a group of alkaloids that at first glance may not appear to be related structurally, namely the tropane alkaloids, e.g. 1, and the lycopodium alkaloids such as lycopodine 2. Studies to elucidate the mechanism by which the tropane nucleus is formed are ongoing. The simplicity of the structure belies the difficulty of the problem which has seen much work over the past 40 years without a definitive, mechanistically satisfying picture emerging. I have summarized the extant evidence in a recent review ( Topics in Current Chemistry Vol. 209 pp. 177-206, Springer Verlag, 2000.
	Vitamin B6 and Ginkgotoxin. There is considerable evidence that the biosynthesis of pyridoxine 3 is different in prokaryotes(bacteria) and eukaryotes, but only in the former group of organisms, specifically in E. coli, has it been possible to elucidate this process in detail. Ginkgotoxin 4, the 4’-O-methylether of pyridoxine, is a neurotoxin that occurs in the leaves of the maidenhair tree, Ginkgo biloba. Cell cultures and seedlings of the tree produce enough of this toxin to allow the study of the biosynthesis of this vitamin in plants. While first results suggested that the biosynthetic pathway in E. coli and Ginkgo is related (Fiehe et al. J. Nat. Prod., 2000, 63, 185-189), as yet unpublished results have shown unequivocally that this is not the case. We are investigating the biosynthesis of ginkgotoxin and of pyridoxine in yeast as models for the eukaryotic pathway using both chemical and biochemical approaches.
	Tolytoxin. Tolytoxin is a cytotoxic compound formed by the blue-green alga ( cyano bacterium) Scytonema ocellatum. It was discovered several years ago by the group of Prof. Moore in collaboration with Dr Greg Patterson, formerly also of this department. We have begun to search for the genecluster that encodes the formation of this natural product. The goal of this work is to understand how the stereochemistry of the methyl groups is controlled and to use this information to prepare analogs of this compound for biological evaluation. The mechanism of formation of the unusual enamide moiety is also of interest.
	ISOLATION AND STRUCTURE ELUCIDATION. In collaboration with Dr. Susan Mooberry at the Southwest Foundation for Biomedical Research in San Antonio, TX, we have been screening for and isolating natural products with activity against the cytoskeleton, specifically microtubules and microfilaments. These structures are vital for a variety of cell functions and are formed by the reversible polymerization of proteins. Our biological assay detects compounds that interfere with the polymerization as well as with breakdown of assembled cytoskeletal structures.
					Recent examples of active compounds isolated include the microtubule poison taccalonolide A 1 from a plant and the antimicrofilament agent nomofungin 2 from a cultured endophytic fungus. We are currently studying the chemistry of taccalonolide to understand which structural features of the molecule are essential for biological activity.

Some recent publications:

• Norman, B.H., Hemscheidt, T., Schultz, R.M. and Andis, S.L.. Total synthesis of cryptophycin analogs. Isosteric replacement of the C-D ester J. Org. Chem., 1998, 63, 5288-5294
• Burgoyne, D.L.; Hemscheidt, T.; Moore, R.E. and Runnegar, M.T. Biosynthesis of cylindrospermopsin in Cylindrospermum raceborskii.J. Org. Chem. 2000, 65, 152-156
• Hemscheidt, T. Tropane and related alkaloids. Top. in Curr. Chem. Vol. 209, pp.175-206, Springer Verlag, 2000
• Fiehe, K., Arenz, A., Drewke,C., Hemscheidt, T., Richardson, R. T. and Leistner, E. Biosynthesis of 4’-O-Methylpyridoxine (Ginkgotoxin) from primary precursors. J. Nat. Prod., 2000, 63, 185-189
• van der Kaaden, J.D., Hemscheidt, T. and Mooberry, S.L. Mappain, A new cytotoxic stilbene from Macaranga mappa. J. Nat. Prod., 2000, 63, xxx