Biosynthesis of Beneficial Alkaloids

Prof. Meinhart H. Zenk

Lehrstuhl fur Pharmazeutische Biologie,Ludwig-Maximilians-Universit?t M?nchen
Karlstr. 29, 80333 M?nchen, Germany

Alkaloids have a considerable role amongst natural products used in medicine. With the advent of molecular biology, it is now possible to engineer pathways for these natural products to conform with human needs. The prerequisite, however, is first to map out the complete pathway for a given compound at the metabolite and enzyme level. Examples will be given for the isoquinoline pathway, leading to morphine both in the poppy plant and in mammals. The biosynthesis of colchicine, which is characterized by a unique tropolone ring, will be discussed in detail as well as galanthamine, a potential drug directed against Alzheimer's disease. The formation of the taxane nucleus, present in the anticancer drug taxol, which is formed by the alternative terpenoid pathway involving 1-deoxyxylulose will be presented.

In considerable detail, the biosynthesis to morphine alkaloids will be presented. Starting from two molecules of tyrosine, the complete pathway leading to (S)-reticuline will be described. (S)-reticuline is an important branchpoint intermediate in isoquinoline alkaloid biosynthesis. In the morphine pathway this intermediate is transformed to dihydroreticuline, which then in turn is reduced to the (R)-configuration. This latter compound serves as a direct precursor to the morphinan alkaloids. The role of cytochrome P-450 enzymes in this transformation will be stressed and also the metabolic channelling between laticifers and surrounding parenchyma cells. The problem of trafficking and storage will be addressed.

The necessity to completely understand pathways leading to alkaloids prior to successful modification of plants and plant cell cultures will be discussed.