Berberine from Berberis species

Figure 10. The structure of 5 -methoxyhydnocarpin-D, an MDR inhibitor isolated from Berberis species that enhances the antibacterial activity of berberine.

A new method of bioactivity-directed fractionation, based on multidrug resistant pump (MDR) inhibition in Staphylococcus aureus, was reported for medicinal plants. This work resulted in the isolation, from berberine-containing Berberis species, two compounds that are themselves devoid of antibacterial activity, but that form potent synergistic couples with a sub-inhibitory concentration of berberine. The bacterial MDR pump inhibitors were identified as the flavonolignan 2 and the porphyrin 3 [98]. The isoflavones not only enhanced the antibacterial activity of the natural product, berberine. Fig. 4, but also the activity of synthetic... 

Chandra, P. and Purohit, A. N. 1980. Berberine contents and alkaloid profile of Berberis species from different altitudes. Biochem. Syst. Ecol. 8 379-380. 

Figure 2.6 Biosynthesis of berberine from (5)-reticuline in Berberis species and Coptis japonica. BBE, berberine bridge enzyme SCMT, (5)-scoulerine-9-0-methyltransferase CAS, (5)-canadine synthase STOX, tetrahydroberberine oxidase COX, enzyme found in Coptis japonica.

The formation of the methylenedioxy bridge in Berberis has been found to be caused by the demethylating activity of a peroxidase (POD) found within the vesicle. It was also found that the cytochrome P450-requiring enzyme (canadine synthase) from microsomes of Berberis, Thalictrum and Coptis species formed the methylene bridge in (S)-tetrahydrocolumbamine (Ikezawa et al, 2003), but not in the quaternary alkaloid columbamine (Galneder et al, 1988 Zenk, 1995). Because of the substrate specificity of canadine s)mthase, the berberine pathway is considered to be that presented in Fig. 2.5 (Rueffer and Zenk, 1994). Columbamine, once proposed as an alternative route to berberine, is however converted to palmatine by a specific methyltransferase first isolated from Berberis wilsoniae cell cultures (Rueffer and Zenk, 1985 Ikezawa et al, 2003). 

Scoulerine (145 R = H), the main constituent of Argemone albiflora, had not been previously obtained from Argemone species.The previously named alkaloid HF 1 isolated from Hunnemannia fumariaefolia was found to be identical with ( —)-scoulerine. The co-occurrence of (— )-tetrahydropalmatine (145 R = Me) and (-f )-armepavine in Argemone turnerae has been established for the first time.The isolation and characterization of two artefact alkaloids, berberine chloroform (146 R + R = CH2 R = H,CCl3) and palmatine chloroform (146 R = R = Me, R = H,CCl3), from Berberis lycium have... 

The biosynthesis of protoberberine alkaloids, including berberine, has been extensively studied, and all the enzymes of the biosynthetic pathway have been characterized (11,121,391,508). Interestingly the pathway leading to berberine in Berberis was found to be different from that in Coptis and Thalictrum (509). In the former species berberine is formed from columbamine, in the latter plant species from tetrahydroberberine (121). The production of isoquinoline alkaloids, including the protoberberine alkaloids, by plant cell cultures have been reviewed by Riiffer (390) and Ikuta (510). Table XXVI summarizes patents concerning the production of berberine by means of plant cell cultures. In Table XXVII a summary is given of the occurrence of berberine in some plant cell cultures. 

The lack of strict specificity for the enzymes involved in the initial conversion to (5)-reticuline (20) suggests that stereochemical control does not occur at this stage of biosynthesis (Zenk, 1985). The use of plant cell cultures (both callus and suspension types) from different species of plants that produce benzylisoquinoline alkaloids has proven to be a powerful approach for the isolation of enzymes and intermediates in the pathways leading to these compounds (Zenk et al., 1985). For example, the use of cell-free extracts of Berberis cultures permitted Zenk and co-workers to isolate and characterize all eight enzymes involved in the conversion of dopamine (22) and 4-hydroxyphenylacetaldehyde (19) to (5)-reticuline and, subsequently, to berberine. 

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