Acridone alkaloid biosynthesis

Acridone alkaloids comprise a relatively small group of alkaloids that are found solely in some Rutaceae genera. Some 100 examples of this alkaloid group have been isolated and these include the monomeric acridones and the acridone-coumarin dimers (acrimarines) isolated from Citrus plants some binary alkaloids have recently been isolated and described (Takamura et al, 1995). 

The monomeric acridone alkaloids are derived from anthranilic acid and acetate via a polyketide. First studies, in which [ C]-acetate was utilized by cell cultures of Ruta graveolens, indicated that the C-ring of the acridone nucleus was acetate derived. Further research revealed that anthranilic acid is specifically incorporated into the A-ring of rutacridone (Baumert et al, 1982). 

Synthesized 1,3-dihydroxy-N-methylacridone is readily incorporated into rutacridone by cell-free extracts of Ruta graveolens (Maier et al, 1993). It has been hypothesized that the final step in the biosynthesis of these alkaloids 

The Ruta alkaloids are usually found in idioblasts and early experiments using fluorescent microscopy, and Ruta graveolens showed heavy deposits of acridone alkaloids in the xylem (Wink and Roberts, 1998). 

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Baumert A, Schmidt J, Groger D (1993) Synthesis and mass spectral analysis of coenzyme a thioesters of anthranilic acid and its iV-methyl derivative involved in acridone alkaloid biosynthesis. Phytochem Anal 4 165-170... 

Keywords alkaloid biosynthesis alkaloid genes nicotine tropane alkaloids pyrrolizidine alkaloids benzylisoquinoline alkaloids monoterpene indole alkaloids ergot alkaloids acridone alkaloids purine alkaloids taxol betalains... 

C]Tryptophan gave inactive alkaloids but tritiated 2,4-dihydroxy-quinoline (34) and its N-methyl derivative were incorporated into (47) (0.009 % and 0.020% respectively) an early route had suggested the derivation of what was essentially (34) from tryptophan. Radioisotope dilution showed the presence of both these quinoline precursors together with iV-acetyl- and N-methyl-anthranilic acid in A. baueri. A satisfactory incorporation of N-methylanthranilic acid into (47) was found in Evodia xanthoxyloides, and this, together with its natural occurrence, indicates that early methylation may be important in the biosynthesis of acridone alkaloids. 

PMT and H6H, which catalyze the first and last steps, respectively, in the biosynthesis of the tropane alkaloid scopolamine (Scheme 3), were localized to the pericycle in the roots of A. belladonna and Hyoscyamus muticus (Fig. 2A) 132,145). PMT also catalyzes the first step in nicotine biosynthesis (Scheme 3) and has been localized to the endodermis, outer cortex, and xylem in N. sylvestris (244,245). In contrast, TR-I, an intermediate enzyme in the tropane alkaloid pathway, resides in the endodermis and nearby cortical cells (Fig. 2A) (135) thus, intermediates of tropane alkaloid metabolism must also be transportai between cell types. The biosynthesis and storage of acridone alkaloids were also associated with endodermis in Ruta graveolens (246). 

Tables 24.1-24.31 list the different types of alkaloids indicated with then-sources [1-162], and include research on quinolin/ones, quinazolin/one, and acridone alkaloids also listed in other reviews [1-42]. In order to bring up-to-data the distribution of these alkaloids the search was carried out in Chemical Abstracts (SciFinder) and Web of Science (to June, 2012). The biosynthesis of the alkaloids is discussed. In recent years, a number of these alkaloids have been found to possess real pharmacological activity, which will be discussed in the following sections.

No data is available on the biosynthesis of dimeric acridone alkaloids, which have been found in Rutaceae. Acridone-coumarin/xanthone/Ugnin dimers have also been found in Rutaceae (Table 24.17). The bark of the New Caledonia tree Sarcomelicope megistophylla (Rutaceae) have yielded an intriguing range of... 

Scheme 24.10 Biosynthesis (for 33 and 34, l",2"-dehydro) and biogenesis of the acridone alkaloids...

Rohde B, Hans J, Martens S, Baumert A, Hunziker P, Matem U (2008) Anthranilate N-methyltransferase, a branch-point enzyme of acridone biosynthesis. Plant J 53 541-553 Maier W, Schumann B, Groger D (1990) Biosynthesis of acridone alkaloids formation of rutacridone by cell-free extracts of Ruta graveolens cell suspension cultures. FEBS Lett 263 289-291... 

The biosynthetic pathway to rutacridone, which was isolated from Ruta graveolens (Rutaceae), was studied in detail using the cell culture method [4,5]. According to these results, the biosynthetic precursors of rutacridone are anthranilic acid, acetic acid, and an isopentenyl unit, as in the case of the quinoline alkaloids described in the previous section. However, in the biosynthesis of rutacridone, two additional C2 units participate in the biosynthesis of the acridone nucleus compared with the biosynthesis of quinoline alkaloids. 

The biosynthesis of the main groups of quinoline, acridone, and quinazoline alkaloids is established. However, a great deal of more detailed work remains to be done. The topics included here have been selected to stimulated further experimental biosynthetic research in the area. 

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