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(Last
modification: 12. May 2010)
Proposal: Type III PKS in quinoline alkaloid biosynthesis
(Key
reference for proposal: Dewick, 1997)
There
are promising candidates for the participation of a one-step condensation in
the biosynthesis of certain alkaloids: the
quinolines
(the same backbone is in
quinine, but careful: this is derived from an indole alkaloid!).
The family of Rutaceae
apparently has lots of these alkaloids. If you want to know more: there are
regular reviews of these compounds and their medicinal potential (Michael,
1997; 1999; 2000; 2001; 2002; 2004; 2005; 2007).
The proposed reaction involves anthraniloyl-CoA (or N-methylanthraniloyl-CoA) as starter and one
condensation with malonyl-CoA to synthesize the backbone. See also the
interesting description in Dewick (1997).
Figure 1 shows the principle:
The next figure shows some examples for compounds possibly
synthesized via such reaction:
To the best of my knowledge the enzyme reaction has not yet been demonstrated in
extracts from plants synthesizing such natural products, and there are also no
cDNA candidates for such reaction.
However, there are some rather interesting experiments with
the
benzalacetone synthase (BAS);
they provide good arguments for the hypothesis that type III PKS could be
involved in the biosynthesis of certain
quinoline alkaloids. The physiological
function of BAS uses 4-coumaroyl-CoA as starter and performs one condensation
with malonyl-CoA; this reaction synthesizes the backbone of the main aroma
component in raspberry (more...). The recombinant BAS from Rheum palmatum
(more...) was
tested with anthraniloyl-CoA and N-methylanthraniloyl-CoA:
it accepted both, and not only with malonyl-CoA as chain extender, but
methylmalonyl-CoA was also accepted
(Abe
et al., 2006); see the reaction scheme below. The highest product yield
actually was with the combination
N-methylanthraniloyl-CoA and methylmalonyl-CoA, and that was quite
unexpected. Another remarkable finding: the enzyme always carried out only one
condensation with these substrates. This was a bit surprising since this BAS could
easily carry out two condensation reactions with 4-coumaroyl-CoA, its
physiological substrate, and actually two condensations instead of one were the
dominant reactions at pH 6 (more...).
Taken together, these
findings provide good points for a hypothesis that type III PKS might play key
roles in the biosynthesis of certain quinoline alkaloids.
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References
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Abe, I., Abe, T., Wanibuchi, K., Noguchi, H., 2006.
Enzymatic
formation of quinolone alkaloids by a plant type III polyketide synthase.
Organic Letters 8, 6063-6065.
Benzalacetone
synthase from Rheum palmatum efficiently catalyzed condensation
of N-methylanthraniloyl-CoA (or anthraniloyl-CoA) with
malonyl-CoA (or methylmalonyl-CoA) to produce 4-hydroxy-2(1H )-quinolones,
a novel alkaloidal scaffold produced by a type III polyketide synthase (PKS).
Manipulation of the functionally divergent type III PKSs by
non-physiological substrate thus provides an efficient method for
production of pharmaceutically important quinolone alkaloids
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Dewick, P. M., 1997. Medicinal Natural
Products - A Biosynthetic Approach, page 351. John Wiley & Sons,
Chichester.
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Reviews
-
Michael, J. P., 1997. Quinoline, quinazoline and acridone alkaloids.
Natural Product Reports 14, 11-20.
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Michael, J. P., 1999. Quinoline, quinazoline and acridone alkaloids.
Natural Product Reports 16, 697-709.
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Michael, J. P., 2000. Quinoline, quinazoline and acridone alkaloids.
Natural Product Reports 17, 603-620.
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Michael, J. P., 2001. Quinoline, quinazoline and acridone alkaloids.
Natural Product Reports 18, 543-559.
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Michael, J. P., 2002. Quinoline, quinazoline and acridone alkaloids.
Natural Product Reports 19, 742-760.
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Michael, J. P., 2003. Quinoline, quinazoline and acridone alkaloids.
Natural Product Reports 20, 476-493.
-
Michael, J. P., 2004. Quinoline, quinazoline and acridone alkaloids.
Natural Product Reports 21, 650-668.
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Michael, J. P., 2005. Quinoline, quinazoline and acridone alkaloids.
Natural Product Reports 22, 627-646.
-
Michael, J. P., 2007. Quinoline, quinazoline and acridone alkaloids.
Natural Product Reports 24, 223-246.
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