Biosynthesis tropane alkaloids

Humphrey AJ, O Hagan D (2001) Tropane alkaloid biosynthesis. A century old problem unresolved. Nat Prod Rep 18 494-502... 

Figure 7.9 Intercellular and subcellular trafficking in alkaloid biosynthesis. A. Tropane alkaloid biosynthesis in Hyoscyamus muticus. B. Terpenoid indole alkaloid biosynthesis in Catharanthus roseus. C. Trafficking of the berberine bridge enzyme in Papaver somniferum cell cultures.

HASHIMOTO, T., YAMADA, Y., Tropane alkaloid biosynthesis Regulation and application, pp. 122-134, in Proceedings of the Seventh Annual Pennsylvania State Symposium in Plant Physiology, American Society of Plant Physiologists Press, Rockville. 1992. 

NAKAJIMA, K., HASHIMOTO, T., Two tropinone reductases, that catalyze opposite stereospecific reductions in tropane alkaloid biosynthesis, are localized in plant root with different cell-specific patterns. Plant Cel Physiol., 1999,40, 1099-1107. 

HASHIMOTO, T., HAYASHI, A., AMANO, Y, KOHNO, J., IWANARI, H., USUDA, S., YAMADA, Y., Hyoscyamine 6P-hydroxylase, an enzyme involved in tropane alkaloid biosynthesis, is localized at the pericycle of the root. J. Biol. Chem., 1991,266, 4648-4653. 

Several enzymes of tropane alkaloid biosynthesis have been purified and characterized from root cultures namely, putrescine N-methyltransferase from D. stramonium (Walfon et al, 1994) and H. niger (Hibi et al, 1992) and fropinone reducfases I and II from Atropa belladonna (Drager and Schaal, 1994), D. stramonium (Porfsfeffen et al, 1992, 1994) and H. niger (Hashimoto and Yamada, 1994). TR I and TR II have been characterized by X-ray crystallography (Nakajima et al, 1998). 

Rabot, S., Peerless, A.C.J. and Robins, R.J. (1995) Tigloyl-CoA pseudotropine acyl transferase a novel enzyme of tropane alkaloid biosynthesis. Phytochemistry, 39, 315-22. 

Tropane alkaloid biosynthesis has been studied at the biochemical level, and several enzymes from the biosynthetic pathway have been isolated and cloned, although the pathway has not been elncidated completely at the genetic level (Fig. 3b) (138). L-arginine is converted to the nonproteogenic amino acid L-omithine by the nrease enzyme arginase. Ornithine decarboxylase then decarboxylates ornithine to yield the diamine pntrescine. In Hyoscyamus, Duboisia, and Atropa, putrescine serves as the common precnrsor for the tropane alkaloids. 

There are considerable literatures on the production of tropane alkaloids in tissue and cell cultures derived firom various parts of intact plants [4]. In a number of cases, root differentiation is required for enhanced tropane alkaloid biosynthesis [3, 5]. The production of the economically valuable tropane alkaloids, scopolamine and hyoscyamine, by these cultures has not been commercially successful, however, root cultures are so far the best system to investigate the production and biosynthesis of tropane alkaloids. 

A key branch point in tropane alkaloid biosynthesis is the conversion of tropinone into either tropine or pseudotropine (or i/ -tropine), which possess opposite stereochemistry at the 3-hydroxyl position. Two different NADPH-dependent enzymes catalyze the stereospecilic reduction of tropinone the 3-carbonyl of tropinone is reduced to the 3a-hydroxy group of tropine by tropinone reductase I (TR-I) and to the 3jS-hydroxy group of pseudotropine by tropinone reductase II (TR-II). Genes encoding both TR-I and TR-II have been identified in the tropinone... 

Keywords. Tropanes, Alkaloids, Biosynthesis, Mannich condensation... 

The question of whether (22) is produced by Path D1 or D2 really amounts to the question of whether an enzyme can form an enol or enolate of a methyl ketone, e.g. at C-4 of acetoacetate or at C-3 of hygrine (16). Current thinking on the role of hygrine (16) in tropane alkaloid biosynthesis would suggest that this is not possible. If one considers all four pathways of Scheme 8 and the subsequent steps required to convert (16) or (22) into tropinone (18), shown in Scheme 10, one can see that pathways Cl, C2 and Dl, respectively, involve enolization of a methyl ketone, which is not nearly as easy as enolization of a -dicarbonyl compound. Only Path D2, which invokes (21) and (22) as intermediates, postulates that all of the carbon-carbon bond-forming reactions receive the benefit of stabilization of the nucleophile via a -dicarbonyl system (assiuning the acetate imits are intro duced stepwise via malonate or its CoA ester). The only experimental fact not in accord with this last proposal is the failure so far to achieve incorporation of (21) into (1) or (19). A new proposal for the formation of (22) which circiun-vents this problem will be introduced in Section 5 of this contribution. 

Artificial polyploidy bioreactor hairy roots hyoscyamine plant cell cultures scopolamine tropane alkaloids biosynthesis... 

Tropane alkaloid Biosynthesis Scopolamine, nicotine, hygrine, calystegines Bl, calystegines B2, spermidine, spermine, cocaine, tropinone, littorine, tropine... 

Jirschitzka J, Schmidt GW, Reichelt M, Schneider B, Gershenzon J, D Auria JC (2012) Plant tropane alkaloid biosynthesis evolved independently in the Solanaceae and Erythroxylaceae. Proc Natl Acad Sci U S A109 (Copyright (C) 2012 U.S. National Library of Medicine.) 10304-10309... 

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