Aristolochene

This enzyme [EC 2.5.1.40] catalyzes the conversion of trms,trans-fainesyl diphosphate (or, trans,trans-farnesyl pyrophosphate) to aristolochene and diphosphate (or, pyrophosphate). The enzyme-catalyzed reaction proceeds through an initial internal transfer of the farnesyl... 

OCTOPINE DEHYDROGENASE ARGININOSUCCINATE LYASE ARGININOSUCCINATE SYNTHETASE ARISTOLOCHENE SYNTHASE Arogenate dehydrogenase,... 

F. Ewing. 5-Epi-aristolochene is a common precursor of the sesquiterpenoid phytoalexins capsidiol and debneyol. Phytochemistry 1989 28(3) 775-779. Borys, D. J., S. C. Setzer, L. J. Ling. CNS depression in an infant after the ingestion of tobacco A case report. Vet Hum Toxicol 1988 30(1) 20-22. Deutsch, H. M., K. Green, and L. H. Zalkow. Water soluble high molecular weight components from plants with potent intraocular pressure lowering activity. Curr Eye Res 1987 6(7) 949-950. 

Most of the compounds shown in Figure 22-4 are derived from the C15 famesyl diphosphate. There are more than 300 known cyclic structures among these sesquiterpenes, and many sesquiterpene synthases have been characterized.91/91a Aristolochene is formed by the action of a 38-kDa cyclase that has been isolated from species of Penicillium and Aspergillus,92"4 Notice that the synthesis must involve two cyclization steps and migration of a methyl group. Three-dimensional structures are known for at least two terpene synthases,95 96 and comparison of gene sequences suggests that many others have similar structures. 

The 5-epi-aristoIochene synthase of tobacco makes the 5-epimer of aristolochene (Fig. 22-4). It binds the diphosphate group within a central cavity using two Mg2+ ions held by carboxylates, some of which are in the DDXXD sequence found also in polyprenyl diphosphate synthases. The enzyme active sites of both the epi-aristolochene synthase and a pentale-nene synthase from Streptomyces96 are rich in polar groups that form hydrogen-bonded networks and which participate in proton abstraction and donation during the rearrangement reactions that must occur. 

Aristolochene, parent hydrocarbon of many fungal toxins... 

Figure 22-4 More terpenes and related substances. The numbers in parentheses on the aristolochene structure are those of atoms in the precursor farnesyl diphosphate.

The formation of the sesquiterpene (+)-5-epi-aristolochene (2) represents, from a biosynthetic point of view, the transformation requiring the fewest steps among those discussed in this review. A single enzyme, tobacco 5-epi-aristolochene synthase (TEAS), converts the biosynthetic precursor, farnesyl diphosphate (6), to... 

Fig. 3 Proposed mechanisms for the formation of (+)-5-epi-aristolochene (2) and (-)-premnaspir-odiene (3) from famesyl-diphosphate (6) by the action of TEAS and HPS, respectively...

Unlike the biosynthetic route to 2 and 3, the synthetic approaches to these molecules are characterized, instead, by deconstruction of terpene natural products further along the biosynthetic pathway. Preparation of (+)-5-epi-aristolochene (2) has so far only been carried out using a semisynthetic strategy from the natural product 12 [27], which is available from pepper (Capsicum annum) fruits in high quantities [28]. The synthetic route started with O-acetylation of 12 to give... 

Figure 10.11 A proposed pathway for the biosynthesis of capsidiol in elicitor-treated tobacco cell cultures. Earlier work had not resolved how 5-epi-aristolochene, synthesized from FPP by the action of 5-epi-aristolochene synthase, was converted to capsidiol.

Figure 10.12 Gas chromatograms of the reaction products formed upon incubation of microsomes isolated from yeast over-expressing a tobacco terpene hydroxylase gene (panels A C) (CYP71D20) or harboring only the expression vector DNA (control) (B D). Microsomes were incubated with 5-epi-aristolochene (A B) or 1-deoxycapsidiol (C D) in the presence (blue line) or absence (red line) of NADPH. 5-epi-aristolochene, 1-deoxycapsidiol and capsidiol were all verified by MS.58...

CANE, D. E., TSANTRIZOS, Y. S., Aristolochene synthase. Elucidation of the cryptic germacrene A synthase activity using the anomalous substrate dihydrofamesyl diphosphate, J. Amer. Chem. Soc., 1996,118,10037-10040. 

CANE, D. E., KANG, I., Aristolochene synthase purification, molecular cloning, high-level expression in Escherichia coli, and characterization of the Aspergillus terreus cyclase, Arch. Biochem. Biophys., 2000,376,354-364. 

CARUTHERS, J. M., KANG, I., RYNKIEWICZ, M. J., CANE, D. E., CHRISTIANSON, D. W., Crystal structure determination of aristolochene synthase from the blue cheese mold, Penicillium roqueforti, J. Biol. Chem., 2000, 275, 25533-25539. 

STARKS, C. M., BACK, K. W., CHAPPELL, J., NOEL, J. P, Structural basis for cyclic terpene biosynthesis by tobacco 5- epi-aristolochene synthase, Science, 1997, 111, 1815-1820. 

Whitehead, I.M., Threlfall, D.R., Ewing, D.F., 5-epi-aristolochene is a common precursor of the sesquiterpenoid phytoalexins capsidiol and debneyol, Phytochemistry, 1989,28,775-779. 

Hoshino, T., Yamaura, T., Imaishi, H., Chida, M., Yoshizawa, Y., Higashi, K., Ohkawa, H., Mizutani, J., 5-e/w-aristolochene 3-hydroxylase from green pepper, Phytochemistry, 1995,38,609-613. 

RALSTON, L., KWON, S. T., SCHOENBECK, M., RALSTON, J., SCHENK, D. J., COATES, R. M., CHAPPELL, J., Cloning, heterologous expression, and functional characterization of 5-epi-aristolochene-l,3-dihydroxylase from tobacco (Nicotiana tabacum., Arch. Biochem. Biophys., 2001, 393,222-235. 

Cane, D.E., and Bryant, C. (1994). Aristolochene synthase. Mechanism-based inhibition of a terpenoid cyclase. J Am Chem Soc 116 12063-12064. 

The recently published crystal structure of tobacco epi-aristolochene synthase (a sesquiterpene synthase) has provided the first look at the three-dimensional configuration of a plant terpene s)mthase (Starks et al, 1997). 

Figure 5.8 Examples of oxidative secondary transformations in terpenoid biosynthesis, (a) Hydroxylation of epi-aristolochene at the 3-position by a cytochrome P450-dependent terpene hydroxylase in Capsicum annuum (Hoshino et ai, 1995). (b) Conversion of GA12 to CA9 by a 2-oxoglutarate-dependent dioxygenase involved in gibberellin biosynthesis.

---