Office of Biotechnology Publications Office of Biotechnology 11-11-2016 Tropane and Granatane Alkaloid Biosynthesis: A Systematic Analysis Neill Kim Texas Tech University Olga Estrada Texas Tech University Benjamin Chavez Texas Tech University Charles Stewart Jr. Iowa State University, [email protected] John C. D’Auria Texas Tech University Follow this and additional works at: https://lib.dr.iastate.edu/biotech_pubs Part of the Biochemical and Biomolecular Engineering Commons, and the Biotechnology Commons Recommended Citation Kim, Neill; Estrada, Olga; Chavez, Benjamin; Stewart, Charles Jr.; and D’Auria, John C., "Tropane and Granatane Alkaloid Biosynthesis: A Systematic Analysis" (2016). Office of Biotechnology Publications. 11. https://lib.dr.iastate.edu/biotech_pubs/11 This Article is brought to you for free and open access by the Office of Biotechnology at Iowa State University Digital Repository. It has been accepted for inclusion in Office of Biotechnology Publicationsy b an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. Tropane and Granatane Alkaloid Biosynthesis: A Systematic Analysis Abstract The tropane and granatane alkaloids belong to the larger pyrroline and piperidine classes of plant alkaloids, respectively. Their core structures share common moieties and their scattered distribution among angiosperms suggest that their biosynthesis may share common ancestry in some orders, while they may be independently derived in others. Tropane and granatane alkaloid diversity arises from the myriad modifications occurring ot their core ring structures. Throughout much of human history, humans have cultivated tropane- and granatane-producing plants for their medicinal properties. This manuscript will discuss the diversity of their biological and ecological roles as well as what is known about the structural genes and enzymes responsible for their biosynthesis. In addition, modern approaches to producing some pharmaceutically important tropanes via metabolic engineering endeavors are discussed. Keywords tropane alkaloids, granatane alkaloids, secondary metabolism, metabolic engineering Disciplines Biochemical and Biomolecular Engineering | Biotechnology Comments This article is published as Kim, Neill, Olga Estrada, Benjamin Chavez, Charles Stewart, and John C. D’Auria. "Tropane and granatane alkaloid biosynthesis: a systematic analysis." Molecules 21, no. 11 (2016): 1510. DOI: 10.3390/molecules21111510. Posted with permission. This article is available at Iowa State University Digital Repository: https://lib.dr.iastate.edu/biotech_pubs/11 molecules Review Tropane and Granatane Alkaloid Biosynthesis: A Systematic Analysis Neill Kim 1,†, Olga Estrada 1,†, Benjamin Chavez 1, Charles Stewart Jr. 2 and John C. D’Auria 1,* 1 Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061, USA; [email protected] (N.K.); [email protected] (O.E.); [email protected] (B.C.) 2 Office of Biotechnology, Iowa State University, Ames, IA 50011-1079, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-806-834-7348; Fax: +1-806-742-1289 † These authors contributed equally to this article. Academic Editor: Michael Wink Received: 30 September 2016; Accepted: 7 November 2016; Published: 11 November 2016 Abstract: The tropane and granatane alkaloids belong to the larger pyrroline and piperidine classes of plant alkaloids, respectively. Their core structures share common moieties and their scattered distribution among angiosperms suggest that their biosynthesis may share common ancestry in some orders, while they may be independently derived in others. Tropane and granatane alkaloid diversity arises from the myriad modifications occurring to their core ring structures. Throughout much of human history, humans have cultivated tropane- and granatane-producing plants for their medicinal properties. This manuscript will discuss the diversity of their biological and ecological roles as well as what is known about the structural genes and enzymes responsible for their biosynthesis. In addition, modern approaches to producing some pharmaceutically important tropanes via metabolic engineering endeavors are discussed. Keywords: tropane alkaloids; granatane alkaloids; secondary metabolism; metabolic engineering 1. Introduction Plants are sessile organisms and thus evolved natural products or “specialized metabolites” as a chemical response to both biotic and abiotic forces. Specialized metabolites are used by plants to defend themselves and communicate with other plants and organisms in their environments. Whilst the chemical diversity of plant specialized metabolites is vast, with total numbers thought to exceed over 200,000 structures, common themes of structure and function are the result of repeated and convergent evolution of both their biosynthesis and biological roles [1]. Moreover, the chemical structures and underlying biosynthetic enzymes of specialized metabolites serve as inspiration to medicinal and natural product chemists. Many specialized metabolites are pharmacologically active and have been used by humans for therapeutic and recreational purposes since the beginning of recorded history. In particular alkaloids, pharmacologically active cyclic nitrogen containing metabolites derived from amino acids, are known for their pharmacological effects and frequently serve as the starting point for drug development [2]. Some of the oldest domesticated medicinal plants have been those that produce alkaloids. For example, Erythroxylum coca, a species notable for the production of the tropane alkaloid cocaine (1), was used in Peruvian households at least 8000 years ago [3]. Similarly, pomegranate (Punica granatum) has a history of cultivation that goes back at least 10,000 years in Egypt and is well-known for the production of granatane alkaloids [4]. Tropane (TA) and granatane (GA) alkaloids are structural homologues, sharing similar chemical compositions and core scaffolds. Despite their similarities, TAs and GAs show different distribution patterns across the plant kingdom. The N-methyl-8-azabicyclo[3.2.1]-octane core structure of TAs is Molecules 2016, 21, 1510; doi:10.3390/molecules21111510 www.mdpi.com/journal/molecules Molecules 2016, 21, 1510 2 of 25 Molecules 2016, 21, 1510 2 of 24 found in in over over 200 200 alkaloids alkaloids [2,5 [2,,6]5,6 (Figure] (Figure 1).1 ).In In contrast, contrast, N-methyl-9-azabicyclo[3.3.1]-nonane,N-methyl-9-azabicyclo[3.3.1]-nonane, the core the scaffoldcore scaffold of GAs, of GAs, appears appears in considerably in considerably fewer fewer alkaloid alkaloid metabolites metabolites (Figure (Figure 1).1). The The bicyclic corecore structures of TAs and GAs differ by only one carbon atom, yet this difference alters the conformational preferences of each of the core skeletons [[7].7]. Furthe Furthermore,rmore, the presence or absence of a single carbon atom in the core rings of TAs andand GAsGAs altersalters theirtheir chemicalchemical andand pharmacologicalpharmacological activities.activities. Figure 1. ((aa)) The The tropane tropane core core skeleton; skeleton; ( (bb)) The The bicyclic bicyclic granatane granatane core core skeleton. skeleton. Both Both structures structures depict depict their chemically accepted carbon numbering. 1.1. Similarities and Differences in Medicinal Properties Despite their structural similarities TAs and GAsGAs have distinct medicinal properties. TAs have been considered panaceas througho throughoutut recorded history, especially because of their anticholinergic properties. Anticholinergics Anticholinergics are area class a classof compounds of compounds used as useddrugs asto block drugs the to action block of the the actionacetylcholine of the neurotransmitteracetylcholine neurotransmitter to treat motion tosickness treat motionand diseas sicknesses such and as Alzheimer’s diseases such and asParkinson’s Alzheimer’s [8]. andThe methylatedParkinson’s nitrogen [8]. 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