Chapter 1 Rhoeadine Alkaloids

Rönsch, Hasso

doi:10.1016/s0099-9598(08)60113-3

Cited by 5 publications

(4 citation statements)

References 161 publications

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“…Similarly, the role of MTs in the many “unusual” BIA branch pathways has not been investigated. This includes pathways biosynthesizing the rhoeadine alkaloids present in P. rheas (Rönsch, 1986), benzylprotoberberines (e.g., Latifolian A) occurring in Gnetum latifolium (Rochfort et al, 2005), hexahydrobenzophenanthridines (e.g., Corygaline A) occurring in Corydalis bungeana (Gao et al, 2018), as well as the dimeric and trimeric BIAs reported in many species (Schiff, 1991). Biosynthesis of aporphine alkaloids in Nelumbo nucifera (Proteales) has recently received some attention; however, most analyses assumed that central BIA biosynthesis is the same as in Ranunculales and, furthermore, that N. nucifera OMT and NMT homologs catalyze the same reactions as reported in other species (Menéndez-Perdomo and Facchini, 2018).…”

Section: Future Directionsmentioning

confidence: 99%

Molecular Origins of Functional Diversity in Benzylisoquinoline Alkaloid Methyltransferases

Morris

Facchini

2019

Front. Plant Sci.

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O - and N -methylations are ubiquitous and recurring features in the biosynthesis of many specialized metabolites. Accordingly, the methyltransferase (MT) enzymes catalyzing these modifications are directly responsible for a substantial fraction of the vast chemodiversity observed in plants. Enabled by DNA sequencing and synthesizing technologies, recent studies have revealed and experimentally validated the trajectories of molecular evolution through which MTs, such as those biosynthesizing caffeine, emerge and shape plant chemistry. Despite these advances, the evolutionary origins of many other alkaloid MTs are still unclear. Focusing on benzylisoquinoline alkaloid (BIA)-producing plants such as opium poppy, we review the functional breadth of BIA N - and O -MT enzymes and their relationship with the chemical diversity of their host species. Drawing on recent structural studies, we discuss newfound insight regarding the molecular determinants of BIA MT function and highlight key hypotheses to be tested. We explore what is known and suspected concerning the evolutionary histories of BIA MTs and show that substantial advances in this domain are within reach. This new knowledge is expected to greatly enhance our conceptual understanding of the evolutionary origins of specialized metabolism.

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Section: Future Directionsmentioning

confidence: 99%

Molecular Origins of Functional Diversity in Benzylisoquinoline Alkaloid Methyltransferases

Morris

Facchini

2019

Front. Plant Sci.

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“…Specifically, 1-benzazepine is featured in the angiotensin-converting enzyme (ACE) inhibitor benazepril and the cholesteryl ester transfer protein (CETP) inhibitor drug candidate evacetrapib (Figure ). While 2- and 3-benzazepines are quite common in Nature (e.g., aurantioclavine and communesin from fungi and rhoeadine and chilenine from plants , ), 1-benzazepine-containing natural products are relatively rare, with the only reported examples being the two related plant alkaloids, goniomine and kopsiyunnanine L, and penioxalamine A from Penicillium oxalicum (Figure ).…”

Section: Introductionmentioning

confidence: 99%

Biosynthesis of a New Benzazepine Alkaloid Nanangelenin A from Aspergillus nanangensis Involves an Unusual l-Kynurenine-Incorporating NRPS Catalyzing Regioselective Lactamization

Gilchrist

Phan

et al. 2020

J. Am. Chem. Soc.

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1-Benzazepine is a pharmaceutically important scaffold but is rare among natural products. Nanangelenin A (1), containing an unprecedented 3,4-dihydro-1-benzazepine-2,5-dione-N-prenyl-N-acetoxy-anthranilamide scaffold, was isolated from a novel species of Australian fungus, Aspergillus nanangensis. Genomic and retrobiosynthetic analyses identified a putative nonribosomal peptide synthetase (NRPS) gene cluster (nan). The detailed biosynthetic pathway to 1 was established by heterologous pathway reconstitution in A. nidulans, which led to biosynthesis of intermediates nanagelenin B-F (2-5 and 7). We demonstrated that the NRPS NanA incorporates anthranilic acid (Ant) and L-kynurenine (L-Kyn), which is supplied by a dedicated indoleamine-2,3-dioxygenase NanC encoded in the gene cluster. Using heterologous in vivo assays and mutagenesis, we demonstrated that the C-terminal condensation (C T ) and thiolation (T 3 ) domains of NanA are responsible for the regioselective cyclization of the tethered Ant-L-Kyn dipeptide to form the unusual benzazepine scaffold in 1. We also showed that NanA-C T catalyzes the regioselective cyclization of a surrogate synthetic substrate, Ant-L-Kyn-N-acetylcysteamine, to give the benzazepine scaffold, while spontaneous cyclization of the dipeptide yielded the alternative kinetically favored benzodiazepine scaffold. The discovery of 1 and the characterization of NanA have expanded the chemical and functional diversities of fungal NRPSs.

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“…Other initial reactions are C–C phenol coupling or formation of C–C bonds between the isoquinoline and the benzyl moiety leading to aporphines, pavines and isopavines. Alternatively, ( S )‐scoulerine is formed by oxidative C–C bond formation between the N ‐methyl group and carbon‐2 of the benzyl moiety, giving rise to phthalideisoquinolines, protoberberines and protopines, which can be further modified to papaverrubines/rhoeadines and benzophenanthridines (Kutchan, 1998; Rönsch, 1986). Whereas all of these classes of benzylisoquinolines are formed by modification of ( S )‐reticuline, the pathway to the morphinans is initiated by the conversion of stereochemistry at C‐1 from ( S )‐ to ( R )‐reticuline, catalysed in a two‐step reaction including an oxidation of ( S )‐reticuline by 1,2‐dehydroreticuline synthase to the 1,2,‐dehydroreticulinium ion and subsequent reduction of the ion to ( R )‐reticuline by 1,2,‐dehydroreticulinium ion reductase (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Comparative transcript and alkaloid profiling in Papaver species identifies a short chain dehydrogenase/reductase involved in morphine biosynthesis

Ziegler¹,

et al. 2006

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Plants of the order Ranunculales, especially members of the species Papaver, accumulate a large variety of benzylisoquinoline alkaloids with about 2500 structures, but only the opium poppy (Papaver somniferum) and Papaver setigerum are able to produce the analgesic and narcotic morphine and the antitussive codeine. In this study, we investigated the molecular basis for this exceptional biosynthetic capability by comparison of alkaloid profiles with gene expression profiles between 16 different Papaver species. Out of 2000 expressed sequence tags obtained from P. somniferum, 69 show increased expression in morphinan alkaloid-containing species. One of these cDNAs, exhibiting an expression pattern very similar to previously isolated cDNAs coding for enzymes in benzylisoquinoline biosynthesis, showed the highest amino acid identity to reductases in menthol biosynthesis. After overexpression, the protein encoded by this cDNA reduced the keto group of salutaridine yielding salutaridinol, an intermediate in morphine biosynthesis. The stereoisomer 7-epi-salutaridinol was not formed. Based on its similarities to a previously purified protein from P. somniferum with respect to the high substrate specificity, molecular mass and kinetic data, the recombinant protein was identified as salutaridine reductase (SalR; EC 1.1.1.248). Unlike codeinone reductase, an enzyme acting later in the pathway that catalyses the reduction of a keto group and which belongs to the family of the aldo-keto reductases, the cDNA identified in this study as SalR belongs to the family of short chain dehydrogenases/reductases and is related to reductases in monoterpene metabolism.

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Chapter 1 Rhoeadine Alkaloids

Cited by 5 publications

References 161 publications

Molecular Origins of Functional Diversity in Benzylisoquinoline Alkaloid Methyltransferases

Molecular Origins of Functional Diversity in Benzylisoquinoline Alkaloid Methyltransferases

Biosynthesis of a New Benzazepine Alkaloid Nanangelenin A from Aspergillus nanangensis Involves an Unusual l-Kynurenine-Incorporating NRPS Catalyzing Regioselective Lactamization

Comparative transcript and alkaloid profiling in Papaver species identifies a short chain dehydrogenase/reductase involved in morphine biosynthesis

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