Biosynthesis of quinolizidine alkaloids in lupins: mechanistic considerations and prospects for pathway elucidation

Mancinotti, Davide; Frick, Karen M.; Geu‐Flores, Fernando

doi:10.1039/d1np00069a

Cited by 26 publications

(49 citation statements)

References 78 publications

(217 reference statements)

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“…Given the precedent for O-acylations in generating leaving groups for elimination in natural product biosynthesis, (29,30) we next screened BAHD acyltransferase family enzymes for activity, as six unique gene sequences from this family could be found in cluster131. Addition of one acyltransferase (PtACT-1) to the transient co-expression system led to consumption of both (S, S)-5 and (R, The production of (S, S)-6 and (R, S)-6 was consistent with our hypothesis for elimination-mediated formation of the proposed diene (8). Because formation of 8 would require oxidation of the O-acetylated substrate(s), we next screened CYP and 2OGD family enzymes found within cluster131.…”

Section: Discovery Of Novel Scaffold-generating Enzymessupporting

confidence: 86%

“…This is exemplified within the lysine-derived quinolizidine and Lycopodium alkaloids, which serve as the precursors for hundreds of potent, neuroactive compounds,( 7 ) and whose scaffolds are thought to be constructed by unique, undefined chemical transformations for which no enzyme catalyst has been identified in nature. ( 8, 9 ) This inability to predict enzymes that build alkaloid scaffolds confounds the rapid elucidation of biosynthetic pathways in plants, and suggests that there are novel enzyme classes within plant metabolism yet to be identified.…”

Section: Main Textmentioning

confidence: 99%

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Neofunctionalized carbonic anhydrases in the biosynthesis of neuroactive plant alkaloids

Nett

Dho

Tsai

et al. 2022

Preprint

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Plants synthesize numerous alkaloids that mimic animal neurotransmitters. The diversity of alkaloid structures is achieved through the generation and tailoring of unique carbon scaffolds. However, many neuroactive alkaloids belong to a scaffold class for which no biosynthetic route or enzyme catalyst is known. By studying highly coordinated, tissue-specific gene expression in plants that produce neuroactive Lycopodium alkaloids, we identified a new enzyme class for alkaloid biosynthesis: neofunctionalized α-carbonic anhydrases (CAHs). We show that three CAH-like (CAL) enzymes are involved in a cryptic biosynthetic route to a key bicyclic precursor of the Lycopodium alkaloids, and additionally, we describe a series of oxidative tailoring steps that generate the optimized acetylcholinesterase inhibition activity of huperzine A. Our findings suggest a broader involvement of CAL enzymes in specialized metabolism and provide an example for how successive scaffold tailoring steps can drive potency against a natural protein target of interest.

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Section: Discovery Of Novel Scaffold-generating Enzymessupporting

confidence: 86%

Section: Main Textmentioning

confidence: 99%

Neofunctionalized carbonic anhydrases in the biosynthesis of neuroactive plant alkaloids

Nett

Dho

Tsai

et al. 2022

Preprint

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“…In literature, this alkaloid is mainly associated with Lupinus sp. Seeds and described as a minor component 86 , although quinolizidine alkaloids are also synthesised in several tissues of other Fabaceae genera, for instance Genista , Cytisus , and Laburnum 87 , 88 . If this molecule really derived from ingestion of lupin beans, the present outcome would constitute the first clue of consumption of legumes in central-southern Lazio during the Neolithic.…”

Section: Discussionmentioning

confidence: 99%

Neolithic dental calculi provide evidence for environmental proxies and consumption of wild edible fruits and herbs in central Apennines

D’Agostino

Marco

Marvelli³

et al. 2022

Commun Biol

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Looking for a biological fingerprint relative to new aspects of the relationship between humans and natural environment during prehistoric times is challenging. Although many issues still need to be addressed in terms of authentication and identification, microparticles hidden in ancient dental calculus can provide interesting information for bridging this gap of knowledge. Here, we show evidence about the role of edible plants for the early Neolithic individuals in the central Apennines of the Italian peninsula and relative cultural landscape. Dental calculi from human and animal specimens exhumed at Grotta Mora Cavorso (Lazio), one of the largest prehistoric burial deposits, have returned an archaeobotanical record made up of several types of palaeoecological proxies. The organic fraction of this matrix was investigated by a multidisciplinary approach, whose novelty consisted in the application of next generation sequencing to ancient plant DNA fragments, specifically codifying for maturase K barcode gene. Panicoideae and Triticeae starches, together with genetic indicators of Rosaceae fruits, figs, and Lamiaceae herbs, suggested subsistence practices most likely still based on wild plant resources. On the other hand, pollen, and non-pollen palynomorphs allowed us to outline a general vegetational framework dominated by woodland patches alternated with meadows, where semi-permanent settlements could have been established.

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“…In the legume family (Leguminosae/Fabaceae), more than 170 chemical structures belonging to this class of compounds were found, occurring particularly in the lupin species ( Lupinus spp.) [ 2 ]; for this reason, they are commonly referred as “lupin alkaloids” (LAs) [ 3 ]. They are also notable in the genera Baptisia, Thermopsis, Genista, Cytisus, Laburnum, and Sophora [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Development of an HPLC-MS/MS Method for the Determination of Alkaloids in Lupins

et al. 2023

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Lupin alkaloids (LAs) represent a class of toxic secondary metabolites in plants, in particular in Lupinus spp.; they are produced as a defense mechanism due to their strong bitter taste and are very dangerous for human and animals. In this work, a sensitive and reliable high performance liquid chromatography—tandem mass spectrometry (HPLC-MS/MS) analytical method for the identification and quantification of thirteen lupin alkaloids was developed and validated according to FDA guidelines. Efficient extraction and clean-up steps, carried out by solid-phase extraction, were finely tuned on the basis of the characteristics of the analytes and lupin samples, providing good selectivity with minimized matrix interference. The effectiveness of the method was proven by the satisfactory recovery values obtained for most of the analytes and a matrix effect ≤23% for all tested levels. In addition, a sensitive and reliable determination of the target compounds was obtained; LOQs were between 1 and 25 µg Kg−1, i.e., below the requested maximum levels (<200 mg Kg−1). The method was applied to evaluate the LAs profile in different batches of raw L. albus L. samples, varying in size and across farming treatments.

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Biosynthesis of quinolizidine alkaloids in lupins: mechanistic considerations and prospects for pathway elucidation

Abstract: This review summarizes the different hypotheses surrounding the biosynthesis of quinolizidine alkaloids in lupins and discusses strategies for gene discovery and pathway elucidation.

Cited by 26 publications

References 78 publications

Neofunctionalized carbonic anhydrases in the biosynthesis of neuroactive plant alkaloids

Neofunctionalized carbonic anhydrases in the biosynthesis of neuroactive plant alkaloids

Neolithic dental calculi provide evidence for environmental proxies and consumption of wild edible fruits and herbs in central Apennines

Development of an HPLC-MS/MS Method for the Determination of Alkaloids in Lupins

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