Identification and characterization of methyltransferases involved in benzylisoquinoline alkaloids biosynthesis from Stephania intermedia

Zhao, Wanli; Shen, Chen; Zhu, Jinqian; Ou, Chenhui; Liu, Manyu; Dai, Wenling; Liu, Xiufeng; Liu, Jihua

doi:10.1007/s10529-019-02785-0

Cited by 13 publications

(8 citation statements)

References 35 publications

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“…Similarly, products 13 (m/z = 314.17) and 12 (m/z = 328.19) were confirmed as armepavine and 7-O-methylmagnocurarine, respectively (Figure S8e,f). These LC-MS/MS data analyses were consistent with previous reports in BIA-containing species, such as N. nucifera, Papaver rhoeas, and Stephania intermedia (Men endez-Perdomo Oh et al, 2018;Sim et al, 2015;Xiao et al, 2018;Zhao et al, 2020). Conclusively, among the six LcOMTs and the four LcNMTs in L. chinense, the LcOMT1 is a BIA 6OMT that regiospecifically methylates (S)-norcoclaurine (1) at the C6 site, LcOMT3 is a BIA 7OMT accepting (S)-coclaurine (2) and its derivates as substrates, and LcNMT1 catalyzes (S)-coclaurine (2) into mono-or dimethylated products (Figure 2a,b).…”

Section: Lcomt1 Methylates (S)-norcoclaurine Lcomt3 and Lcnmt1 Methyl...supporting

confidence: 91%

Characterization of benzylisoquinoline alkaloid methyltransferases in Liriodendron chinense provides insights into the phylogenic basis of angiosperm alkaloid diversity

et al. 2022

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SUMMARY Benzylisoquinoline alkaloids (BIAs) are a class of plant secondary metabolites with great pharmacological value. Their biosynthetic pathways have been extensively elucidated in the species from the Ranunculales order, such as poppy and Coptis japonica, in which methylation events play central roles and are directly responsible for BIA chemodiversity. Here, we combined BIA quantitative profiling and transcriptomic analyses to identify novel BIA methyltransferases (MTs) from Liriodendron chinense, a basal angiosperm plant. We identified an N‐methyltransferase (LcNMT1) and two O‐methyltransferases (LcOMT1 and LcOMT3), and characterized their biochemical functions in vitro. LcNMT1 methylates (S)‐coclaurine to produce mono‐ and dimethylated products. Mutagenesis experiments revealed that a single‐residue alteration is sufficient to change its substrate selectivity. LcOMT1 methylates (S)‐norcoclaurine at the C6 site and LcOMT3 methylates (S)‐coclaurine at the C7 site, respectively. Two key residues of LcOMT3, A115 and T301, are identified as important contributors to its catalytic activity. Compared with Ranunculales‐derived NMTs, Magnoliales‐derived NMTs were less abundant and had narrower substrate specificity, indicating that NMT expansion has contributed substantially to BIA chemodiversity in angiosperms, particularly in Ranunculales species. In summary, we not only characterized three novel enzymes that could be useful in the biosynthetic production of valuable BIAs but also shed light on the molecular origin of BIAs during angiosperm evolution.

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Section: Lcomt1 Methylates (S)-norcoclaurine Lcomt3 and Lcnmt1 Methyl...supporting

confidence: 91%

Characterization of benzylisoquinoline alkaloid methyltransferases in Liriodendron chinense provides insights into the phylogenic basis of angiosperm alkaloid diversity

et al. 2022

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“…2 C). Notably, S. intermedia CNMTs have been correlated with the N -methylation of secondary and tertiary amines in ( R )-1-benzylisoquinolines biosynthesis 29 . Key active site residues identified in Coptis japonica CNMT (CjCNMT) 30 and involved in BIA binding and catalysis were conserved in NnCNMT (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Similarly, N -methylation of available 1-benzylisoquinoline substrates was not detected for either the NnCNMT recombinant enzyme candidate or in plant protein extracts. Notably, NnCNMT displays 80% amino acid sequence identity with a recently characterized enzyme (SiCNMT1) that purportedly catalyzes the N -methylation of ( R )-coclaurine 29 . Phylogenetic analysis showed that NnCNMT was also closely related to SiCNMT2, which catalyzes the single and double N -methylation of ( R )-coclaurine yielding N -methylcoclaurine and magnocurarine (reported as isolotusine in sacred lotus), respectively 29 .…”

Section: Discussionmentioning

confidence: 99%

“…Notably, NnCNMT displays 80% amino acid sequence identity with a recently characterized enzyme (SiCNMT1) that purportedly catalyzes the N -methylation of ( R )-coclaurine 29 . Phylogenetic analysis showed that NnCNMT was also closely related to SiCNMT2, which catalyzes the single and double N -methylation of ( R )-coclaurine yielding N -methylcoclaurine and magnocurarine (reported as isolotusine in sacred lotus), respectively 29 . Key active site residues involved in BIA-binding and catalysis have been determined for CjCNMT 30 , which favors ( R )-coclaurine turnover in vitro 53 , and these positions are fully conserved in NnCNMT; thus, it is possible that NnCNMT strictly accepts ( R )-coclaurine, but this substrate was not available to test.…”

Section: Discussionmentioning

confidence: 99%

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Elucidation of the (R)-enantiospecific benzylisoquinoline alkaloid biosynthetic pathways in sacred lotus (Nelumbo nucifera)

Menéndez-Perdomo

Facchini

2023

Sci Rep

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Benzylisoquinoline alkaloids (BIAs) are a structurally diverse group of plant specialized metabolites found mainly in members of the order Ranunculales, including opium poppy (Papaver somniferum), for which BIA biosynthetic pathways leading to the critical drugs morphine, noscapine, and sanguinarine have been elucidated. Sacred lotus (Nelumbo nucifera), in the order Proteales, accumulates medicinal BIAs in the proaporphine, aporphine, and bisbenzylisoquinoline structural subgroups with a prevalence of R enantiomers, opposed to the dominant S configuration occurring in the Ranunculales. Nevertheless, distinctive BIA biosynthetic routes in sacred lotus have not been explored. In planta labeling experiments and in vitro assays with recombinant enzymes and plant protein extracts showed that dopamine and 4-hydroxyphenylacetaldehyde derived from l-tyrosine serve as precursors for the formation of (R,S)-norcoclaurine in sacred lotus, whereas only (R)-norcoclaurine byproducts are favored in the plant by action of R-enantiospecific methyltransferases and cytochrome P450 oxidoreductases (CYPs). Enzymes responsible for the R-enantiospecific formation of proaporphine (NnCYP80Q1) and bisbenzylisoquinoline (NnCYP80Q2) scaffolds, and a methylenedioxy bridge introduction on aporphine substrates (NnCYP719A22) were identified, whereas additional aspects of the biosynthetic pathways leading to the distinctive alkaloid profile are discussed. This work expands the availability of molecular tools that can be deployed in synthetic biology platforms for the production of high-value alkaloids.

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“…One of the main active ingredients of CYHS, tetrahydropalmatine, also known as fumarate B (dl-THP), 90 prevents hyperlipidemia, 91 attenuates neuronal apoptosis induced by cerebral ischemia-reperfusion injury, 92 offers neuroprotection, 93 has antitumor effects, 94 provides analgesia, 95 prevents memory impairment, 96 and ameliorates the development of anxiety and depression. 97,98 Asparagus cochinchinensis (Lour.)…”

Section: Polygala Tenuifolia Willdmentioning

confidence: 99%

<p>Traditional Chinese Medicine Jiuwei Zhenxin Granules in Treating Depression: An Overview</p>

Wang

2020

NDT

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Depression is known as "Yu Zheng" in traditional Chinese medicine (TCM). Jiuwei Zhenxin granules (JZG) is a type of TCM. According to TCM theory, it nourishes the heart and spleen, tonifies Qi, and tranquilizes the spirit, and may also has effects in the treatment of depression. Here, we systematically reviewed recent basic and clinical experimental studies of JZG and depression, including studies of the pharmacological mechanisms, active ingredients, and clinical applications of JZG in depression treatment. This review will deepen our understanding of the pharmacological mechanisms, drug interactions, and clinical applications of TCM prescriptions and provide a basis for the development of new drugs in the treatment of depression.

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Identification and characterization of methyltransferases involved in benzylisoquinoline alkaloids biosynthesis from Stephania intermedia

Cited by 13 publications

References 35 publications

Characterization of benzylisoquinoline alkaloid methyltransferases in Liriodendron chinense provides insights into the phylogenic basis of angiosperm alkaloid diversity

Characterization of benzylisoquinoline alkaloid methyltransferases in Liriodendron chinense provides insights into the phylogenic basis of angiosperm alkaloid diversity

Elucidation of the (R)-enantiospecific benzylisoquinoline alkaloid biosynthetic pathways in sacred lotus (Nelumbo nucifera)

<p>Traditional Chinese Medicine Jiuwei Zhenxin Granules in Treating Depression: An Overview</p>

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