Family portraits: the enzymes behind benzylisoquinoline alkaloid diversity

Dastmalchi, Mehran; Park, Myung Ryeol; Morris, Jeremy S.; Facchini, Peter J.

doi:10.1007/s11101-017-9519-z

Cited by 52 publications

(55 citation statements)

References 145 publications

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“…The CYP82, CYP719, and CYP80 superfamilies are involved in BIA biosynthesis through multiple reactions. Moreover, according to the CYP nomenclature report, CYP80 is more common in plants belonging to the order Ranunculales [21,23]. Accordingly, in our results, more transcripts of the CYP82 and CYP719 superfamilies were found compared to those of the other CYPs.…”

Section: Cytochrome Profilessupporting

confidence: 67%

“…These CYPs are largely responsible for species-specific metabolite biosynthesis. The CYP80 superfamily of these enzymes is specific to plants in the order Ranunculales [21], and contains key enzymes for BIA biosynthesis; indeed, 20% of the enzymes involved in the BIA biosynthesis pathway are cytochromes (CYP), including CYP80, CYP82, CYP96, and CYP719 (with reference to the KEGG pathway map00950) [21][22][23]. These enzymes play roles in the biosynthesis of morphine, codeine, magnoflorine, berbamunine, norreticuline, crinine, sanguinarine, noscapine, and narcotoline metabolites [22].…”

Section: Introductionmentioning

confidence: 99%

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Transcriptional Profiles of Secondary Metabolite Biosynthesis Genes and Cytochromes in the Leaves of Four Papaver Species

Kim

Jung

et al. 2018

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Poppies are well-known plants in the family Papaveraceae that are rich in alkaloids. This family contains 61 species, and in this study we sequenced the transcriptomes of four species’ (Papaver rhoeas, Papaver nudicaule, Papaver fauriei, and Papaver somniferum) leaves. These transcripts were systematically assessed for the expression of secondary metabolite biosynthesis (SMB) genes and cytochromes, and their expression profiles were assessed for use in bioinformatics analyses. This study contributed 265 Gb (13 libraries with three biological replicates) of leaf transcriptome data from three Papaver plant developmental stages. Sequenced transcripts were assembled into 815 Mb of contigs, including 226 Mb of full-length transcripts. The transcripts for 53 KEGG pathways, 55 cytochrome superfamilies, and benzylisoquinoline alkaloid biosynthesis (BIA) were identified and compared to four other alkaloid-rich genomes. Additionally, 22 different alkaloids and their relative expression profiles in three developmental stages of Papaver species were assessed by targeted metabolomics using LC-QTOF-MS/MS. Collectively, the results are given in co-occurrence heat-maps to help researchers obtain an overview of the transcripts and their differential expression in the Papaver development life cycle, particularly in leaves. Moreover, this dataset will be a valuable resource to derive hypotheses to mitigate an array of Papaver developmental and secondary metabolite biosynthesis issues in the future.

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Section: Cytochrome Profilessupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Transcriptional Profiles of Secondary Metabolite Biosynthesis Genes and Cytochromes in the Leaves of Four Papaver Species

Kim

Jung

et al. 2018

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“…Naltrexone and naloxone are increasingly important drugs used to alleviate addiction or rescue patients from overdose fatality (Johnson et al ., ; Coe and Walsh, ). Opiates are members of a structurally and pharmacologically diverse array of specialized plant metabolites known as benzylisoquinoline alkaloids (BIAs) (Dastmalchi et al ., ). The original BIA scaffold is formed by the condensation of the L ‐tyrosine derivatives dopamine and 4‐hydroxyphenylacetaldehyde (4‐HPAA), yielding ( S )‐norcoclaurine.…”

Section: Introductionmentioning

confidence: 97%

Codeinone reductase isoforms with differential stability, efficiency and product selectivity in opium poppy

et al. 2018

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Codeinone reductase (COR) catalyzes the reversible NADPH-dependent reduction of codeinone to codeine as the penultimate step of morphine biosynthesis in opium poppy (Papaver somniferum). It also irreversibly reduces neopinone, which forms by spontaneous isomerization in aqueous solution from codeinone, to neopine. In a parallel pathway involving 3-O-demethylated analogs, COR converts morphinone to morphine, and neomorphinone to neomorphine. Similar to neopine, the formation of neomorphine by COR is irreversible. Neopine is a minor substrate for codeine O-demethylase (CODM), yielding morphine. In the plant, neopine levels are low and neomorphine has not been detected. Silencing of CODM leads to accumulation of upstream metabolites, such as codeine and thebaine, but does not result in a shift towards higher relative concentrations of neopine, suggesting a mechanism in the plant for limiting neopine production. In yeast (Saccharomyces cerevisiae) engineered to produce opiate alkaloids, the catalytic properties of COR lead to accumulation of neopine and neomorphine as major products. An isoform (COR-B) was isolated from opium poppy chemotype Bea's Choice that showed higher catalytic activity than previously characterized CORs, and it yielded mostly neopine in vitro and in engineered yeast. Five catalytically distinct COR isoforms (COR1.1-1.4 and COR-B) were used to determine sequence-function relationships that influence product selectivity. Biochemical characterization and site-directed mutagenesis of native COR isoforms identified four residues (V25, K41, F129 and W279) that affected protein stability, reaction velocity, and product selectivity and output. Improvement of COR performance coupled with an ability to guide pathway flux is necessary to facilitate commercial production of opiate alkaloids in engineered microorganisms.

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“…Many of these tailoring enzymes have promiscuous activities (Fig. B) , and their sequestration in distinct cell types maintains product specificity in the BIA pathway.…”

Section: Pathway Sequestration Leads To Alkaloid Diversity In Opium Pmentioning

confidence: 99%

“…Biosynthesis of morphinan‐type alkaloids – including morphine and codeine – is separated into two cell types: upstream reactions in the sieve elements and the final three steps in laticifers . The laticifer‐localized steps are catalyzed by the promiscuous tailoring enzymes thebaine 6‐ O ‐demethylase (T6ODM), codeinone reductase (COR), and codeinone O ‐demethylase (CODM) . A key outcome of pathway separation is that, although CODM and T6ODM have activity with many nonphysiologically relevant BIA intermediates in vitro , these substrates are unavailable in vivo (Fig.…”

Section: Pathway Sequestration Leads To Alkaloid Diversity In Opium Pmentioning

confidence: 99%

Location, location! cellular relocalization primes specialized metabolic diversification

Schenck

2019

The FEBS Journal

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Specialized metabolites are structurally diverse and cell‐ or tissue‐specific molecules produced in restricted plant lineages. In contrast, primary metabolic pathways are highly conserved in plants and produce metabolites essential for all of life, such as amino acids and nucleotides. Substrate promiscuity – the capacity to accept non‐native substrates – is a common characteristic of enzymes, and its impact is especially apparent in generating specialized metabolite variation. However, promiscuity only leads to metabolic diversity when alternative substrates are available; thus, enzyme cellular and subcellular localization directly influence chemical phenotypes. We review a variety of mechanisms that modulate substrate availability for promiscuous plant enzymes. We focus on examples where evolution led to modification of the ‘cellular context’ through changes in cell‐type expression, subcellular relocalization, pathway sequestration, and cellular mixing via tissue damage. These varied mechanisms contributed to the emergence of structurally diverse plant specialized metabolites and inform future metabolic engineering approaches.

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Family portraits: the enzymes behind benzylisoquinoline alkaloid diversity

Cited by 52 publications

References 145 publications

Transcriptional Profiles of Secondary Metabolite Biosynthesis Genes and Cytochromes in the Leaves of Four Papaver Species

Transcriptional Profiles of Secondary Metabolite Biosynthesis Genes and Cytochromes in the Leaves of Four Papaver Species

Codeinone reductase isoforms with differential stability, efficiency and product selectivity in opium poppy

Location, location! cellular relocalization primes specialized metabolic diversification

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