Chemical ecology of pyrrolizidine alkaloids

Hartmann, Thomas

doi:10.1007/s004250050508

Cited by 265 publications

(211 citation statements)

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“…Pyrrolizidine alkaloids (PAs) are plant secondary metabolites characteristic of several genera within the Asteraceae and Boraginaceae, and sporadically present in the Fabaceae and Orchidaceae (Hartmann, 1999). PAs are formed by the esterification of a necic acid and a necine base, and comprise more than 400 chemical structures identified from ca.…”

Section: Introductionmentioning

confidence: 99%

“…In humans, exposure to PAs contained in herbal teas, medicines, contaminated cereals, pollen and honey has been related to acute and chronic liver toxicity, such as the veno-occlusive disease, especially in children (Edgar et al, 2002;Kempf et al, 2010;Molyneux et al, 2011;Wiedenfeld and Edgar, 2011). The role of PAs as plant chemical defenses against phytophagous insects has been widely documented (Hartmann, 1999). Indeed, PAs may have evolved in response to the consumption pressure from invertebrate herbivores (Doorduin and Vrieling, 2011;Hartmann, 1999).…”

Section: Introductionmentioning

confidence: 99%

“…The role of PAs as plant chemical defenses against phytophagous insects has been widely documented (Hartmann, 1999). Indeed, PAs may have evolved in response to the consumption pressure from invertebrate herbivores (Doorduin and Vrieling, 2011;Hartmann, 1999).…”

Section: Introductionmentioning

confidence: 99%

“…However, after ingested by herbivores they are reduced into tertiary amines in the gut and metabolized by cytochrome P 450 s, originating reactive metabolites that interact with proteins and nucleic acids (Hartmann, 1999;Fu et al, 2004). The toxicity of PAs strongly depends on some molecular features (Hartmann, 1999; Moyano et al, 2006;Stegelmeier et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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Diversity of pyrrolizidine alkaloids in native and invasive Senecio pterophorus (Asteraceae): Implications for toxicity

2014

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Diversity of pyrrolizidine alkaloids in native and invasive Senecio pterophorus (Asteraceae): Implications for toxicity

2014

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“…This enzyme, homospermidine synthase, catalyzes in an NAD ϩ -dependent reaction the transfer of the aminobutyl moiety of spermidine to a primary amino group of putrescine (25,26). Homospermidine, the product of this reaction, provides the carbon skeleton of the necine base moiety specific to the pyrrolizidine alkaloids (27,28). Molecular cloning of this enzyme revealed a cDNA with a high sequence homology to fungal and human deoxyhypusine synthase (53% and 61% amino acid identity, respectively), indicating a close phylogenetic relationship between the two enzymes.…”

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confidence: 99%

Deoxyhypusine Synthase from Tobacco

Ober

Hartmann

1999

Journal of Biological Chemistry

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Deoxyhypusine synthase catalyzes the formation of a deoxyhypusine residue in the translation eukaryotic initiation factor 5A (eIF5A) precursor protein by transferring an aminobutyl moiety from spermidine onto a conserved lysine residue within the eIF5A polypeptide chain. This reaction commences the activation of the initiation factor in fungi and vertebrates. A mechanistically identical reaction is known in the biosynthetic pathway leading to pyrrolizidine alkaloids in plants. Deoxyhypusine synthase from tobacco was cloned and expressed in active form in Escherichia coli. It catalyzes the formation of a deoxyhypusine residue in the tobacco eIF5A substrate as shown by gas chromatography coupled with a mass spectrometer. The enzyme also accepts free putrescine as the aminobutyl acceptor, instead of lysine bound in the eIF5A polypeptide chain, yielding homospermidine. Conversely, it accepts homospermidine instead of spermidine as the aminobutyl donor, whereby the reactions with putrescine and homospermidine proceed at the same rate as those involving the authentic substrates. The conversion of deoxyhypusine synthase-catalyzed eIF5A deoxyhypusinylation pinpoints a function for spermidine in plant metabolism. Furthermore, and quite unexpectedly, the substrate spectrum of deoxyhypusine synthase hints at a biochemical basis behind the sparse and skew occurrence of both homospermidine and its pyrrolizidine derivatives across distantly related plant taxa.The eukaryotic initiation factor 5A (eIF5A), 1 a small 17.4-kDa protein, is activated by a post-translational modification of a specific lysine residue to hypusine (N ⑀ -(4-amino-2-hydroxybutyl)lysine) in an enzyme-catalyzed two-step mechanism (reviewed in Refs. 1 and 2). In the first step, the aminobutyl moiety of the polyamine spermidine is transferred by deoxyhypusine synthase (EC 1.1.1.249) in an NAD ϩ -dependent reaction to the ⑀-amino group of a specific lysine residue in the eIF5A precursor protein to form deoxyhypusine. In the second step, deoxyhypusine hydroxylase (EC 1.14.99.29) catalyzes the hydroxylation of the deoxyhypusine residue to hypusine. Activated eIF5A is the only protein in which the unusual amino acid hypusine has been detected to date (3, 4), the modification is one of the most specific post-translational modifications known (5, 6). eIF5A seems to be ubiquitous among eukaryotes (7) and archaebacteria (8). Its amino acid sequence is highly conserved, and the 12 amino acids surrounding the hypusine residue are identical in all eukaryotes studied. Although known for nearly 2 decades, the function of eIF5A is still obscure. Because of its in vitro activity in stimulating methionyl puromycin synthesis (9), eIF5A was classified as a protein synthesis initiation factor, though subsequent doubts have arisen as to whether initiation of protein synthesis is a major function of this protein (2). Using a yeast mutant, it was shown that depletion of eIF5A causes an immediate inhibition of cell growth but only a moderate inhibition (30%) of total protein synthe...

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Development of an activity assay for characterizing deoxyhypusine synthase and its diverse reaction products

et al. 2020

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Deoxyhypusine synthase transfers an aminobutyl moiety from spermidine to the eukaryotic translation factor 5A (eIF5A) in the first step of eIF5A activation. This exclusive posttranslational modification is conserved in all eukaryotes. Activated eIF5A has been shown to be essential for cell proliferation and viability. Recent reports have linked the activation of eIF5A to several human diseases. Deoxyhypusine synthase, which is encoded by a single gene copy in most eukaryotes, was duplicated in several plant lineages during evolution, the copies being repeatedly recruited to pyrrolizidine alkaloid biosynthesis. However, the function of many of these duplicates is unknown. Notably, deoxyhypusine synthase is highly promiscuous and can catalyze various reactions, often of unknown biological relevance. To facilitate indepth biochemical studies of this enzyme, we report here the development of a simple and robust in vitro enzyme assay. It involves pre-column derivatization of the polyamines taking part in the reaction and FEBS Open Bio (2020)

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Chemical ecology of pyrrolizidine alkaloids

Cited by 265 publications

References 90 publications

Diversity of pyrrolizidine alkaloids in native and invasive Senecio pterophorus (Asteraceae): Implications for toxicity

Diversity of pyrrolizidine alkaloids in native and invasive Senecio pterophorus (Asteraceae): Implications for toxicity

Deoxyhypusine Synthase from Tobacco

Development of an activity assay for characterizing deoxyhypusine synthase and its diverse reaction products

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