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Alkaloid biosynthesis is a central topic in plant specialized metabolism because many alkaloids have ecological, pharmacological, and biotechnological relevance. Isoquinoline alkaloids (IAs) and Amaryllidaceae alkaloids (AAs) are both connected to aromatic amino acid metabolism, but they differ in taxonomic distribution, scaffold-forming chemistry, pathway resolution, and biotechnological development. This review compares the historical and methodological trajectories that have shaped IA and AA pathway elucidation, from compound isolation, radiotracer experiments, and biochemical inference to transcriptomics, metabolomics, functional enzymology, isotope-guided active-tissue identification, regulatory studies, and heterologous pathway reconstruction. In IAs, especially benzylisoquinoline alkaloids, broad genomic and transcriptomic resources have supported candidate gene discovery and functional characterization of several branches, including morphinan, protoberberine, benzophenanthridine, and aporphine-related pathways. In contrast, AA biosynthesis has advanced more recently through function-driven approaches that clarified key steps such as N4OMT-mediated 4'-O-methylation, NBS/NR-mediated norbelladine formation, CYP96T-dependent regioselective oxidative coupling, and transient reconstruction of major scaffold-forming branches. Remaining gaps include the unresolved enzymatic formation of 3,4-dihydroxybenzaldehyde in AAs and incomplete functional validation across less-studied IA scaffold classes. By integrating biochemical logic, omics-guided discovery, enzyme evolution, tissue specificity, regulation, and synthetic biology, this review identifies priorities for future alkaloid pathway discovery and sustainable production.
The interaction between ergot alkaloids in endophyte-infected (E+) tall fescue (Festuca arundinacea) seed and pyrrolizidine alkaloids (PA) in tansy ragwort (TR; Senecio jacobaea) when simultaneously fed to sheep was investigated. Because of the hepatogenic effects of prolactin (PRL), it was hypothesized that low serum PRL induced by ergot alkaloids would increase the susceptibility of sheep to hepatotoxicity induced by PA. Sheep are normally resistant to PA-induced hepatotoxicity. Twenty-four wether lambs weighing 34.1 +/- 2.3 kg were used after being randomly assigned to 1 of 6 treatments of 4 wethers each. The diets offered were a control basal diet containing endophyte-free (E-) tall fescue seed, control + carbon tetrachloride (CCL4), E+ tall fescue basal diet, E+2CCl4, E(-)+TR, or E+2TR. The diets were composed of 50% alfalfa meal, 34.5% rolled barley, 5% soybean meal, 4% cane molasses, 0.5% trace mineralized salt and 6% tall fescue (E- or E+) seed. In the 2 TR treatments 25% of the alfalfa was replaced by TR. Interaction between ergot alkaloids in E+ tall fescue and PA in TR was assessed by gamma glutamyl transferase (GGTP) activity and/or sulfobromophthalein (BSP) clearance rate, both of which measure liver function. Serum GGTP activity was measured on days 14 and 28; plasma BSP clearance was monitored on days 28 and 70 by collection of blood at 4, 8 and 16 min after i.v. BSP injection. Serum PRL assays were performed on days 14, 70 and 84. Serum GGTP activity was elevated by CCl4 drenching on days 14 and 28. On day 28 TR feeding reduced GGTP activity, but there was no difference between the 2 TR treatments. There was no difference in the mean BSP half-times (t1/2) and % BSP retentions on day 28 among any of the 6 treatments. On day 70, there was no difference in the t1/2 or % BSP retention 4 min after BSP injection among any of the treatments. At 8 min after BSP injection, however, % BSP retention was significantly higher for the control +CCl4 than for the E+2CCl4 treatment. At 16 min after BSP injection, the E+ treatment had a higher mean % BSP retention value than the E+2CCl4 treatment; there were no differences among the other treatments. Serum PRL levels were reduced by E+ or CCl4 on all 3 dates of PRL evaluation. The lack of interaction between ergot alkaloids in E+ tall fescue seed and PA in TR as assessed by GGTP activity and/or BSP clearance in sheep may imply that the target sites o the 2 alkaloids are metabolically different. The low serum PRL with E+ did not increase susceptibility of sheep to CCl4 or PA.
Cepharanthin (CE), a bisbenzylisoquinoline alkaloid drug, was tested in vitro and in vivo with chemotherapeutic agents, vincristine (VCR), vinblastine (VLB), and vindesine (VDS). The activity of these agents alone or in combination was tested against a human colon cancer cell line (RPMI 4788) or a human uterine cervical cancer cell line (HeLa), using a modified microcytotoxicity-viable cell staining assay. In the in vitro study, the antiproliferative activities of each vinca alkaloid were enhanced additively or synergistically by combination with CE in RPMI 4788 cells as well as HeLa cells. The sequential exposure of the RPMI 4788 cells or HeLa cells to both CE and each vinca alkaloid agent showed evidence of a more significant potentiation. The antiproliferative activity of the combination of each vinca alkaloid agent(VCR, VLB, or VDS) with CE was almost equivalent to the effect of each vinca alkaloid agent alone which was potentiated by CE tenfold through several hundredfold. In an experimental model of tumor growth and survival, in which RPMI 4788 cells were transplanted subcutaneously or intraperitoneally into BALB/c nu/nu mice respectively, CE (1 mg/kg) alone exerted not significant inhibitory activity against tumor growth or survival, and VCR (0.25 mg/kg) alone partially inhibited these antitumor activities. Furthermore, the antitumor effects of VCR were elevated synergistically by the simultaneous administration of CE. These studies indicate that due to their therapeutic potential, combinations of vinca alkaloid agent with CE might be a promising therapy for some human cancers.
Madagascar periwinkle, Catharanthus roseus (L.) G. Don, a medicinally important plant, produces anticancer dimeric alkaloids, vinblastine and vincristine, in the leaves and accumulates antihypertensive alkaloids, ajmalicine and serpentine, in the roots. This plant grows wild in distant tropical and sub-tropical geographical locations with different agro-climates and shows wide variations in morphological and alkaloid yield-related traits. In order to understand the correlation between the expression of terpenoid indole alkaloid (TIA) pathway genes and accumulation of related alkaloids, six different genetic resources of C. roseus, including the medicinal cultivars Nirmal, Prabal, Dhawal, the mutants gsr-3 and gsr-6, and one horticultural variety, Pacifica blush, were studied. The expression profiles of one early and two late TIA biosynthetic pathway genes, namely, strictosidine synthase, desacetoxyvindoline 4-hydroxylase and deacetyl vindoline 4-O-acetyl transferase were analyzed in these plants. A positive correlation between transcript abundance and accumulation of related alkaloids was observed in the different genetic resources. The potential of these TIA biosynthetic pathway genes for use in screening of high-yielding C. roseus germplasm has been discussed.
Mantelline frogs of the genus Mantella contain a variety of pumiliotoxin, allopumiliotoxin and homopumiliotoxin alkaloids in their skin. Pyrrolizidines, indolizidines and quinolizidines are also present. In contrast, captive-raised frogs (Mantella aurantiaca) have no alkaloids detectable in skin extracts. Frogs fed alkaloid-dusted fruit flies accumulate alkaloids into their skin. Thus, these mantelline frogs, like the neotropical dendrobatid frogs, appear dependent on dietary sources for their skin alkaloids and have the requisite alkaloid-sequestering system(s).
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