PubMed · 9364778
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A Estévez-Braun, A G González. 1997. Coumarins.. https://doi.org/10.1039/np9971400465
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Coumarins are structurally diverse phenylpropanoid derivatives with ecological and pharmacological significance, yet the biosynthetic logic underlying their diversification remains incompletely understood in non-model medicinal plants. Angelica pubescens (Apiaceae), widely used in traditional Chinese medicine, accumulates a rich repertoire of furanocoumarins and dihydrofuranocoumarins, making it an ideal system to investigate this metabolic complexity. Here, we combined chromosome-level genome assembly, transcriptome and metabolite profiling, phylogenetics, and heterologous expression assays to dissect coumarin biosynthesis in A. pubescens. We identified two functionally specialized O-methyltransferases, ApOMT1 and ApOMT2, which catalyze regioselective methylation of xanthotoxol and bergaptol to yield the furanocoumarins xanthotoxin and bergapten. We also characterized ApCYP736A121, a cytochrome P450 enzyme that converts osthenol to the dihydrofuranocoumarin columbianetin via a previously unknown mechanism. Gene expression and metabolite accumulation patterns across tissues and developmental stages revealed functional partitioning among pathway branches. Phylogenetic and syntenic analyses indicated that ApOMT1 and ApOMT2 arose through subfunctionalization following gene duplication, whereas ApCYP736A121 evolved via neofunctionalization from a distantly related CYP736 ancestor. Together, our findings uncover dual biosynthetic routes to structurally distinct coumarins in A. pubescens and provide insights into the evolutionary mechanisms contributing to metabolic innovation in Apiaceae. This work lays a foundation for future efforts to engineer coumarin pathways and understand their ecological functions in medicinal plants.
Heat shock proteins (HSPs) have a cytoprotective role in several human diseases, including ischemia and viral infection. Nuclear factor-kappaB (NF-kappaB) is a critical regulator of inflammation and virus replication. Here we report that a class of serine protease inhibitors with NF-kappaB-inhibitory activity are potent HSP inducers via activation of heat shock transcription factor 1 (HSF1) in human cells. 3,4-Dichloroisocoumarin, the most effective compound, rapidly induces HSF1 DNA binding activity and phosphorylation, leading to transcription and translation of heat shock genes for a period of several hours. HSF1 activation is independent of de novo protein synthesis and is correlated in a concentration- and time-dependent manner with NF-kappaB inhibition. Cysteine protease inhibitors E64 and calpain inhibitor II, which do not block NF-kappaB activation, do not induce HSF DNA binding activity. HSP induction by 3,4-dichloroisocoumarin is associated with antiviral activity during rhabdovirus infection. These results identify a new class of HSP inducers and indicate a link between the regulatory pathways of HSF and NF-kappaB, suggesting novel strategies to simultaneously switch on cytoprotective genes and down-regulate inflammatory and viral genes.
Use of the fragrance 6-methylcoumarin (6-MC) in cosmetic products has declined significantly due to numerous reports of photoallergic contact dermatitis associated with its use. We have determined that 6-MC undergoes direct photolysis with an estimated half-life of 83 minutes when illuminated with mid-latitude U.S., noon-centered, equinox sunlight and a quantum yield for photolysis at 313 nm of phi = 3 x 10(-3). The work presented here also provides evidence that singlet molecular oxygen ((1)O2) is formed in illuminated solutions containing 6-MC. An estimated value of phi = 0.01 is reported for the (1)O2 quantum yield at 313 nm. Formation of (1)O2 is significant because it is known to react with a variety of biomolecules and it is possible that (1)O2 formation is at least partially responsible for reports of 6-MC photoallergenicity and phototoxicity.