page_title: Angelicin
section_title: Biological synthesis
hierarchical_section_title: Angelicin / Biological synthesis
caption_attribution_description: English: Formation of angelicin from umbelliferone
context_page_description: Angelicin is the parent compound in a family of naturally occurring organic compounds known as the angular furanocoumarins. Structurally, it can be considered as benzapyra-2-one fused with a furan moiety in the 7,8-position. Angelicin is commonly found in certain Apiaceae and Fabaceae plant species such as Bituminaria bituminosa. It has a skin permeability coefficient of -2.46. The maximum absorption is observed at 300 nm. The ¹HNMR spectrum is available; the infrared and mass spectra of angelicin can be found in this database. The sublimation of angelicin occurs at 120 °C and the pressure of 0.13 Pa. Angelicin is a coumarine.
context_section_description: The biosynthesis of angelicin can be described as a variation in the biological synthesis of furanocoumarins. It begins from the capture of organic carbon by photosynthesis and the formation of carbohydrates. Subsequently, the carbohydrates become the substrates of the shikimic acid pathway where they are converted to phenylalanine and tyrosine. Enzymes such as ammonialyases, methylases and hydroxylases then transform these amino acids to cinnamic acid derivatives which undergo o-hydroxylation yielding coumarins. The coumarins can undergo further reactions such as prenylation and oxidation to give multiple furanocoumarins one of which is angelicin.
  Here, the biosynthesis of angelicin is described in more detail starting at L-phenylalanine as a precursor. The phenylalanine undergoes a non-oxidative deamination by phenylalanine ammonia-lyase (PAL) to trans-cinnamic acid. Afterwards, the trans-cinnamic acid is hydroxylated at the para position by trans-cinnamate 4-monooxygenase (C4H) which utilizes NADPH, H⁺ and O₂. The product, p-coumaric acid, is then converted to umbelliferone, the important intermediate of biosynthesis pathway.
  4-Coumaric acid 2-hydroxylase (C2’H) hydroxylates the p-coumaric acid at the ortho position. Notably, this reaction uses alpha-ketoglutarate which is reduced to succinate both of which are involved in the Krebs cycle. The newly formed trans-dihydrocinnamic acid undergoes a photochemical isomerization to a cis isomer which spontaneously lactonizes to yield umbeliferone.
  Subsequently, umbelliferone 6-prenyltransferase (PT) couples umbelliferone with prenyl diphosphate to give osthenol and pyrophosphate. Osthenol is oxidized to (+)-columbianetin by (+)-columbianetin synthase (CS), a putative plant cytochrome P450, although the details of this reaction are not clear. The biosynthesis is terminated with the oxidation of (+)-columbianetin yielding angelicin by angelicin synthase (AS) which is also considered as the enzyme of cytochrome P450 family.
  It is noteworthy that the biosynthesis of angelicin diverges at the umbelliferone as it is also converted to psoralen, the isomer of angelicin. In fact, psoralen, from which the family of linear furanocoumarins descends, is by far much more abundant in plants than angelicin. As a result, most herbivorous insects are resistant to psoralen. Now, it is increasingly recognized that plants devised the pathway leading to angelicin as an alternative defense mechanism. For example, angelicin enhances the toxicity of psoralen by acting as an inhibitor of the detoxifying cytochrome P450 in insects. Moreover, the comparison of the protein sequences of psoralen synthase and angelicin synthase shows a 70% identity overall and 40% identity in the substrate recognition sites. This implies that the biosynthesis of angelicin is a relatively recently evolved trait.
caption: Formation of angelicin from umbelliferone.[13]
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