The benzodiazepine-like natural product tilivalline is produced by the entomopathogenic bacterium Xenorhabdus eapokensis
Fig 6
Proposed tilivallin (1) biosynthesis of X. eapokensis.
Chorismate is a main product of the shikimic acid pathway modified by various enzymes to precursors accepted by XtvA. NRPS enzymes XtvA and XtvB activate anthranilic acid or proline (and analogs thereof), respectively, due to ATP hydrolysis and bind resulting aminoacyl adenylates to corresponding thiolation domains (T). After condensation domain (C) mediated reaction of the T domain bound aminoacyls, resulting dipeptide undergoes a reductive cyclisation by action of the terminal reduction domain (Re) release mechanism resulting a pyrrolobenzodiazepine core structure (16, 17). Finally post NRPS, free indole (or derivatives thereof) is added non enzymatically, resulting in the production of 1. Compound abbreviations: ADIC = 2-amino-4-deoxy isochorismate, DHHA = 6-amino-5-hydroxycyclohexa-1,3-diene-1-carboxylate, 3-HAA = 3-hydroxyanthranilic acid, 5-HAA = 5-hydroxyanthranilic acid, 3,5-DHAA = 3,5-dihydroxyanthranilic acid, 4,5-DHAA = 4,5-dihydroxyanthranilic acid. Enzyme abbreviations: AdsX = ADIC synthase, PhzD = ADIC hydrolase, DhbX = DHHA dehydrogenase, TomO = salicylyl-coenzyme A 5-hydroxylase (anthranlilic acid oxygenase), TomEF = phenol-2-monooxygenase reductase/oxygenase, XtvAB = TV NRPS module 1 and 2.