Stigonematalean cyanobacteria Fischerella sp. and Hapalosiphon sp. produce the biogenetically related hapalindole, ambiguine, fischerindole, and welwitindolindone alkaloid-terpenoid natural products. This hapalindole-like family represents an intriguing group of natural products, due to their antimicrobial and anti-tumor activity, complicated synthesis, and halogenated/non-halogenated product pairs. The recent identification of a 36 kb welwitindolinone (wel) biosynthetic gene cluster in Hapalosiphon welwitschii UTEX B1830 and a 42 kbp ambiguine (amb) biosynthetic gene cluster in Fischerella ambigua UTEX 1903, and in vitro characterization of several enzymes confirmed a common biosynthesis starting point using the intermediates geranyl pyrophosphate (fate highlighted blue in products shown below) and 3-((Z)-2′-isocyanoethenyl)indole (fate highlighted red in products below). In contrast, other characterized enzymes such as the regio-specific aromatic prenyl transferase (AmbP3), or the N-methyl transferase (WelM) represent non-conserved highly substrate-specific tailoring enzymes found only in their respective specific wel or amb pathway. One functionalization of particular interest is the regio- and stereospecific incorporation of a chlorine atom to an unactivated sp3 carbon in this biosynthetic hapalindole family. Recently, we reported a nonheme iron enzyme (WelO5) that can chlorinate an aliphatic carbon in 12-epi-fischerindole U and 12-epi-hapalindole C, representing the first example of stereospecific halogenation of a small-molecule by an enzyme free of an associated peptidyl or acyl carrier protein. This stereospecific chlorination of an aliphatic small-molecule has potential implications for cleaner improved industrial synthesis of enantiomerically pure alkyl halides. Current efforts focus on the amb gene cluster homolog of WelO5, AmbO5, and elucidating the core hapalindole biosynthesis and the redox biochemistry leading to the oxidative elaboration of ambiguines and welwitindolinones via four Rieske-type oxygenases.

Hapalindole-linked welwitindolinone and ambiguine gene clusters from Stigonematalean cyanobacteria are delivering interesting chemistry via an unprecedented stereoselective halogenation of an sp3-carbon by a freestanding enzyme encoded within wel

249th National Meeting (2015)

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