Perquinolines A–C: Unprecedented Bacterial Tetrahydroisoquinolines Involving an Intriguing Biosynthesis

Abstract

Metabolic profiling of Streptomyces sp.IB2014/016-6l ed to the identification of three new tetrahydroisoquinoline natural products,p erquinolines A-C (1-3). Labelled precursor feeding studies and the cloning of the pqr biosynthetic gene cluster revealed that 1-3 are assembled by the action of several unusual enzymes.The biosynthesis starts with the condensation of succinyl-CoA and l-phenylalanine catalyzedbythe amino-7-oxononanoate synthase-like enzyme PqrA, representing rare chemistry in natural product assembly.T he second condensation and cyclization events are conducted by PqrG,anenzyme resembling an acyl-CoA ligase.L ast, ATP-grasp RimK-type ligase PqrI completes the biosynthesis by transferring a gaminobutyric acid or b-alanine moiety.T he discovered pathway represents an ew route for assembling the tetrahydroisoquinoline cores of natural products.

Microparticles enhance the formation of seven major classes of natural products in native and metabolically engineered actinobacteria through accelerated morphological development

“…chlorinus NRRL B‐24108 (Rodriguez Estevez et al, 2018), tetracycline‐type oxytetracycline using S. rimosus ATCC 10970 (Pethick et al, 2013), tetrahydroisochinoline‐type perquinolines using S. sp . IB2014/016‐6 (Rebets et al, 2019), and anthramycin‐type usabamycins using S. albus subsp. chlorinus NRRL B‐24108 (nybomycin) (Rodriguez Estevez et al, 2018).…”

“…chlorinus NRRL B‐24108 (nybomycin) (Rodriguez Estevez et al, 2018), Streptomyces rimosus ATCC 10970 (oxytetracycline) (Pethick et al, 2013), Streptomyces sp. IB2014/016‐6 (perquinolines) (Rebets et al, 2019), Streptomyces lividans ΔYA9 (usabamycins) (Ahmed et al, 2020)[Color figure can be viewed at wileyonlinelibrary.com]…”

Deciphering Biosynthetic Enzymes Leading to 4-Chloro-6-Methyl-5,7-Dihydroxyphenylglycine, a Non-Proteinogenic Amino Acid in Totopotensamides

“…9 The nonproteinogenic amino acid ClMeDPG in TPMs is proposed to be derived from 3,5-dihydroxyphenylglycine (DPG), a common building block in many bioactive natural products, 11 such as glycopeptides (balhimycin, chloroeremomycin, vancomycin, ristocetin, and teicoplanin), 12−18 linear peptide feglymycin, 19 and tetrahydroisoquinolines perquinolines A−C (Figure 1). 20 The biosynthetic pathway for DPG has been established by in vivo genetic studies or in vitro biochemical characterizations to consist of five enzymes in glycopeptide antibiotics. 12−18 (1,3-dihydroxy-5-oxo-cyclohex-3-enyl) acetyl-CoA (4), 12,14 which is dehydrated to 3,5-dihydroxyphenylacetate-CoA (DPA-CoA) (5) by the enoyl-CoA dehydratases DpgB and DpgD (Figure 1).…”

“…It should be noted that DpgB and DpgD are shown as enoyl-CoA dehydratases to perform the same dehydration reaction to convert 4 to DPA-CoA (5) (Figure 1). 14 Interestingly, TotC2 and PqrD are found to encode enoyl-CoA dehydratases in BGCs for TPMs and perquinolines, 9,20 as a single copy of DpgB/DpgD (Figure 1). In addition, the halogenase TotH and the methyltransferase TotM are proposed to further modify DPG (7) to form ClMeDPG in 1 (Figure 1).…”

“…The nonproteinogenic amino acid ClMeDPG in TPMs is proposed to be derived from 3,5-dihydroxyphenylglycine (DPG), a common building block in many bioactive natural products, such as glycopeptides (balhimycin, chloroeremomycin, vancomycin, ristocetin, and teicoplanin), − linear peptide feglymycin, and tetrahydroisoquinolines perquinolines A–C (Figure ). The biosynthetic pathway for DPG has been established by in vivo genetic studies or in vitro biochemical characterizations to consist of five enzymes in glycopeptide antibiotics. − DpgA, a type III polyketide synthase, is shown to assemble four malonyl-CoAs to produce (1,3-dihydroxy-5-oxo-cyclohex-3-enyl) acetyl-CoA ( 4 ), , which is dehydrated to 3,5-dihydroxyphenylacetate-CoA (DPA-CoA) ( 5 ) by the enoyl-CoA dehydratases DpgB and DpgD (Figure ). DpgC, a metal-free and cofactor-independent dioxygenase, performs a four-electron oxidation on the Cα of DPA-CoA ( 5 ) to incorporate two oxygen atoms and to subsequently cleave the thioester bond to generate the α-keto acid 3,5-dihydroxyphenylglyoxylate (DPGX, 6 ). ,, Usually, these four enzyme-encoding genes dpgABCD are translationally coupled.…”