RESUMO
Prephenate decarboxylases are a small family of enzymes which initiate a specialized divergence from the shikimate pathway, where prephenate (2) is decarboxylated without aromatization. In addition to effecting a challenging chemical transformation, prephenate decarboxylases have been implicated in the production of rare specialized metabolites, sometimes directly constructing bioactive warheads. Many of the biosynthetic steps to natural products derived from prephenate decarboxylases remain elusive. Here, we review prephenate decarboxylase research thus far and highlight natural products that may be derived from biosynthetic pathways involving prephenate decarboxylases. We also highlight commonly encountered challenges in the structure elucidation of these natural products. Prephenate decarboxylases are a gateway into understudied biosynthetic pathways which present a high potential for the discovery of novel and bioactive natural products, as well as new biosynthetic enzymes.
Assuntos
Produtos Biológicos , Carboxiliases , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Carboxiliases/metabolismo , Carboxiliases/química , HumanosRESUMO
Hybrid genome-mining/15N-NMR was used to target compounds containing piperazate (Piz) residues, leading to the discovery of caveamides A (1) and B (2) from Streptomyces sp. strain BE230, isolated from New Rankin Cave (Missouri). Caveamides are highly dynamic molecules containing an unprecedented ß-ketoamide polyketide fragment, two Piz residues, and a new N-methyl-cyclohexenylalanine residue. Caveamide B (2) exhibited nanomolar cytotoxicity against several cancer cell lines and nanomolar antimicrobial activity against MRSA and E. coli.
Assuntos
Escherichia coli , Staphylococcus aureus Resistente à Meticilina , Streptomyces , Humanos , Estrutura Molecular , Streptomyces/química , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Testes de Sensibilidade Microbiana , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Alanina/química , Alanina/farmacologia , Alanina/análogos & derivados , Ensaios de Seleção de Medicamentos Antitumorais , Peptídeos/química , Peptídeos/farmacologia , Peptídeos/isolamento & purificação , Linhagem Celular Tumoral , PiridazinasRESUMO
Entomopathogenic fungus Metarhizium majus contains the nine-gene PPZ cluster, with ppzA, encoding a peramine-producing nonribosomal peptide synthetase, as the central component. In this work, the roles of two α-ketoglutarate, iron-dependent oxygenases encoded by the PPZ genes ppzC and ppzD were elucidated. PpzD was found to produce both trans-4-hydroxy-l-proline and trans-3-hydroxy-l-proline in a 13.1:1 ratio, yielding a key precursor for peramine biosynthesis. PpzC was found to act directly on peramine, yielding the novel analogue 8-hydroxyperamine.