Isonitrile Formation by a Non-heme Iron(II)-dependent Oxidase/Decarboxylase

Abstract

The electron-rich isonitrile is an important functionality in bioactive natural products, but its biosynthesis has been restricted to the IsnA family of isonitrile synthases. We here provide the first structural and biochemical evidence of an alternative mechanism for isonitrile formation. ScoE, a putative non-heme iron(II)-dependent enzyme from Streptomyces coeruleorubidus, was shown to catalyze the conversion of (R)-3-((carboxymethyl)amino)butanoic acid to (R)-3-isocyanobutanoic acid through an oxidative decarboxylation mechanism. This work further provides a revised scheme for the biosynthesis of a unique class of isonitrile lipopeptides, members of which are critical for the virulence of pathogenic mycobacteria.[a]

Chalkophore mediated respiratory oxidase flexibility controlsM. tuberculosisvirulence

“…However, it is unknown whether copper acquisition, and resistance to copper deprivation, are part of the virulence program of M. tuberculosis. M. tuberculosis synthesizes diisonitrile lipopeptide natural products directed by the 5 gene nrp operon, present in M. tuberculosis and M. marinum, but not nonpathogenic mycobacteria (17)(18)(19)(20). The nrp operon is induced by copper deprivation and growth of M. tuberculosis lacking diisonitrile lipopeptide biosynthesis is inhibited in copper limiting conditions (21), establishing diisonitrile lipopeptides as mycobacterial chalkophores.…”

Mechanistic Insights Into Substrate Positioning Across Non-heme Fe(II)/alpha-ketoglutarate-dependent Halogenases and Hydroxylases

“…[6][7][8] To perform their biological functions, Fe(II)/a-KG-dependent enzymes have evolved to carry out distinct chemical transformations spanning hydroxylation [9][10][11] and halogenation 12,13 to isonitrile formation. 14,15 Despite their diverse reactivities, they utilize a highly conserved coordination environment centered around a mononuclear high-spin iron center. This coordination environment typically consists of a facial triad composed of two histidines and either an aspartate or glutamate for hydroxylases or an alanine or glycine for halogenases.…”

An Ugi-like Biosynthetic Pathway Encodes Bombesin Receptor Subtype-3 Agonists

“…7 For the second biosynthetic route, ScoE-type nonheme iron(II)-dependent enzymes catalyze isocyanide formation via an oxidative decarboxylation mechanism, and this pathway has similarly been linked to virulence in mycobacteria. 16,17 Isocyanide substrates have also garnered broad synthetic utility in multicomponent reactions, such as the Passerini three-component reaction 18 and the Ugi four-component reaction. 19 The former employs a carboxylic acid, a carbonyl compound, and an isocyanide as the three components that lead to α-acyloxyamides, whereas the latter incorporates a fourth amine substrate to yield α-acylaminoamides.…”