Characterization and application of the Fe(ii) and α-ketoglutarate dependent hydroxylase FrbJ

DeSieno, Matthew A.; Donk, Wilfred A. van der; Zhao, Huimin

doi:10.1039/c1cc13597j

Cited by 10 publications

(8 citation statements)

References 23 publications

(28 reference statements)

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“…The frbG gene is not essential for the biosynthesis of 12a in E. coli , implying that this enzyme serves a tailoring role. This was confirmed by showing that purified FrbG hydroxylates C2 of 12a to form 192 , , also known as FR-33289, which had been observed previously in cultures of Streptomyces rubellomurinus . FrbJ is unreactive toward 191 in vitro but converts 12a to ( R )- 192 with kinetic parameters of k cat = 147 min –1 , K M = 289 μM, and k cat / K M = 8.48 × 10 3 M –1 s –1 .…”

Section: Pathways For Synthesizing Complex Pn Natural Productssupporting

confidence: 77%

Phosphonate Biochemistry

2016

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Organophosphonic acids are unique as natural products in terms of stability and mimicry. The C-P bond that defines these compounds resists hydrolytic cleavage, while the phosphonyl group is a versatile mimic of transition-states, intermediates, and primary metabolites. This versatility may explain why a variety of organisms have extensively explored the use organophosphonic acids as bioactive secondary metabolites. Several of these compounds, such as fosfomycin and bialaphos, figure prominently in human health and agriculture. The enzyme reactions that create these molecules are an interesting mix of chemistry that has been adopted from primary metabolism as well as those with no chemical precedent. Additionally, the phosphonate moiety represents a source of inorganic phosphate to microorganisms that live in environments that lack this nutrient; thus, unusual enzyme reactions have also evolved to cleave the C-P bond. This review is a comprehensive summary of the occurrence and function of organophosphonic acids natural products along with the mechanisms of the enzymes that synthesize and catabolize these molecules.

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Section: Pathways For Synthesizing Complex Pn Natural Productssupporting

confidence: 77%

Phosphonate Biochemistry

2016

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“…We and others have previously evaluated the structure–activity relationships (SAR) of fosmidomycin and FR-900098 as inhibitors of several DXR homologues as well as various microbial pathogens. − Fosmidomycin binds to DXR competitively with substrate DOXP and uncompetitively with cofactor NADPH . SAR studies on fosmidomycin analogues reveal that the retrohydroxamate or hydroxamate moiety should be retained to mimic the crucial interaction of fosmidomycin with the divalent metal cation. ,,,− , Similarly, the phosphonate moiety should be retained as it forms numerous hydrogen bonds with neighboring amino acid residues. − A three-carbon linker between the two moieties is also found to be crucial for DXR inhibition .…”

Section: Introductionmentioning

confidence: 99%

MEPicides: α,β-Unsaturated Fosmidomycin Analogues as DXR Inhibitors against Malaria

et al. 2018

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Severe malaria due to Plasmodium falciparum remains a significant global health threat. DXR, the second enzyme in the MEP pathway, plays an important role to synthesize building blocks for isoprenoids. This enzyme is a promising drug target for malaria due to its essentiality as well as its absence in humans. In this study, we designed and synthesized a series of α,β-unsaturated analogues of fosmidomycin, a natural product that inhibits DXR in P. falciparum. All compounds were evaluated as inhibitors of P. falciparum. The most promising compound, 18a, displays on-target, potent inhibition against the growth of P. falciparum (IC = 13 nM) without significant inhibition of HepG2 cells (IC > 50 μM). 18a was also tested in a luciferase-based Plasmodium berghei mouse model of malaria and showed exceptional in vivo efficacy. Together, the data support MEPicide 18a as a novel, potent, and promising drug candidate for the treatment of malaria.

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“…We then examined the function of the predicted Fe/2OG dioxygenase FfnD (XP_018236329.1). FfnD shares weak sequence identity (18-24 %) to phosphonate biosynthetic Fe/2OG dioxygenases FrbJ (FR-900098 biosynthesis) [28] and DhpA (dehydrophos biosynthesis), [29] including the predicted active site residues involved in Fe(II) and 2OG binding (Figure S4). The Fe/ 2OG oxygenase DhpA has been shown to perform α-hydroxylation of 8 to form 1,2-dihydroxyethylphosphonic acid 11, therefore we hypothesized FfnD would perform a similar reaction (Scheme 2A).…”

Section: Phosphonoacetaldehyde Reductase Ffncmentioning

confidence: 99%

Biosynthesis of the Fungal Organophosphonate Fosfonochlorin Involves an Iron(II) and 2‐(Oxo)glutarate Dependent Oxacyclase

et al. 2021

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The fungal metabolite Fosfonochlorin features a chloroacetyl moiety that is unusual within known phosphonate natural product biochemistry. Putative biosynthetic genes encoding Fosfonochlorin in Fusarium and Talaromyces spp. were investigated through reactions of encoded enzymes with synthetic substrates and isotope labelling studies. We show that the early biosynthetic steps for Fosfonochlorin involve the reduction of phosphonoacetaldehyde to form 2-hydroxyethylphosphonic acid, followed by oxidative intramolecular cyclization of the resulting alcohol to form (S)-epoxyethylphosphonic acid. The latter reaction is catalyzed by FfnD, a rare example of a nonheme iron/2-(oxo)glutarate dependent oxacyclase. In contrast, FfnD behaves as a more typical oxygenase with ethylphosphonic acid, producing (S)-1-hydroxyethylphosphonic acid. FfnD thus represents a new example of a ferryl generating enzyme that can suppress the typical oxygen rebound reaction that follows abstraction of a substrate hydrogen by a ferryl oxygen, thereby directing the substrate radical towards a fate other than hydroxylation.

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Characterization and application of the Fe(ii) and α-ketoglutarate dependent hydroxylase FrbJ

Cited by 10 publications

References 23 publications

Phosphonate Biochemistry

Phosphonate Biochemistry

MEPicides: α,β-Unsaturated Fosmidomycin Analogues as DXR Inhibitors against Malaria

Biosynthesis of the Fungal Organophosphonate Fosfonochlorin Involves an Iron(II) and 2‐(Oxo)glutarate Dependent Oxacyclase

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