Spectroscopic Studies of Isopenicillin N Synthase

Chen, V J; Orville, A.M.; Harpel, Mark R.; Frolik, Charles A.; Surerus, Kristene K.; Münck, Eckard; Lipscomb, John D.

doi:10.1016/s0021-9258(20)88239-8

Cited by 142 publications

(108 citation statements)

References 26 publications

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“…Reconversion of [2H4]anthranilic acid into tryptophan naturally yields 2H,material and reincorporation of this material into (125) would give metabolite devoid of a label at position 5a. This is consistent with the observation that the C-5a proton in (125) was labelled to the extent of only 70% of the average for positions 1 through 4.…”

Section: Indoxyl Derivatives and Indole Glucosinolatessupporting

confidence: 92%

The biosynthesis of plant alkaloids and nitrogenous microbial metabolites

Herbert¹

1992

Nat. Prod. Rep.

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Section: Indoxyl Derivatives and Indole Glucosinolatessupporting

confidence: 92%

The biosynthesis of plant alkaloids and nitrogenous microbial metabolites

Herbert¹

1992

Nat. Prod. Rep.

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“…In natural product biosynthesis, NHI enzymes play key roles in catalyzing a diverse range of oxidation reactions, from simple hydroxylation to dynamic skeletal reconstructions. ,− During our investigation of talaromyolide biosynthesis, we found that the four NHI enzymes form two pairs of heterodimer complexes, TlxJ-TlxI and TlxA-TlxC. In nature, NHI enzymes with the conserved DSBH fold exist in various oligomeric forms, − but the heterodimer formation has never been reported. TlxI or TlxC might bind to the substrates for TlxJ-TlxI and work as an onsite inhibitor in vivo .…”

Section: Discussionmentioning

confidence: 95%

Heterodimeric Non-heme Iron Enzymes in Fungal Meroterpenoid Biosynthesis

Awakawa

Mori

et al. 2021

J. Am. Chem. Soc.

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hydroxymellein and 4,5-seco-drimane substructures, isolated from the marine fungus Talaromyces purpureogenus. We have identified the biosynthetic gene cluster tlxA-J by heterologous expression in Aspergillus, in vitro enzyme assays, and CRISPR-Cas9-based gene inactivation. Remarkably, the heterodimer of non-heme iron (NHI) enzymes, TlxJ-TlxI, catalyzes three steps of oxidation including a key reaction, hydroxylation at C-5 and C-9 of 12, the intermediate with 3-ketohydroxydrimane scaffold, to facilitate a retro-aldol reaction, leading to the construction of the 4,5secodrimane skeleton and characteristic ketal scaffold of 1−6. The products of TlxJ-TlxI, 1 and 4, were further hydroxylated at C-4′β by another NHI heterodimer, TlxA-TlxC, and acetylated by TlxB to yield the final products, 3 and 6. The X-ray structural analysis coupled with site-directed mutagenesis provided insights into the heterodimer TlxJ-TlxI formation and its catalysis. This is the first report to show that two NHI proteins form a heterodimer for catalysis and utilizes a novel methodology to create functional oxygenase structures in secondary metabolite biosynthesis.

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“…creates a vacant Fe II coordination site into which O 2 can bind (the valine isopropyl side chain is proposed to inhibit the ligation of water molecules to this site). Like other related nonheme iron(II) enzymes, in the resting state, iron is in the highspin Fe II state 192 probably reecting the weak ligand eld of the coordinating residues. 201 ACV binding may increase the affinity of IPNS for dioxygen by increasing the hydrophobicity of the active site 199 and/or by reducing the Fe II /Fe III redox potential (as formation of the S-Fe II bond likely increases the electron density on Fe II ).…”

Section: Isopenicillin N Synthasementioning

confidence: 95%

“…190 4.4.2 MECHANISM OF IPNS. A detailed mechanism for IPNS catalysis has been proposed 189 on the basis of kinetic, 191 spectroscopic, [192][193][194] modelling, 195 crystallographic, and substrate analogues studies 106,189,[196][197][198][199][200] (Fig. 13).…”

Section: Isopenicillin N Synthasementioning

confidence: 99%

The enzymes of β-lactam biosynthesis

et al. 2013

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The β-lactam antibiotics and related β-lactamase inhibitors are amongst the most important small molecules in clinical use. Most, but not all, β-lactams including penicillins, cephalosporins, and clavulanic acid are produced via fermentation or via modification of fermented intermediates, with important exceptions being the carbapenems and aztreonam. The desire for more efficient routes to existing antibiotics and for access to new and synthetically challenging ones stimulates continued interest in β-lactam biosynthesis. We review knowledge of the pathways leading to β-lactam antibiotics focusing on the mechanisms, structures and biocatalytic applications of the enzymes involved.

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Spectroscopic Studies of Isopenicillin N Synthase

Cited by 142 publications

References 26 publications

The biosynthesis of plant alkaloids and nitrogenous microbial metabolites

The biosynthesis of plant alkaloids and nitrogenous microbial metabolites

Heterodimeric Non-heme Iron Enzymes in Fungal Meroterpenoid Biosynthesis

The enzymes of β-lactam biosynthesis

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