Asparenomycin C

Asparenomycin C

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Asparenomycin C
Category Bioactive by-products
Catalog number BBF-00108
CAS 81018-71-5
Molecular Weight 324.35
Molecular Formula C14H16N2O5S

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Description

Asparenomycin C is a carbapenem antibiotic produced by Streptomyces tokunonensis sp. (PA-31088) and Srt.argenteolus (PA-39504). It has anti-gram-positive and negative bacteria activity, can inhibit a variety of β-lactamases, and also has an effect on β-lactamase-producing strains.

Specification

IUPAC Name (5R,6Z)-3-[(E)-2-acetamidoethenyl]sulfanyl-6-(1-hydroxypropan-2-ylidene)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
Canonical SMILES CC(=C1C2CC(=C(N2C1=O)C(=O)O)SC=CNC(=O)C)CO
InChI InChI=1S/C14H16N2O5S/c1-7(6-17)11-9-5-10(22-4-3-15-8(2)18)12(14(20)21)16(9)13(11)19/h3-4,9,17H,5-6H2,1-2H3,(H,15,18)(H,20,21)/b4-3+,11-7-/t9-/m1/s1
InChI Key OXRGPSLVPTUXTM-OWEQPZDNSA-N

Properties

Appearance Light Yellow Powder
Antibiotic Activity Spectrum Gram-positive bacteria; Gram-negative bacteria
Solubility Soluble in Methanol, DMSO, Water

Reference Reading

1. Structural characterization of cobalamin-dependent radical S-adenosylmethionine methylases
Hayley L Knox, Squire J Booker Methods Enzymol. 2022;669:3-27. doi: 10.1016/bs.mie.2021.12.013. Epub 2022 Jan 28.
Cobalamin-dependent radical S-adenosylmethionine (SAM) methylases catalyze key steps in the biosynthesis of numerous biomolecules, including protein cofactors, antibiotics, herbicides, and other natural products, but have remained a relatively understudied subclass of radical SAM enzymes due to their inherent insolubility upon overproduction in Escherichia coli. These enzymes contain two cofactors: a [4Fe-4S] cluster that is ligated by three cysteine residues, and a cobalamin cofactor typically bound by residues in the N-terminal portion of the enzyme. Recent advances in the expression and purification of these enzymes in their active states and with both cofactors present has allowed for more detailed biochemical studies as well as structure determination by X-ray crystallography. Herein, we use KsTsrM and TokK to highlight methods for the structural characterization of cobalamin-dependent radical SAM (RS) enzymes and describe recent advances in in the overproduction and purification of these enzymes.
2. Structure of a B12-dependent radical SAM enzyme in carbapenem biosynthesis
Hayley L Knox, Erica K Sinner, Craig A Townsend, Amie K Boal, Squire J Booker Nature. 2022 Feb;602(7896):343-348. doi: 10.1038/s41586-021-04392-4. Epub 2022 Feb 2.
Carbapenems are antibiotics of last resort in the clinic. Owing to their potency and broad-spectrum activity, they are an important part of the antibiotic arsenal. The vital role of carbapenems is exemplified by the approval acquired by Merck from the US Food and Drug Administration (FDA) for the use of an imipenem combination therapy to treat the increased levels of hospital-acquired and ventilator-associated bacterial pneumonia that have occurred during the COVID-19 pandemic1. The C6 hydroxyethyl side chain distinguishes the clinically used carbapenems from the other classes of β-lactam antibiotics and is responsible for their low susceptibility to inactivation by occluding water from the β-lactamase active site2. The construction of the C6 hydroxyethyl side chain is mediated by cobalamin- or B12-dependent radical S-adenosylmethionine (SAM) enzymes3. These radical SAM methylases (RSMTs) assemble the alkyl backbone by sequential methylation reactions, and thereby underlie the therapeutic usefulness of clinically used carbapenems. Here we present X-ray crystal structures of TokK, a B12-dependent RSMT that catalyses three-sequential methylations during the biosynthesis of asparenomycin A. These structures, which contain the two metallocofactors of the enzyme and were determined in the presence and absence of a carbapenam substrate, provide a visualization of a B12-dependent RSMT that uses the radical mechanism that is shared by most of these enzymes. The structures provide insight into the stereochemistry of initial C6 methylation and suggest that substrate positioning governs the rate of each methylation event.
3. Sequential C-H Methylation Catalyzed by the B12 -Dependent SAM Enzyme TokK: Comprehensive Theoretical Study of Selectivities
Wen-Hao Deng, Rong-Zhen Liao Chemistry. 2023 Feb 1;29(7):e202202995. doi: 10.1002/chem.202202995. Epub 2022 Dec 9.
TokK is a B12 -dependent radical SAM enzyme involved in the biosynthesis of the β-lactam antibiotic asparenomycin A. It can catalyze three methylations on different sp3 -hybridized carbon positions to introduce an isopropyl side chain at the β-lactam ring of pantetheinylated carbapenem. Herein, we report a quantum chemical study of the reaction mechanism of TokK. A stepwise ''push-pull'' radical relay mechanism is proposed for each methylation: a 5'-deoxyadenosine radical first abstracts a hydrogen atom from the substrate in the active site, then methylcobalamin directionally donates a methyl group to the substrate. More importantly, calculations were able to uncover the origin of observed chemoselectivity and stereoselectivity for the first methylation and regioselectivity for the following two methylations. Further detailed distortion/interaction analysis can help to unravel the main factors controlling the selectivities. Our findings of sequential methylations by TokK could have profound implications for studying other B12 -dependent radical SAM enzymes.

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