Chemoenzymatic synthesis of β-carboline derivatives using McbA, a new ATP-dependent amide synthetase

Ji, Changtao; Chen, Qi; Li, Qinglian; Huang, Hongbo; Song, Yongxiang; Ma, Junying; Ju, Jianhua

doi:10.1016/j.tetlet.2014.07.004

Cited by 19 publications

(22 citation statements)

References 17 publications

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“…This variant lacks the Ser689 attachment site to the PPant group that is involved in thioester formation and therefore would only allow the formation of the acyl adenylate and not the thioester. [26][27][28][29][30] Our current results are not able to establish if this reaction is enzyme catalyzed. [26][27][28][29][30] Our current results are not able to establish if this reaction is enzyme catalyzed.…”

Section: Zuschriftencontrasting

confidence: 77%

“…Conversion to ilepcimide 20 (79 %) was still observed with this variant, suggesting that adenylation activity alone is sufficient for amidation, presumably by nucleophilic attack onto the acyl adenylate ( Figure 2B), ar eaction which has been observed with other adenylating and phosphorylating enzymes,including NRPS and glutamine synthetase. [26][27][28][29][30] Our current results are not able to establish if this reaction is enzyme catalyzed.…”

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confidence: 77%

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Adenylation Activity of Carboxylic Acid Reductases Enables the Synthesis of Amides

et al. 2017

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Carboxylic acid reductases (CARs) catalyze the reduction of a broad range of carboxylic acids to aldehydes using the cofactors adenosine triphosphate and nicotinamide adenine dinucleotide phosphate, and have become attractive biocatalysts for organic synthesis. Mechanistic understanding of CARs was used to expand reaction scope, generating biocatalysts for amide bond formation from carboxylic acid and amine. CARs demonstrated amidation activity for various acids and amines. Optimization of reaction conditions, with respect to pH and temperature, allowed for the synthesis of the anticonvulsant ilepcimide with up to 96 % conversion. Mechanistic studies using site-directed mutagenesis suggest that, following initial enzymatic adenylation of substrates, amidation of the carboxylic acid proceeds by direct reaction of the acyl adenylate with amine nucleophiles.

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Section: Zuschriftencontrasting

confidence: 77%

contrasting

confidence: 77%

Adenylation Activity of Carboxylic Acid Reductases Enables the Synthesis of Amides

et al. 2017

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“…Thus, Ind3 is functionally distinct from PCLs and more similar to a group of amide ligase or synthetase enzymes, such as NovL, McbA, and XimA, involved in the biosynthesis of novobiocin, marinacarbolines, and xiamenmycin, respectively. All of these enzymes activate carboxylates for nucleophilic attack by donor amino groups to bring together monomers (26)(27)(28). However, phylogenetic analysis reveals that Ind3 is distinct from those enzymes (SI Appendix, Fig.…”

Section: +mentioning

confidence: 99%

In vitro reconstitution of indolmycin biosynthesis reveals the molecular basis of oxazolinone assembly

Alkhalaf

Ryan

2015

Proc. Natl. Acad. Sci. U.S.A.

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The bacterial tryptophanyl-tRNA synthetase inhibitor indolmycin features a unique oxazolinone heterocycle whose biogenetic origins have remained obscure for over 50 years. Here we identify and characterize the indolmycin biosynthetic pathway, using systematic in vivo gene inactivation, in vitro biochemical assays, and total enzymatic synthesis. Our work reveals that a phenylacetateCoA ligase-like enzyme Ind3 catalyzes an unusual ATP-dependent condensation of indolmycenic acid and dehydroarginine, driving oxazolinone ring assembly. We find that Ind6, which also has chaperone-like properties, acts as a gatekeeper to direct the outcome of this reaction. With Ind6 present, the normal pathway ensues. Without Ind6, the pathway derails to an unusual shunt product. Our work reveals the complete pathway for indolmycin formation and sets the stage for using genetic and chemoenzymatic methods to generate indolmycin derivatives as potential therapeutic agents.

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“…promise for the application of this enzyme to reactions with aw ider substrate spectrum. [14] These studies prompted us to further examine the activity of McbA to include arange of bcarboline and other aryl carboxylic acid acceptors.W ea lso determined the structure of McbA in complex with AMP and 6,which revealed the substrate binding interactions within the active site,and may serve as aplatform for protein engineering to expand the substrate specificity of this and related ABS enzymes.…”

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confidence: 99%

“…As ample of the pure enzyme (1 mg mL À1 ;9 .4 nmol) was applied to the coupling of 0.4 mm acid 6 and 0.6 mm 2-phenylethylamine a, in the presence of 2mm ATPona nanalytical scale,a nd full conversion to product amide 6awas observed within 1husing HPLC.The standard amide product was prepared by reacting the b-carboline ester with the amine in DMSO at 90 8 8C( see the Supporting Information). We then further explored the constraints on substrate structure in the McbA-catalyzed reaction, but, in contrast to previous work, [14] we focused on the structure of the carboxylic acid acceptor (Scheme 2).…”

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confidence: 99%

The Broad Aryl Acid Specificity of the Amide Bond Synthetase McbA Suggests Potential for the Biocatalytic Synthesis of Amides

et al. 2018

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Amide bond formation is one of the most important reactions in pharmaceutical synthetic chemistry. The development of sustainable methods for amide bond formation, including those that are catalyzed by enzymes, is therefore of significant interest. The ATP‐dependent amide bond synthetase (ABS) enzyme McbA, from Marinactinospora thermotolerans, catalyzes the formation of amides as part of the biosynthetic pathway towards the marinacarboline secondary metabolites. The reaction proceeds via an adenylate intermediate, with both adenylation and amidation steps catalyzed within one active site. In this study, McbA was applied to the synthesis of pharmaceutical‐type amides from a range of aryl carboxylic acids with partner amines provided at 1–5 molar equivalents. The structure of McbA revealed the structural determinants of aryl acid substrate tolerance and differences in conformation associated with the two half reactions catalyzed. The catalytic performance of McbA, coupled with the structure, suggest that this and other ABS enzymes may be engineered for applications in the sustainable synthesis of pharmaceutically relevant (chiral) amides.

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Chemoenzymatic synthesis of β-carboline derivatives using McbA, a new ATP-dependent amide synthetase

Cited by 19 publications

References 17 publications

Adenylation Activity of Carboxylic Acid Reductases Enables the Synthesis of Amides

Adenylation Activity of Carboxylic Acid Reductases Enables the Synthesis of Amides

In vitro reconstitution of indolmycin biosynthesis reveals the molecular basis of oxazolinone assembly

The Broad Aryl Acid Specificity of the Amide Bond Synthetase McbA Suggests Potential for the Biocatalytic Synthesis of Amides

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