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Publications (10 of 19) Show all publications
Zhang, K., Sheng, X., Deiana, L., Svensson Grape, E., Inge, A. K., Himo, F. & Córdova, A. (2022). Solvent Dependency in Stereoselective δ-Lactam Formation of Chiral α-Fluoromalonate Derivatives: Stereodivergent Synthesis of Heterocycles with Fluorine Containing Stereocenters Adjacent to Tertiary Stereocenters. Advanced Synthesis and Catalysis, 364(5), 958-965
Open this publication in new window or tab >>Solvent Dependency in Stereoselective δ-Lactam Formation of Chiral α-Fluoromalonate Derivatives: Stereodivergent Synthesis of Heterocycles with Fluorine Containing Stereocenters Adjacent to Tertiary Stereocenters
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2022 (English)In: Advanced Synthesis and Catalysis, ISSN 1615-4150, E-ISSN 1615-4169, Vol. 364, no 5, p. 958-965Article in journal (Refereed) Published
Abstract [en]

The discovery and investigation of solvent dependency in stereoselective intramolecular amidation of chiral 5-aminofunctionalized-2-fluoromalonate ester derivatives, which gives access to highly functionalized δ-lactams with a quaternary fluorine-containing stereocenter, is disclosed. Experimental work together with density functional theory calculations led to understanding of how to direct and switch the stereochemical outcome of the stereoselective δ-lactam formation. The merging of this solvent-dependent stereoselective switch with asymmetric catalysis and cascade reactions gives access to an unprecedented strategy for stereodivergent synthesis of all possible stereoisomers of fluorine-containing stereocenters adjacent to tertiary stereocenters of a wide range of heterocyclic compounds with 95->99% ee in one-pot. It is also useful for application in total synthesis of fluorine-containing pharmaceuticals.

Keywords
Solvent dependency, Stereoselective intramolecular amidation, Fluorine-containing quaternary stereocenters, Stereodivergent synthesis, Heterocycles
National Category
Chemical Sciences
Identifiers
urn:nbn:se:su:diva-202323 (URN)10.1002/adsc.202101404 (DOI)000748604700001 ()2-s2.0-85123889058 (Scopus ID)
Available from: 2022-02-22 Created: 2022-02-22 Last updated: 2022-03-28Bibliographically approved
Sheng, X. & Himo, F. (2021). Mechanisms of metal-dependent non-redox decarboxylases from quantum chemical calculations. Computational and Structural Biotechnology Journal, 19, 3176-3186
Open this publication in new window or tab >>Mechanisms of metal-dependent non-redox decarboxylases from quantum chemical calculations
2021 (English)In: Computational and Structural Biotechnology Journal, E-ISSN 2001-0370, Vol. 19, p. 3176-3186Article in journal (Refereed) Published
Abstract [en]

Quantum chemical calculations are today an extremely valuable tool for studying enzymatic reaction mechanisms. In this mini-review, we summarize our recent work on several metal-dependent decarboxylases, where we used the so-called cluster approach to decipher the details of the reaction mechanisms, including elucidation of the identity of the metal cofactors and the origins of substrate specificity. Decarboxylases are of growing potential for biocatalytic applications, as they can be used in the synthesis of novel compounds of, e.g., pharmaceutical interest. They can also be employed in the reverse direction, providing a strategy to synthesize value-added chemicals by CO2 fixation. A number of non-redox metal-dependent decarboxylases from the amidohydrolase superfamily have been demonstrated to have promiscuous carboxylation activities and have attracted great attention in the recent years. The computational mechanistic studies provide insights that are important for the further modification and utilization of these enzymes in industrial processes. The discussed enzymes are: 5-carboxyvanillate decarboxylase, gamma-resorcylate decarboxylase, 2,3-dihydroxybenzoic acid decarboxylase, and iso-orotate decarboxylase.

Keywords
Biocatalysis, Decarboxylase, Reaction mechanism, Density functional theory, Transition state
National Category
Biological Sciences Chemical Sciences
Identifiers
urn:nbn:se:su:diva-197807 (URN)10.1016/j.csbj.2021.05.044 (DOI)000684817100017 ()34141138 (PubMedID)
Available from: 2021-10-15 Created: 2021-10-15 Last updated: 2022-02-25Bibliographically approved
Hofer, G., Sheng, X., Braeuer, S., Payer, S. E., Plasch, K., Goessler, W., . . . Glueck, S. M. (2021). Metal Ion Promiscuity and Structure of 2,3-Dihydroxybenzoic Acid Decarboxylase of Aspergillus oryzae. ChemBioChem, 22(4), 652-656
Open this publication in new window or tab >>Metal Ion Promiscuity and Structure of 2,3-Dihydroxybenzoic Acid Decarboxylase of Aspergillus oryzae
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2021 (English)In: ChemBioChem, ISSN 1439-4227, E-ISSN 1439-7633, Vol. 22, no 4, p. 652-656Article in journal (Refereed) Published
Abstract [en]

Broad substrate tolerance and excellent regioselectivity, as well as independence from sensitive cofactors have established benzoic acid decarboxylases from microbial sources as efficient biocatalysts. Robustness under process conditions makes them particularly attractive for preparative-scale applications. The divalent metal-dependent enzymes are capable of catalyzing the reversible non-oxidative (de)carboxylation of a variety of electron-rich (hetero)aromatic substrates analogously to the chemical Kolbe-Schmitt reaction. Elemental mass spectrometry supported by crystal structure elucidation and quantum chemical calculations verified the presence of a catalytically relevant Mg2+ complexed in the active site of 2,3-dihydroxybenoic acid decarboxylase from Aspergillus oryzae (2,3-DHBD_Ao). This unique example with respect to the nature of the metal is in contrast to mechanistically related decarboxylases, which generally have Zn2+ or Mn2+ as the catalytically active metal.

Keywords
biocatalysis, computational chemistry, enzyme structure, metal-identity, ortho-benzoic acid decarboxylase
National Category
Chemical Sciences Biological Sciences
Identifiers
urn:nbn:se:su:diva-189358 (URN)10.1002/cbic.202000600 (DOI)000591395000001 ()33090643 (PubMedID)
Available from: 2021-01-21 Created: 2021-01-21 Last updated: 2024-07-04Bibliographically approved
Xu, Z., Yao, P., Sheng, X., Li, J., Li, J., Yu, S., . . . Zhu, D. (2020). Biocatalytic Access to 1,4-Diazepanes via Imine Reductase-Catalyzed Intramolecular Asymmetric Reductive Amination. ACS Catalysis, 10(15), 8780-8787
Open this publication in new window or tab >>Biocatalytic Access to 1,4-Diazepanes via Imine Reductase-Catalyzed Intramolecular Asymmetric Reductive Amination
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2020 (English)In: ACS Catalysis, E-ISSN 2155-5435, Vol. 10, no 15, p. 8780-8787Article in journal (Refereed) Published
Abstract [en]

An enzymatic intramolecular asymmetric reductive amination has been developed for the synthesis of chiral 1,4-diazepanes. Several enantiocomplementary IREDs were identified for the synthesis of (R)- and (S)-5-chloro-2-(5-methyl-1,4-diazepan-1-yl)benzo[d]oxazole with high enan- tioselectivity. The catalytic efficiency of (R)-selective IRED from Leishmania major (IR1) and (S)-selective IRED from Micromonospora echinaurantiaca IR25) was 0.027 and 0.962 s(-1) mM(-1), respectively. To further improve the catalytic efficiency of IR1, its double mutant Y194F/D232H was identified by saturation mutagenesis and iterative combinatorial mutagenesis, which exhibited 61-fold in the catalytic efficiency relative to that of wild-type enzyme. The density functional calculations and molecular dynamics simulations provided some insights into the molecular basis for the improved activity of mutant Y194F/D232H. Furthermore, Y194F/D232H and IR25 were applied to access a range of different substituted 1,4-diazepanes with high enantiomeric excess (from 93 to >99%). This study offers an effective method for construction of chiral 1,4-diazepanes of pharmaceutical importance via imine reductase-catalyzed intramolecular reductive amination of the corresponding aminoketones.

Keywords
imine reductase, intramolecular asymmetric reductive amination, chiral amine, 1, 4-diazepane, Suvorexant
National Category
Chemical Sciences
Identifiers
urn:nbn:se:su:diva-185400 (URN)10.1021/acscatal.0c02400 (DOI)000562075000069 ()
Available from: 2020-12-04 Created: 2020-12-04 Last updated: 2024-07-04Bibliographically approved
Sheng, X. & Himo, F. (2020). Computational Study of Pictet-Spenglerase Strictosidine Synthase: Reaction Mechanism and Origins of Enantioselectivity of Natural and Non-Natural Substrates. ACS Catalysis, 10(22), 13630-13640
Open this publication in new window or tab >>Computational Study of Pictet-Spenglerase Strictosidine Synthase: Reaction Mechanism and Origins of Enantioselectivity of Natural and Non-Natural Substrates
2020 (English)In: ACS Catalysis, E-ISSN 2155-5435, Vol. 10, no 22, p. 13630-13640Article in journal (Refereed) Published
Abstract [en]

Strictosidine synthase (STR) catalyzes the Pictet-Spengler (PS) condensation between tryptamine and secologanin, leading to the formation of (S)-strictosidine. The product is a central intermediate in the biosynthesis of various indole alkaloids, many of which are pharmaceutically important. STRs have relatively broad scopes for both the amine and aldehyde substrates, making them attractive biocatalyst candidates for applications in organic synthesis. An interesting feature of STR discovered recently is the switched enantiopreference of the reaction using short-chain aliphatic aldehydes in comparison to the natural secologanin substrate. Herein, we use quantum chemical calculations to investigate the detailed reaction mechanism and the origins of enantioselectivity of STR, considering both natural and non-natural substrates. The calculated overall barrier is in a good agreement with the measured rate constant, and the nature of the rate-determining step is consistent with kinetic isotope effect experiments. Importantly, the enantioselectivity for the reactions of both natural and non-natural substrates are well reproduced. A systematic analysis of energy profiles of the entire reactions and the geometries of the key transition states and intermediates along the pathways leading to the different enantiomers of the products provides a rationalization for the observed inversion of enantioselectivity.

Keywords
biocatalysis, Pictet-Spengler reaction, strictosidine synthase, enantioselectivity, reaction mechanism, computational chemistry
National Category
Chemical Sciences
Identifiers
urn:nbn:se:su:diva-189924 (URN)10.1021/acscatal.0c03758 (DOI)000592978900047 ()
Available from: 2021-02-06 Created: 2021-02-06 Last updated: 2024-07-04Bibliographically approved
Sheng, X., Kazemi, M., Żądło-Dobrowolska, A., Kroutil, W. & Himo, F. (2020). Mechanism of Biocatalytic Friedel-Crafts Acylation by Acyltransferase from Pseudomonas protegens. ACS Catalysis, 10(1), 570-577
Open this publication in new window or tab >>Mechanism of Biocatalytic Friedel-Crafts Acylation by Acyltransferase from Pseudomonas protegens
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2020 (English)In: ACS Catalysis, E-ISSN 2155-5435, Vol. 10, no 1, p. 570-577Article in journal (Refereed) Published
Abstract [en]

Acyltransferases isolated from Pseudomonas protegens (PpATase) and Pseudomonas fluorescens (PfATase) have recently been reported to catalyze the Friedel-Crafts acylation, providing a biological version of this classical organic reaction. These enzymes catalyze the cofactor-independent acylation of monoacetylphloroglucinol (MAPG) to diacetylphloroglucinol (DAPG) and phloroglucinol (PG) and have been demonstrated to have a wide substrate scope, making them valuable for potential applications in biocatalysis. Herein, we present a detailed reaction mechanism of PpATase on the basis of quantum chemical calculations, employing a large model of the active site. The proposed mechanism is consistent with available kinetics, mutagenesis, and structural data. The roles of various active site residues are analyzed. Very importantly, the Asp137 residue, located more than 10 angstrom from the substrate, is predicted to be the proton source for the protonation of the substrate in the rate-determining step. This key prediction is corroborated by site-directed mutagenesis experiments. Based on the current calculations, the regioselectivity of PpATase and its specificity toward non-natural substrates can be rationalized.

Keywords
biocatalysis, Friedel-Crafts acylation, acyltransferase, reaction mechanism, density functional theory
National Category
Chemical Sciences
Identifiers
urn:nbn:se:su:diva-178629 (URN)10.1021/acscatal.9b04208 (DOI)000506725100061 ()31929947 (PubMedID)
Available from: 2020-03-11 Created: 2020-03-11 Last updated: 2024-07-04Bibliographically approved
Sheng, X., Kazemi, M., Planas, F. & Himo, F. (2020). Modeling Enzymatic Enantioselectivity using Quantum Chemical Methodology. ACS Catalysis, 10(11), 6430-6449
Open this publication in new window or tab >>Modeling Enzymatic Enantioselectivity using Quantum Chemical Methodology
2020 (English)In: ACS Catalysis, E-ISSN 2155-5435, Vol. 10, no 11, p. 6430-6449Article in journal (Refereed) Published
Abstract [en]

The computational study of enantioselective reactions is a challenging task that requires high accuracy, as very small energy differences have to be reproduced. Quantum chemical methods, most commonly density functional theory, are today an important tool in this pursuit. This Perspective describes recent efforts in modeling asymmetric reactions in enzymes by means of the quantum chemical cluster approach. The methodology is described briefly and a number of illustrative case studies performed recently at our laboratory are presented. The reviewed enzymes are limonene epoxide hydrolase, soluble epoxide hydrolase, arylmalonate decarboxylase, phenolic acid decarboxylase, benzoylformate decarboxylase, secondary alcohol dehydrogenase, acyl transferase, and norcoclaurine synthase. The challenges encountered in each example are discussed, and the modeling lessons learned are highlighted.

Keywords
enzymology, biocatalysis, enantioselectivity, asymmetric synthesis, quantum chemistry, cluster approach, reaction mechanism, transition state
National Category
Chemical Sciences
Identifiers
urn:nbn:se:su:diva-183801 (URN)10.1021/acscatal.0c00983 (DOI)000538766900048 ()
Available from: 2020-08-05 Created: 2020-08-05 Last updated: 2024-07-04Bibliographically approved
Sheng, X. & Himo, F. (2019). Enzymatic Pictet-Spengler Reaction: Computational Study of the Mechanism and Enantioselectivity of Norcoclaurine Synthase. Journal of the American Chemical Society, 141(28), 11230-11238
Open this publication in new window or tab >>Enzymatic Pictet-Spengler Reaction: Computational Study of the Mechanism and Enantioselectivity of Norcoclaurine Synthase
2019 (English)In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 141, no 28, p. 11230-11238Article in journal (Refereed) Published
Abstract [en]

The Pictet-Spengler (PS) reaction, i.e., the acidcatalyzed condensation between beta-arylethylamine and an aldehyde or a ketone and the subsequent ring closure, is an important reaction in organic chemistry. A number of enzymes (called Pictet-Spenglerases, PSases) have been identified to catalyze this reaction, usually with very high enantioselectivity, making these enzymes of potential value in biocatalysis. PSases catalyze the key step in the biosynthesis of indole and benzylisoquinoline alkaloids of plant origin, some of which have pharmacological importance. However, the reaction mechanisms and the origins of the selectivity are not fully understood. Herein, we report a quantum chemical investigation of the mechanism and enantioselectivity of norcoclaurine synthase (NCS), an enzyme that catalyzes the PS condensation between dopamine and 4-hydroxyphenylacetaldehyde (4-HPAA). A large model of the active site is designed on the basis of a recent crystal structure, and it is used to calculate the detailed energy profile of the reaction. Good agreement is obtained between the calculated energies and available experimental information. Both the dopamine-first and the HPAA-first binding modes of the substrates reported in the literature are shown to be energetically accessible in the enzyme-substrate complex. However, it is demonstrated that only the dopamine-first pathway is associated with feasible energy barriers. Key active site residues are identified, and their roles in the catalysis are discussed and compared to site-directed mutagenesis experiments. Very importantly, the calculations are able to reproduce and rationalize the observed enantioselectivity of NCS. A detailed analysis of the geometries of the intermediates and transition states helps to pinpoint the main factors controlling the selectivity.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:su:diva-171660 (URN)10.1021/jacs.9b04591 (DOI)000476684700037 ()31265268 (PubMedID)
Available from: 2019-08-21 Created: 2019-08-21 Last updated: 2022-02-26Bibliographically approved
Kazemi, M., Sheng, X. & Himo, F. (2019). Origins of Enantiopreference of Mycobacterium smegmatis Acyl Transferase: A Computational Analysis. Chemistry - A European Journal, 25(51), 11945-11954
Open this publication in new window or tab >>Origins of Enantiopreference of Mycobacterium smegmatis Acyl Transferase: A Computational Analysis
2019 (English)In: Chemistry - A European Journal, ISSN 0947-6539, E-ISSN 1521-3765, Vol. 25, no 51, p. 11945-11954Article in journal (Refereed) Published
Abstract [en]

Acyl transferase from Mycobacterium smegmatis (MsAcT) is a promising biocatalyst because it catalyzes an acyl transfer reaction in aqueous solution, thereby accepting many primary and secondary alcohols as substrates. MsAcT also exhibits high enantioselectivity for a selected number of secondary alcohols. To increase the applicability of this enzyme for the production of optically active compounds, a detailed understanding of the reaction mechanism and the factors that affect enantioselectivity is essential. Herein, quantum chemical calculations are employed to study the reactions of two secondary alcohols, 1-isopropyl propargyl alcohol and 2-hydroxy propanenitrile, for which the enzyme displays opposite enantiopreference, favoring the S enantiomer in the former case and R enantiomer in the latter. A model of the active site has been designed and for both substrates various binding modes are evaluated and the intermediates and transition states along the reaction path are then located. The calculated energy profiles agree with the experimental observations, and reproduce the selectivity outcome. Through a detailed analysis of the geometries of key transition states, insights into the origins of the enantiopreference are obtained.

Keywords
acylation, biocatalysis, density functional calculations, stereopreference, transition states
National Category
Chemical Sciences
Identifiers
urn:nbn:se:su:diva-173128 (URN)10.1002/chem.201902351 (DOI)000482409100001 ()31294500 (PubMedID)
Available from: 2019-10-02 Created: 2019-10-02 Last updated: 2022-02-26Bibliographically approved
Planas, F., Sheng, X., McLeish, M. J. & Himo, F. (2018). A Theoretical Study of the Benzoylformate Decarboxylase Reaction Mechanism. Frontiers in Chemistry, 6, Article ID 205.
Open this publication in new window or tab >>A Theoretical Study of the Benzoylformate Decarboxylase Reaction Mechanism
2018 (English)In: Frontiers in Chemistry, E-ISSN 2296-2646, Vol. 6, article id 205Article in journal (Refereed) Published
Abstract [en]

Density functional theory calculations are used to investigate the detailed reaction mechanism of benzoylformate decarboxylase, a thiamin diphosphate (ThDP)-dependent enzyme that catalyzes the nonoxidative decarboxylation of benzoylformate yielding benzaldehyde and carbon dioxide. A large model of the active site is constructed on the basis of the X-ray structure, and it is used to characterize the involved intermediates and transition states and evaluate their energies. There is generally good agreement between the calculations and available experimental data. The roles of the various active site residues are discussed and the results are compared to mutagenesis experiments. Importantly, the calculations identify off-cycle intermediate species of the ThDP cofactor that can have implications on the kinetics of the reaction.

Keywords
enzyme mechanism, computational chemistry, active site model, benzoylformate decarboxylase, transition state, catalytic mechanism, potential energy profile, thiamin diphosphate
National Category
Organic Chemistry
Identifiers
urn:nbn:se:su:diva-158233 (URN)10.3389/fchem.2018.00205 (DOI)000436258300001 ()29998094 (PubMedID)
Available from: 2018-08-17 Created: 2018-08-17 Last updated: 2022-03-23Bibliographically approved
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ORCID iD: ORCID iD iconorcid.org/0000-0002-6542-6649

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