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  1. Article ; Online: Role of Enzyme and Active Site Conformational Dynamics in the Catalysis by α-Amylase Explored with QM/MM Molecular Dynamics.

    Neves, Rui P P / Fernandes, Pedro A / Ramos, Maria J

    Journal of chemical information and modeling

    2022  Volume 62, Issue 15, Page(s) 3638–3650

    Abstract: We assessed enzyme:substrate conformational dynamics and the rate-limiting glycosylation step of a human pancreatic α-amylase:maltopentose complex. Microsecond molecular dynamics simulations suggested that the distance of the catalytic Asp197 nucleophile ...

    Abstract We assessed enzyme:substrate conformational dynamics and the rate-limiting glycosylation step of a human pancreatic α-amylase:maltopentose complex. Microsecond molecular dynamics simulations suggested that the distance of the catalytic Asp197 nucleophile to the anomeric carbon of the buried glucoside is responsible for most of the enzyme active site fluctuations and that both Asp197 and Asp300 interact the most with the buried glucoside unit. The buried glucoside binds either in a
    MeSH term(s) Carbon ; Catalysis ; Catalytic Domain ; Glucosides ; Humans ; Molecular Dynamics Simulation ; Oxygen ; Quantum Theory ; Water ; alpha-Amylases/chemistry
    Chemical Substances Glucosides ; Water (059QF0KO0R) ; Carbon (7440-44-0) ; alpha-Amylases (EC 3.2.1.1) ; Oxygen (S88TT14065)
    Language English
    Publishing date 2022-07-26
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 190019-5
    ISSN 1549-960X ; 0095-2338
    ISSN (online) 1549-960X
    ISSN 0095-2338
    DOI 10.1021/acs.jcim.2c00691
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Engineering DszC Mutants from Transition State Macrodipole Considerations and Evolutionary Sequence Analysis.

    Neves, Rui P P / Ramos, Maria J / Fernandes, Pedro A

    Journal of chemical information and modeling

    2022  Volume 63, Issue 1, Page(s) 20–26

    Abstract: We describe an approach to identify enzyme mutants with increased turnover using the enzyme DszC as a case study. Our approach is based on recalculating the barriers of alanine mutants through single-point energy calculations at the hybrid QM/MM level in ...

    Abstract We describe an approach to identify enzyme mutants with increased turnover using the enzyme DszC as a case study. Our approach is based on recalculating the barriers of alanine mutants through single-point energy calculations at the hybrid QM/MM level in the wild-type reactant and transition state geometries. We analyze the difference in the electron density between the reactant and transition state to identify sites/residues where electrostatic interactions stabilize the transition state over the reactants. We also assess the insertion of a unit probe charge to identify positions in which the introduction of charged residues lowers the barrier.
    MeSH term(s) Catalysis
    Language English
    Publishing date 2022-12-19
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 190019-5
    ISSN 1549-960X ; 0095-2338
    ISSN (online) 1549-960X
    ISSN 0095-2338
    DOI 10.1021/acs.jcim.2c01337
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: DszA Catalyzes C-S Bond Cleavage through N

    Ferreira, Pedro / Neves, Rui P P / Miranda, Filipa P / Cunha, Ana V / Havenith, Remco W A / Ramos, Maria J / Fernandes, Pedro A

    Journal of chemical information and modeling

    2024  

    Abstract: Due to its detrimental impact on human health and the environment, regulations demand ultralow sulfur levels on fossil fuels, in particular in diesel. However, current desulfurization techniques are expensive and cannot efficiently remove heteroaromatic ... ...

    Abstract Due to its detrimental impact on human health and the environment, regulations demand ultralow sulfur levels on fossil fuels, in particular in diesel. However, current desulfurization techniques are expensive and cannot efficiently remove heteroaromatic sulfur compounds, which are abundant in crude oil and concentrate in the diesel fraction after distillation. Biodesulfurization
    Language English
    Publishing date 2024-04-29
    Publishing country United States
    Document type Journal Article
    ZDB-ID 190019-5
    ISSN 1549-960X ; 0095-2338
    ISSN (online) 1549-960X
    ISSN 0095-2338
    DOI 10.1021/acs.jcim.4c00301
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  4. Article ; Online: Towards the Accurate Thermodynamic Characterization of Enzyme Reaction Mechanisms.

    Neves, Rui P P / Cunha, Ana V / Fernandes, Pedro A / Ramos, Maria J

    Chemphyschem : a European journal of chemical physics and physical chemistry

    2022  Volume 23, Issue 13, Page(s) e202200159

    Abstract: We employed QM/MM molecular dynamics (MD) simulations to characterize the rate-limiting step of the glycosylation reaction of pancreatic α-amylase with combined DFT/molecular dynamics methods (PBE/def2-SVP : AMBER). Upon careful choice of four starting ... ...

    Abstract We employed QM/MM molecular dynamics (MD) simulations to characterize the rate-limiting step of the glycosylation reaction of pancreatic α-amylase with combined DFT/molecular dynamics methods (PBE/def2-SVP : AMBER). Upon careful choice of four starting active site conformations based on thorough reactivity criteria, Gibbs energy profiles were calculated with umbrella sampling simulations within a statistical convergence of 1-2 kcal ⋅ mol
    MeSH term(s) Catalytic Domain ; Molecular Dynamics Simulation ; Quantum Theory ; Thermodynamics
    Language English
    Publishing date 2022-05-19
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2025223-7
    ISSN 1439-7641 ; 1439-4235
    ISSN (online) 1439-7641
    ISSN 1439-4235
    DOI 10.1002/cphc.202200159
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  5. Article ; Online: QM/MM Study of the Reaction Mechanism of Thermophilic Glucuronoyl Esterase for Biomass Treatment.

    Viegas, Matilde F / Neves, Rui P P / Ramos, Maria J / Fernandes, Pedro A

    Chemphyschem : a European journal of chemical physics and physical chemistry

    2022  Volume 23, Issue 20, Page(s) e202200269

    Abstract: Hydrolysis of lignocellulosic biomass, composed of a lignin-carbohydrate-complex (LCC) matrix, is critical for producing bioethanol from glucose. However, current methods for LCC processing require costly and polluting processes. The fungal ... ...

    Abstract Hydrolysis of lignocellulosic biomass, composed of a lignin-carbohydrate-complex (LCC) matrix, is critical for producing bioethanol from glucose. However, current methods for LCC processing require costly and polluting processes. The fungal Thermothelomyces thermophila glucuronoyl esterase (TtGE) is a promising thermophilic enzyme that hydrolyses LCC ester bonds. This study describes the TtGE catalytic mechanism using QM/MM methods. Two nearly-degenerate rate-determining transition states were found, with barriers of 16 and 17 kcal ⋅ mol
    MeSH term(s) Esterases/chemistry ; Lignin/chemistry ; Biomass ; Glucuronic Acid/chemistry ; Protons ; Hydrolysis ; Carbohydrates/chemistry ; Esters/chemistry ; Glucose
    Chemical Substances Esterases (EC 3.1.-) ; Lignin (9005-53-2) ; Glucuronic Acid (8A5D83Q4RW) ; Protons ; Carbohydrates ; Esters ; Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2022-08-04
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2025223-7
    ISSN 1439-7641 ; 1439-4235
    ISSN (online) 1439-7641
    ISSN 1439-4235
    DOI 10.1002/cphc.202200269
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Different Enzyme Conformations Induce Different Mechanistic Traits in HIV-1 Protease.

    Coimbra, João T S / Neves, Rui P P / Cunha, Ana V / Ramos, Maria J / Fernandes, Pedro A

    Chemistry (Weinheim an der Bergstrasse, Germany)

    2022  Volume 28, Issue 42, Page(s) e202201066

    Abstract: The influence of the dynamical flexibility of enzymes on reaction mechanisms is a cornerstone in biological sciences. In this study, we aim to 1) study the convergence of the activation free energy by using the first step of the reaction catalysed by HIV- ...

    Abstract The influence of the dynamical flexibility of enzymes on reaction mechanisms is a cornerstone in biological sciences. In this study, we aim to 1) study the convergence of the activation free energy by using the first step of the reaction catalysed by HIV-1 protease as a case study, and 2) provide further evidence for a mechanistic divergence in this enzyme, as two different reaction pathways were seen to contribute to this step. We used quantum mechanics/molecular mechanics molecular dynamics simulations, on four different initial conformations that led to different barriers in a previous study. Despite the sampling, the four activation free energies still spanned a range of 5.0 kcal ⋅ mol
    MeSH term(s) Catalytic Domain ; HIV Protease/metabolism ; Molecular Dynamics Simulation ; Quantum Theory ; Thermodynamics
    Chemical Substances HIV Protease (EC 3.4.23.-) ; p16 protease, Human immunodeficiency virus 1 (EC 3.4.23.-)
    Language English
    Publishing date 2022-06-27
    Publishing country Germany
    Document type Journal Article
    ZDB-ID 1478547-X
    ISSN 1521-3765 ; 0947-6539
    ISSN (online) 1521-3765
    ISSN 0947-6539
    DOI 10.1002/chem.202201066
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  7. Article ; Online: Mechanistic insights on the reduction of glutathione disulfide by protein disulfide isomerase.

    Neves, Rui P P / Fernandes, Pedro Alexandrino / Ramos, Maria João

    Proceedings of the National Academy of Sciences of the United States of America

    2017  Volume 114, Issue 24, Page(s) E4724–E4733

    Abstract: We explore the enzymatic mechanism of the reduction of glutathione disulfide (GSSG) by the ... ...

    Abstract We explore the enzymatic mechanism of the reduction of glutathione disulfide (GSSG) by the reduced
    Language English
    Publishing date 2017-06-13
    Publishing country United States
    Document type Journal Article
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.1618985114
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  8. Article ; Online: Animal Fatty Acid Synthase: A Chemical Nanofactory.

    Paiva, Pedro / Medina, Fabiola E / Viegas, Matilde / Ferreira, Pedro / Neves, Rui P P / Sousa, João P M / Ramos, Maria J / Fernandes, Pedro A

    Chemical reviews

    2021  Volume 121, Issue 15, Page(s) 9502–9553

    Abstract: Fatty acids are crucial molecules for most living beings, very well spread and conserved across species. These molecules play a role in energy storage, cell membrane architecture, and cell signaling, the latter through their derivative metabolites. ...

    Abstract Fatty acids are crucial molecules for most living beings, very well spread and conserved across species. These molecules play a role in energy storage, cell membrane architecture, and cell signaling, the latter through their derivative metabolites.
    MeSH term(s) Animals ; Catalytic Domain ; Fatty Acid Synthases/chemistry ; Fatty Acid Synthases/metabolism ; Fatty Acids/biosynthesis ; Metabolic Networks and Pathways ; Multienzyme Complexes/chemistry ; Multienzyme Complexes/metabolism ; Polyketide Synthases/chemistry ; Polyketide Synthases/metabolism
    Chemical Substances Fatty Acids ; Multienzyme Complexes ; Polyketide Synthases (79956-01-7) ; Fatty Acid Synthases (EC 2.3.1.85)
    Language English
    Publishing date 2021-06-22
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 207949-5
    ISSN 1520-6890 ; 0009-2665
    ISSN (online) 1520-6890
    ISSN 0009-2665
    DOI 10.1021/acs.chemrev.1c00147
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  9. Article: Animal Fatty Acid Synthase: A Chemical Nanofactory

    Paiva, Pedro / Medina, Fabiola E. / Viegas, Matilde / Ferreira, Pedro / Neves, Rui P. P. / Sousa, João P. M. / Ramos, Maria J. / Fernandes, Pedro A.

    Chemical reviews. 2021 June 22, v. 121, no. 15

    2021  

    Abstract: Fatty acids are crucial molecules for most living beings, very well spread and conserved across species. These molecules play a role in energy storage, cell membrane architecture, and cell signaling, the latter through their derivative metabolites. De ... ...

    Abstract Fatty acids are crucial molecules for most living beings, very well spread and conserved across species. These molecules play a role in energy storage, cell membrane architecture, and cell signaling, the latter through their derivative metabolites. De novo synthesis of fatty acids is a complex chemical process that can be achieved either by a metabolic pathway built by a sequence of individual enzymes, such as in most bacteria, or by a single, large multi-enzyme, which incorporates all the chemical capabilities of the metabolic pathway, such as in animals and fungi, and in some bacteria. Here we focus on the multi-enzymes, specifically in the animal fatty acid synthase (FAS). We start by providing a historical overview of this vast field of research. We follow by describing the extraordinary architecture of animal FAS, a homodimeric multi-enzyme with seven different active sites per dimer, including a carrier protein that carries the intermediates from one active site to the next. We then delve into this multi-enzyme’s detailed chemistry and critically discuss the current knowledge on the chemical mechanism of each of the steps necessary to synthesize a single fatty acid molecule with atomic detail. In line with this, we discuss the potential and achieved FAS applications in biotechnology, as biosynthetic machines, and compare them with their homologous polyketide synthases, which are also finding wide applications in the same field. Finally, we discuss some open questions on the architecture of FAS, such as their peculiar substrate-shuttling arm, and describe possible reasons for the emergence of large megasynthases during evolution, questions that have fascinated biochemists from long ago but are still far from answered and understood.
    Keywords active sites ; animals ; biochemical pathways ; biosynthesis ; biotechnology ; cell membranes ; energy ; evolution ; fatty acids ; fatty-acid synthase ; metabolites ; polyketide synthases
    Language English
    Dates of publication 2021-0622
    Size p. 9502-9553.
    Publishing place American Chemical Society
    Document type Article
    ZDB-ID 207949-5
    ISSN 1520-6890 ; 0009-2665
    ISSN (online) 1520-6890
    ISSN 0009-2665
    DOI 10.1021/acs.chemrev.1c00147
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  10. Article ; Online: Combined in silico and in vitro studies to identify novel antidiabetic flavonoids targeting glycogen phosphorylase.

    Brás, Natércia F / Neves, Rui P P / Lopes, Filipa A A / Correia, Márcia A S / Palma, Angelina S / Sousa, Sérgio F / Ramos, Maria J

    Bioorganic chemistry

    2020  Volume 108, Page(s) 104552

    Abstract: Novel pharmacological strategies for the treatment of diabetic patients are now focusing on inhibiting glycogenolysis steps. In this regard, glycogen phosphorylase (GP) is a validated target for the discovery of innovative antihyperglycemic molecules. ... ...

    Abstract Novel pharmacological strategies for the treatment of diabetic patients are now focusing on inhibiting glycogenolysis steps. In this regard, glycogen phosphorylase (GP) is a validated target for the discovery of innovative antihyperglycemic molecules. Natural products, and in particular flavonoids, have been reported as potent inhibitors of GP at the cellular level. Herein, free-energy calculations and microscale thermophoresis approaches were performed to get an in-depth assessment of the binding affinities and elucidate intermolecular interactions of several flavonoids at the inhibitor site of GP. To our knowledge, this is the first study indicating genistein, 8-prenylgenistein, apigenin, 8-prenylapigenin, 8-prenylnaringenin, galangin and valoneic acid dilactone as natural molecules with high inhibitory potency toward GP. We identified: i) the residues Phe285, Tyr613, Glu382 and/or Arg770 as the most relevant for the binding of the best flavonoids to the inhibitor site of GP, and ii) the 5-OH, 7-OH, 8-prenyl substitutions in ring A and the 4'-OH insertion in ring B to favor flavonoid binding at this site. Our results are invaluable to plan further structural modifications through organic synthesis approaches and develop more effective pharmaceuticals for Type 2 Diabetes treatment, and serve as the starting point for the exploration of food products for therapeutic usage, as well as for the development of novel bio-functional food and dietary supplements/herbal medicines.
    Language English
    Publishing date 2020-12-15
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 120080-x
    ISSN 1090-2120 ; 0045-2068
    ISSN (online) 1090-2120
    ISSN 0045-2068
    DOI 10.1016/j.bioorg.2020.104552
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