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1.
Nature ; 605(7909): 228-229, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35508723
2.
ChemSusChem ; 15(9): e202200640, 2022 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-35514198

RESUMO

In their Editorial for the Special Issue on Biocatalysis as Key to Sustainable Industrial Chemistry, Guest Editors Andrés Alcántara, Pablo Domínguez de María, Jennifer Littlechild, and Roland Wohlgemuth and their co-workers on the European Society of Applied Biocatalysis' (ESAB) Working Group on Sustainable Chemistry Martin Schürmann and Roger Sheldon discuss the Special Issue and the importance of biocatalysis in carrying out cutting-edge industrial chemistry in a sustainable way, as well as the future prospects for the field.


Assuntos
Biotecnologia , Indústrias , Biocatálise , Enzimas , Humanos
4.
J Chem Phys ; 156(13): 134108, 2022 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-35395879

RESUMO

We introduce a reaction-path statistical mechanics formalism based on the principle of large deviations to quantify the kinetics of single-molecule enzymatic reaction processes under the Michaelis-Menten mechanism, which exemplifies an out-of-equilibrium process in the living system. Our theoretical approach begins with the principle of equal a priori probabilities and defines the reaction path entropy to construct a new nonequilibrium ensemble as a collection of possible chemical reaction paths. As a result, we evaluate a variety of path-based partition functions and free energies by using the formalism of statistical mechanics. They allow us to calculate the timescales of a given enzymatic reaction, even in the absence of an explicit boundary condition that is necessary for the equilibrium ensemble. We also consider the large deviation theory under a closed-boundary condition of the fixed observation time to quantify the enzyme-substrate unbinding rates. The result demonstrates the presence of a phase-separation-like, bimodal behavior in unbinding events at a finite timescale, and the behavior vanishes as its rate function converges to a single phase in the long-time limit.


Assuntos
Enzimas , Entropia , Enzimas/química , Cinética , Probabilidade
6.
Science ; 376(6589): 147, 2022 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-35389804
7.
Biomed Environ Sci ; 35(3): 215-224, 2022 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-35317901

RESUMO

Objective: To develop effective alternatives to natural enzymes, it is crucial to develop nanozymes that are economical, resource efficient, and environmentally conscious. Carbon nanomaterials that have enzyme-like activities have been extensively developed as substitutes for traditional enzymes. Methods: Carbide-derived carbons (CDCs) were directly synthesized via a one-step electrochemical method from a MAX precursor using an ammonium bifluoride electrolyte at ambient conditions. The CDCs were characterized by systematic techniques. Results: CDCs showed bienzyme-like activities similar to that of peroxidase and superoxide dismutase. We systematically studied the dependence of CDC enzyme-like activity on different electrolytes and electrolysis times to confirm activity dependence on CDC content. Additionally, the synthesis mechanism and CDC applicability were elaborated and demonstrated, respectively. Conclusion: The demonstrated synthesis strategy eliminates tedious intercalation and delamination centrifugation steps and avoids using high concentrations of HF, high temperatures, and halogen gases. This study paves the way for designing two-dimensional material-based nanocatalysts for nanoenzyme and other applications.


Assuntos
Compostos de Amônio/síntese química , Carbono/química , Técnicas Eletroquímicas , Enzimas , Fluoretos/síntese química , Nanoestruturas , Oxirredução , Humanos
8.
Math Biosci ; 346: 108795, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35257739

RESUMO

Enzymatic (metabolic rate) processes are traditionally modelled by means of Michaelis-Menten type reactions. The experimental setup is usually performed in vitro also denoted as a 'closed system'. In this paper we explore the impact of enzyme turnover on the classical Michaelis-Menten model by modifying it to include enzyme turnover, specifically through zeroth-order synthesis and first-order degeneration of the enzyme. It is shown how enzyme turnover significantly alters the dynamics of substrate, free- and bound enzyme, and impacts the rate with which substrate is converted to a metabolite P. Qualitative and quantitative estimates are derived for the effect of the parameters ksyn, kdeg and kcat on the dynamics of substrate, and free- and bound enzyme. The model integrates four distinct processes, each characterised with its own parameter(s): (i) substrate-enzyme binding, characterised by kon and koff; (ii) the catalytic process, characterised by kcat; (iii) simultaneous re-generation of free enzyme; and (iv) turnover of free enzyme, characterised by kdeg. The properties of the open Michaelis-Menten model have a direct bearing on the drug discovery process, the translation of data to the human situation and on explaining deviating clinical metabolic observations.


Assuntos
Descoberta de Drogas , Enzimas , Catálise , Enzimas/metabolismo , Cinética , Ligação Proteica
9.
J Mol Biol ; 434(7): 167517, 2022 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-35240125

RESUMO

Conformational variation in catalytic residues can be captured as alternative snapshots in enzyme crystal structures. Addressing the question of whether active site flexibility is an intrinsic and essential property of enzymes for catalysis, we present a comprehensive study on the 3D variation of active sites of 925 enzyme families, using explicit catalytic residue annotations from the Mechanism and Catalytic Site Atlas and structural data from the Protein Data Bank. Through weighted pairwise superposition of the functional atoms of active sites, we captured structural variability at single-residue level and examined the geometrical changes as ligands bind or as mutations occur. We demonstrate that catalytic centres of enzymes can be inherently rigid or flexible to various degrees according to the function they perform, and structural variability most often involves a subset of the catalytic residues, usually those not directly involved in the formation or cleavage of bonds. Moreover, data suggest that 2/3 of active sites are flexible, and in half of those, flexibility is only observed in the side chain. The goal of this work is to characterise our current knowledge of the extent of flexibility at the heart of catalysis and ultimately place our findings in the context of the evolution of catalysis as enzymes evolve new functions and bind different substrates.


Assuntos
Biocatálise , Domínio Catalítico , Enzimas , Bases de Dados de Proteínas , Enzimas/química , Ligantes
10.
Appl Microbiol Biotechnol ; 106(5-6): 1813-1835, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35254498

RESUMO

Microbial enzymes have an indispensable role in producing foods, pharmaceuticals, and other commercial goods. Many novel enzymes have been reported from all domains of life, such as plants, microbes, and animals. Nonetheless, industrially desirable enzymes of microbial origin are limited. This review article discusses the classifications, applications, sources, and challenges of most demanded industrial enzymes such as pectinases, cellulase, lipase, and protease. In addition, the production of novel enzymes through protein engineering technologies such as directed evolution, rational, and de novo design, for the improvement of existing industrial enzymes is also explored. We have also explored the role of metagenomics, nanotechnology, OMICs, and machine learning approaches in the bioprospecting of novel enzymes. Overall, this review covers the basics of biocatalysts in industrial and healthcare applications and provides an overview of existing microbial enzyme optimization tools. KEY POINTS: • Microbial bioactive molecules are vital for therapeutic and industrial applications. • High-throughput OMIC is the most proficient approach for novel enzyme discovery. • Comprehensive databases and efficient machine learning models are the need of the hour to fast forward de novo enzyme design and discovery.


Assuntos
Bactérias , Bioprospecção , Enzimas , Fungos , Engenharia de Proteínas , Animais , Bactérias/enzimologia , Biotecnologia , Enzimas/metabolismo , Fungos/enzimologia , Setor de Assistência à Saúde , Indústrias , Metagenômica
11.
Life Sci ; 296: 120441, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35240160

RESUMO

AIMS: Investigating the impact of 17ß estradiol (E2) and its endogenous non-hormonal metabolite 2-methoxyestradiol (2ME) on renal ischemia-reperfusion (RIR) induced kidney injury in ovariectomized (OVX) rats and the role of catechol-O-methyltransferase (COMT) in their effects. MAIN METHODS: Eighty female rats were allocated into eight groups. Control group, Sham group, OVX group, OVX and RIR group, OVX + RIR + E2 group, OVX + RIR + 2ME group, OVX + RIR + E2 + Entacapone group and OVX + RIR + 2ME + Entacapone group, respectively. Twenty-four hours post RIR, creatinine (Cr) and blood urea nitrogen (BUN) were determined in serum, while malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), Glutathione (GSH), myeloperoxidase (MPO), as well as the expressions of COMT, hypoxia inducible factor-1α (HIF-1α) and tyrosine hydroxylase (TH) were assessed in the kidney tissues. KEY FINDINGS: Serum Cr, BUN, MPO, as well as HIF-1α and TH expressions were significantly higher with concomitant decrease in COMT expression, SOD and CAT activities and GSH content observed in OVX and RIR group compared to sham group. E2 and 2ME treatment significantly ameliorated all parameters measured in OVX and RIR rats. On the other hand, Entacapone significantly decreased the effect of E2, with no effect on 2ME treatment. SIGNIFICANCE: E2 ameliorates RIR-induced kidney injury and this effect is mediated, at least in part, via its COMT-mediated conversion to 2ME. Thus, 2ME by the virtue of its pleiotropic pharmacological effects can be used as a safe and effective treatment of RIR injury.


Assuntos
2-Metoxiestradiol/farmacologia , Estradiol/farmacologia , Rim/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Traumatismo por Reperfusão/prevenção & controle , 2-Metoxiestradiol/metabolismo , Animais , Nitrogênio da Ureia Sanguínea , Peso Corporal/efeitos dos fármacos , Catecol O-Metiltransferase/metabolismo , Catecóis/farmacologia , Enzimas/metabolismo , Estradiol/farmacocinética , Feminino , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Rim/irrigação sanguínea , Rim/patologia , Nitrilas/farmacologia , Ovariectomia , Ratos Sprague-Dawley
13.
J Am Chem Soc ; 144(12): 5214-5225, 2022 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-35290055

RESUMO

Achieving convergent synthetic strategies has long been a gold standard in constructing complex molecular skeletons, allowing for the rapid generation of complexity in comparatively streamlined synthetic routes. Traditionally, biocatalysis has not played a prominent role in convergent laboratory synthesis, with the application of biocatalysts in convergent strategies primarily limited to the synthesis of chiral fragments. Although the use of enzymes to enable convergent synthetic approaches is relatively new and emerging, combining the efficiency of convergent transformations with the selectivity achievable through biocatalysis creates new opportunities for efficient synthetic strategies. This Perspective provides an overview of recent developments in biocatalytic strategies for convergent transformations and offers insights into the advantages of these methods compared to their small molecule-based counterparts.


Assuntos
Enzimas , Biocatálise , Enzimas/metabolismo
14.
J Struct Biol ; 214(1): 107835, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35104611

RESUMO

Enzyme promiscuity is the ability of (some) enzymes to perform alternate reactions or catalyze non-cognate substrate(s). The latter is referred to as substrate promiscuity, widely studied for its biotechnological applications and understanding enzyme evolution. Insights into the structural basis of substrate promiscuity would greatly benefit the design and engineering of enzymes. Previous studies on some enzymes have suggested that flexibility, hydrophobicity, and active site protonation state could play an important role in enzyme promiscuity. However, it is not known yet whether substrate promiscuous enzymes have distinctive structural characteristics compared to specialist enzymes, which are specific for a substrate. In pursuit to address this, we have systematically compared substrate/catalytic binding site structural features of substrate promiscuous with those of specialist enzymes. For this, we have carefully constructed dataset of substrate promiscuous and specialist enzymes. On careful analysis, surprisingly, we found that substrate promiscuous and specialist enzymes are similar in various binding/catalytic site structural features such as flexibility, surface area, hydrophobicity, depth, and secondary structures. Recent studies have also alluded that promiscuity is widespread among enzymes. Based on these observations, we propose that substrate promiscuity could be defined as a continuum feature that varies from narrow (specialist) to broad range of substrate preferences. Moreover, diversity of conformational states of an enzyme accessible for ligand binding may possibly regulate its substrate preferences.


Assuntos
Enzimas , Sítios de Ligação , Catálise , Domínio Catalítico , Enzimas/química , Especificidade por Substrato
15.
Proc Natl Acad Sci U S A ; 119(9)2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35217602

RESUMO

All life on Earth is unified by its use of a shared set of component chemical compounds and reactions, providing a detailed model for universal biochemistry. However, this notion of universality is specific to known biochemistry and does not allow quantitative predictions about examples not yet observed. Here, we introduce a more generalizable concept of biochemical universality that is more akin to the kind of universality found in physics. Using annotated genomic datasets including an ensemble of 11,955 metagenomes, 1,282 archaea, 11,759 bacteria, and 200 eukaryotic taxa, we show how enzyme functions form universality classes with common scaling behavior in their relative abundances across the datasets. We verify that these scaling laws are not explained by the presence of compounds, reactions, and enzyme functions shared across known examples of life. We demonstrate how these scaling laws can be used as a tool for inferring properties of ancient life by comparing their predictions with a consensus model for the last universal common ancestor (LUCA). We also illustrate how network analyses shed light on the functional principles underlying the observed scaling behaviors. Together, our results establish the existence of a new kind of biochemical universality, independent of the details of life on Earth's component chemistry, with implications for guiding our search for missing biochemical diversity on Earth or for biochemistries that might deviate from the exact chemical makeup of life as we know it, such as at the origins of life, in alien environments, or in the design of synthetic life.


Assuntos
Fenômenos Bioquímicos , Enzimas/metabolismo , Planeta Terra , Origem da Vida , Biologia Sintética
16.
Angew Chem Int Ed Engl ; 61(18): e202117144, 2022 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-35133704

RESUMO

Fully exploiting the potential of enzymes in cell-free biocatalysis requires stabilization of the catalytically active proteins and their integration into efficient reactor systems. Although in recent years initial steps towards the immobilization of such biomolecules in metal-organic frameworks (MOFs) have been taken, these demonstrations have been limited to batch experiments and to aqueous conditions. Here we demonstrate a MOF-based continuous flow enzyme reactor system, with high productivity and stability, which is also suitable for organic solvents. Under aqueous conditions, the stability of the enzyme was increased 30-fold, and the space-time yield exceeded that obtained with other enzyme immobilization strategies by an order of magnitude. Importantly, the infiltration of the proteins into the MOF did not require additional functionalization, thus allowing for time- and cost-efficient fabrication of the biocatalysts using label-free enzymes.


Assuntos
Enzimas Imobilizadas , Estruturas Metalorgânicas , Biocatálise , Catálise , Enzimas/metabolismo , Enzimas Imobilizadas/metabolismo , Estruturas Metalorgânicas/metabolismo , Proteínas/metabolismo , Solventes
17.
J Mol Biol ; 434(7): 167462, 2022 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-35104498

RESUMO

Understanding how proteins evolved not only resolves mysteries of the past, but also helps address challenges of the future, particularly those relating to the design and engineering of new protein functions. Here we review the work of Dan S. Tawfik, one of the pioneers of this area, highlighting his seminal contributions in diverse fields such as protein design, high throughput screening, protein stability, fundamental enzyme-catalyzed reactions and promiscuity, that underpin biology and the origins of life. We discuss the influence of his work on how our models of enzyme and protein function have developed and how the main driving forces of molecular evolution were elucidated. The discovery of the rugged routes of evolution has enabled many practical applications, some which are now widely used.


Assuntos
Enzimas , Evolução Molecular , Proteínas , Catálise , Evolução Molecular Direcionada , Ensaios de Triagem em Larga Escala
18.
Adv Drug Deliv Rev ; 183: 114143, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35167900

RESUMO

Therapeutic enzymes are valuable biopharmaceuticals in various biomedical applications. They have been successfully applied for fibrinolysis, cancer treatment, enzyme replacement therapies, and the treatment of rare diseases. Still, there is a permanent demand to find new or better therapeutic enzymes, which would be sufficiently soluble, stable, and active to meet specific medical needs. Here, we highlight the benefits of coupling computational approaches with high-throughput experimental technologies, which significantly accelerate the identification and engineering of catalytic therapeutic agents. New enzymes can be identified in genomic and metagenomic databases, which grow thanks to next-generation sequencing technologies exponentially. Computational design and machine learning methods are being developed to improve catalytically potent enzymes and predict their properties to guide the selection of target enzymes. High-throughput experimental pipelines, increasingly relying on microfluidics, ensure functional screening and biochemical characterization of target enzymes to reach efficient therapeutic enzymes.


Assuntos
Enzimas , Ensaios de Triagem em Larga Escala , Catálise , Humanos
19.
Int J Mol Sci ; 23(4)2022 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-35216475

RESUMO

The scientific community and industrial companies have discovered significant enzyme applications to plant material. This rise imparts to changing consumers' demands while searching for 'clean label' food products, boosting the immune system, uprising resistance to bacterial and fungal diseases, and climate change challenges. First, enzymes were used for enhancing production yield with mild and not hazardous applications. However, enzyme specificity, activity, plant origin and characteristics, ratio, and extraction conditions differ depending on the goal. As a result, researchers have gained interest in enzymes' ability to cleave specific bonds of macroelements and release bioactive compounds by enhancing value and creating novel derivatives in plant extracts. The extract is enriched with reducing sugars, phenolic content, and peptides by disrupting lignocellulose and releasing compounds from the cell wall and cytosolic. Nonetheless, depolymerizing carbohydrates and using specific enzymes form and release various saccharides lengths. The latest studies show that oligosaccharides released and formed by enzymes have a high potential to be slowly digestible starches (SDS) and possibly be labeled as prebiotics. Additionally, they excel in new technological, organoleptic, and physicochemical properties. Released novel derivatives and phenolic compounds have a significant role in human and animal health and gut-microbiota interactions, affecting many metabolic pathways. The latest studies have contributed to enzyme-modified extracts and products used for functional, fermented products development and sustainable processes: in particular, nanocellulose, nanocrystals, nanoparticles green synthesis with drug delivery, wound healing, and antimicrobial properties. Even so, enzymes' incorporation into processes has limitations and is regulated by national and international levels.


Assuntos
Enzimas/metabolismo , Compostos Fitoquímicos/isolamento & purificação , Extratos Vegetais/química , Polifenóis , Polissacarídeos , Prebióticos
20.
Carbohydr Res ; 513: 108517, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35152128

RESUMO

The synthesis of five series of 4'-truncated nucleoside phosphonic acid analogues is discussed in this review: (1) 4'-truncated furanose nucleoside phosphonic acid analogues; (2) 4'-truncated pyrrolidine nucleoside phosphonic acid analogues; (3) 4'-truncated carbocyclic nucleoside phosphonic acid analogues; (4) 4'-truncated isoxazole nucleoside phosphonic acid analogues; (5) 4'-truncated miscellaneous nucleoside phosphonic acid analogues. Five different ways are used to make the phosphonate moiety: (i) Michaelis-Arbuzov reaction of RX (X = Br, I, OTf) with trialkyl phosphate; (ii) Lewis acid catalyzed Michaelis-Arbuzov reaction of glycoside with trialkyl phosphite; (iii) nucleophilic addition of a dialkyl phosphite to a carbonyl group; (iv) direct coupling reaction with amino alkyl phosphonate; (v) de novo synthesis of phosphonated-isoxazole and 1,3-dioxolane heterocycles from phosphonated starting materials. Their biological activity results are briefly discussed.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Enzimas/metabolismo , Nucleosídeos/farmacologia , Ácidos Fosforosos/farmacologia , Vírus/efeitos dos fármacos , Animais , Antivirais/síntese química , Antivirais/química , Configuração de Carboidratos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Testes de Sensibilidade Microbiana , Nucleosídeos/síntese química , Nucleosídeos/química , Ácidos Fosforosos/síntese química , Ácidos Fosforosos/química
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