Laura Masgrau

Laura Masgrau
Autonomous University of Barcelona | UAB · Institute of Biotechnology and Biomedicine (IBB)

PhD

About

73
Publications
6,120
Reads
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Introduction
Dr. Laura Masgrau (ORCID:0000-0003-4495-508X) is a computational chemist interested in the study of biological systems. Her main research focus is the computational modeling and design of enzyme reactions and activity, with special focus on carbohydrate processing enzymes and some oxidative enzymes. She is currently a senior researcher funded by the Talent Program of the Universitat Autònoma de Barcelona and since 2019 she has also established a strong collaboration with ZYMVOL Biomodelling.
Additional affiliations
September 2013 - present
Autonomous University of Barcelona
Position
  • Senior Researcher
February 2008 - August 2013
Autonomous University of Barcelona
Position
  • "Ramón y Cajal" Researcher
October 2005 - November 2007
Institute Pasteur, Paris, France
Position
  • Marie-Curie Postdoctoral Fellow

Publications

Publications (73)
Article
Full-text available
In the barley β-D-glucan glucohydrolase, a glycoside hydrolase family 3 (GH3) enzyme, the Trp286/Trp434 clamp ensures β-D-glucosides binding, which is fundamental for substrate hydrolysis during plant growth and development. We employ mutagenesis, high-resolution X-ray crystallography, and multi-scale molecular modelling methods to examine the bind...
Article
Full-text available
DyP-type peroxidases (DyPs) are microbial enzymes that catalyze the oxidation of a wide range of substrates, including synthetic dyes, lignin-derived compounds, and metals, such as Mn²⁺ and Fe²⁺, and have enormous biotechnological potential in biorefineries. However, many questions on the molecular basis of enzyme function and stability remain unan...
Article
Many enzyme reactions present instantaneous disorder. These dynamic fluctuations in the enzyme-substrate Michaelis complexes generate a wide range of energy barriers that cannot be experimentally observed, but that determine the measured kinetics of the reaction. These individual energy barriers can be calculated using QM/MM methods, but then the p...
Article
Carbohydrate processing enzymes are of biocatalytic interest. Glycoside hydrolases and the recently discovered lytic polysaccharide monooxygenase for their use in biomass degradation to obtain biofuels or valued chemical entities. Glycosyltransferases or engineered glycosidases and phosphorylases for the synthesis of carbohydrates and glycosylated...
Article
Multicopper oxidases oxidizes a vast range of aromatic substrates coupled to the reduction of molecular oxygen to water. A vast broad spectrum of applications reflects their high biotechnological importance. The crystal structure of McoA from the hyper-thermophilic bacteria Aquifex aeolicus has the most tightly compact and hydrophobic core among it...
Article
Immunomodulatory glycolipids, among which α-galactosylceramide (KRN7000) is an iconic example, have shown strong therapeutic potential in a variety of conditions ranging from cancer and infection to autoimmune or neurodegenerative diseases. A main difficulty for those channels is that they often provoke a cytokine storm comprising both pro- and ant...
Article
Full-text available
Congenital hypogonadotropic hypogonadism (CHH) is a condition characterized by absent puberty and infertility due to gonadotropin releasing hormone (GnRH) deficiency, which is often associated with anosmia (Kallmann syndrome, KS). We identified loss-of-function heterozygous mutations in anti-Müllerian hormone (AMH) and its receptor, AMHR2, in 3% of...
Article
Full-text available
Substrates associate and products dissociate from enzyme catalytic sites rapidly, which hampers investigations of their trajectories. The high-resolution structure of the native Hordeum exo-hydrolase HvExoI isolated from seedlings reveals that non-covalently trapped glucose forms a stable enzyme-product complex. Here, we report that the alkyl β-d-g...
Article
Full-text available
The synthesis of oligosaccharides and other carbohydrate derivatives is of relevance for the advancement of glycosciences both at the fundamental and applied level. For many years, glycosyl hydrolases (GHs) have been explored to catalyze the synthesis of glycosidic bonds. In particular, retaining GHs can catalyze a transglycosylation (T) reaction t...
Article
Neuroinflammation is an early event during diabetic retinopathy (DR) that impacts the dynamics of microglia polarization. Gliosis is a hallmark of DR and we have reported the beneficial effects of 1R-DSO-ONJ, a member of the sp2-iminosugar glycolipid (sp2-IGL) family, in targeting microglia and reducing gliosis in diabetic db/db mice. Herein, we an...
Chapter
Most biochemical reactions are catalysed by enzymes, and understanding how enzymes ‘work’ at the molecular level is a fundamental problem that can help in the development of enzyme inhibition or enzyme engineering strategies. Computer simulations (especially QM/MM methods) can provide information that is often inaccessible experimentally, like deta...
Article
Aromatic amine dehydrogenase (AADH) and related enzymes are at the heart of debates on the roles of quantum tunnelling and protein dynamics in catalysis. The reaction of tryptamine in AADH involves significant quantum tunnelling in the rate-limiting proton transfer step, shown e.g. by large H/D primary kinetic isotope effects (KIEs), with unusual t...
Article
Full-text available
Glycosyltransferases are enzymes that catalyze a monosaccharide transfer reaction from a donor to an acceptor substrate with the synthesis of a new glycosidic bond. They are highly substrate specific and regioselective, even though the acceptor substrate often presents multiple reactive groups. Currently, many efforts are dedicated to developing bi...
Article
Lipoxygenases (LOXs) are a family of enzymes that catalyze the highly specific hydroperoxidation of polyunsaturated fatty acids, like arachidonic acid. Different stereo- or/and regioisomer hydroperoxidation products lead later to different metabolites that exert opposite physiological effects in the animal body and play a central role in inflammato...
Article
Molecular dynamics simulations and quantum mechanics/molecular mechanics calculations were performed on the in silico Leu597Ala/Ile663Ala double mutant of rabbit ALOX15 (12/15 lipoxygenase). The computational results suggested that subtle steric hindrance by the conserved Leu597 and C-terminal Ile663 residues disturbed H10 abstractions in wildtype...
Article
Full-text available
In the present work we have combined homology modeling, protein-ligand dockings, quantum mechanics/molecular mechanics calculations and molecular dynamics simulations to generate human 5-lipoxygenase (5-LOX):arachidonic acid (AA) complexes consistent with the 5-lipoxygenating activity (which implies hydrogen abstraction at the C7 position). Our res...
Article
ALOX15 (12/15-lipoxygenase) orthologs have been implicated in maturational degradation of intracellular organelles and in the biosynthesis of antiinflammatory and proresolving eicosanoids. Here we hypothesized that lower mammals (mice, rats, pigs) express 12-lipoxygenating ALOX15 orthologs. In contrast, 15-lipoxygenating isoforms are found in highe...
Article
Glycosyltransferases (GTs) are the biocatalysts that synthesize the wide variety of glycans present in nature. The mechanism by which they form a new glycosidic bond preserving the configuration at the anomeric carbon is strongly debated. In the last years, new experimental and computational results are providing very valuable knowledge: the propos...
Article
Lipoxygenases (LOXs) are a family of enzymes involved in the biosynthesis of several lipid mediators. In the case of human 15-LOX, the 15-LOX-1 and 15-LOX-2 isoforms show slightly different reaction regiospecificity and substrate specificity, indicating that substrate binding and recognition may be different, a fact that could be related to their d...
Article
The most common substrate of mammalian lipoxygenases (LOXs) is arachidonic acid (AA). However, 15-LOXs can present dual substrate specificity. These LOXs catalyze the peroxidation of AA, initiated by a H-abstraction step (mainly H13-abstraction) by the Fe(III)-OH- cofactor, and the peroxidation of linoleic acid (LA) after H11-abstraction. In this p...
Article
Glycosyltransferases (GTs) catalyse the biosynthesis of glycosidic linkages by transferring a monosaccharide from a nucleotide sugar donor to an acceptor substrate, and they do that with exquisite regio- and stereospecificity. Retaining GTs act with retention of the configuration at the anomeric carbon of the transferred sugar. Their chemical mecha...
Article
Glycosyltransferases (GTs) comprise a prominent family of enzymes that play critical roles in a variety of cellular processes, including cell signaling, cell development, and host-pathogen interactions. Glycosyl transfer can proceed with either inversion or retention of the anomeric configuration with respect to the reaction substrates and products...
Article
The active site of an enzyme is surrounded by a fluctuating environment of protein and solvent conformational states, and a realistic calculation of chemical reaction rates and kinetic isotope effects of enzyme-catalyzed reactions must take account of this environmental diversity. Ensemble-averaged variational transition state theory with multidime...
Article
The self-consistent charge density functional tight binding/molecular mechanics (SCC-DFTB/MM) and ensemble averaged variational transition state theory/multidimensional tunneling (EA-VTST/MT) methods have been employed to investigate the reaction mechanism and to calculate the rate constant of the NS3/NS4A + NS5A/5B acylation reaction. This reactio...
Article
The regioselective activation of C–H bonds in complex molecules containing several of them is still an exciting challenge in chemistry. However, many enzymes catalyze these processes, and much can be learned from the way they do it. For example, each mammalian lipoxygenase isoenzyme abstracts a hydrogen atom from essentially a unique carbon positio...
Article
Lipoxygenases (LOs) are a family of nonheme iron-containing enzymes that catalyze the hydroperoxidation of several polyunsaturated fatty acids with a huge regio- and stereospecificity. Mammalian 15-LO-1 yields almost exclusively oxygenation at the C13 position of the linoleic acid (LA), its preferred substrate. This is very important because metabo...
Article
We combined quantum mechanics/molecular mechanics calculations with molecular dynamics simulations to study the addition of O2 to the pentadienyl radical of arachidonic acid (AA) catalyzed by the Leu597Val and Leu597Ala mutants of rabbit 15-lipoxygenase (15-rLO). In the Leu597Val mutant, the addition of O2 to C15 of AA is the predominant path, alth...
Article
Full-text available
It is estimated that >50% of proteins are glycosylated with sugar tags that can modulate protein activity through what has been called the sugar code. Here we present the first QM/MM calculations of human GalNAc-T2, a retaining glycosyltransferase, which initiates the biosynthesis of mucin-type O-glycans. Importantly, we have characterized a hydrog...
Article
15-Lipoxygenases (15-LOs) catalyse the peroxidation reaction of arachidonic acid (AA) in mammals with remarkable regio- and stereospecificity. This positional-specific peroxidation is of paramount importance because it determines the nature and biological functions of the final metabolites generated by each LO as a result of the oxidative metabolis...
Article
Glycosyltransferases (GTs) are responsible of glycans' biosynthesis, the most abundant organic molecules in nature. Their biological relevance makes necessary the knowledge of their catalytic mechanism, which in the case of retaining GTs is still a matter of debate. After the initial proposal of a double-displacement mechanism with formation of a c...
Article
15-Lipoxygenases (15-LOs) catalyze the peroxidation reaction of linoleic acid (LA) in mammals producing almost exclusively 13-(S)-hydroperoxyoctadecadienoic acid (13-(S)-HPODE). Although several hypotheses have been formulated, the molecular basis of such enzymatic regiospecificity is unclear. We have here combined quantum mechanics/molecular mecha...
Article
Retaining glycosyltransferases (ret-GTs) are the enzymes responsible for the biosynthesis of highly specific glycosidic bonds and have drawn the interest of the scientific community. The catalytic mechanism of such enzymes is not yet fully understood and its study remains a challenge for both experimental and theoretical researches. In the case of...
Article
Glycosyltransferases (GTs) catalyze the highly specific biosynthesis of glycosidic bonds and, as such, are important both as drug targets and for biotechnological purposes. Despite their broad interest, fundamental questions about their reaction mechanism remain to be answered, especially for those GTs that transfer the sugar with net retention of...
Article
Mammalian lipoxygenases (LOXs) have been implicated in cellular defense response and are important for physiological homeostasis. Since their discovery, LOXs have been believed to function as monomeric enzymes that exhibit allosteric properties. In aqueous solutions, the rabbit 12/15-LOX is mainly present as hydrated monomer but changes in the loca...
Article
cAMP-dependent protein kinase (PKA) is one of the simplest and best understood members of the protein kinase family. In a previous study, we have theoretically studied the complex between PKA and the heptapeptide substrate Kemptide by classical molecular dynamics. On the basis of the results obtained for Kemptide, the aim of the present work is to...
Article
Lipoxygenases (LOs) are implicated in the regulation of metabolic processes and in several human diseases. Revealing their exact role is hindered by an incomplete understanding of their activity, including substrate specificity and substrate alignment in the active site. Recently, it has been proposed that the change in substrate specificity for ar...
Article
Mammalian 15-lipoxygenases (15-LOs) are key pharmaceutical targets under strong investigation because of their implication in atherosclerosis and cancer. Here, we present an atomic-level study of the binding modes of arachidonic acid (AA) to rabbit reticulocyte 15-LO, with a particular insight into the 15-LO:AA complexes consistent with known catal...
Article
The anti-Müllerian hormone type II (AMHRII) receptor is the primary receptor for anti-Müllerian hormone (AMH), a protein produced by Sertoli cells and responsible for the regression of the Müllerian duct in males. AMHRII is a membrane protein containing an N-terminal extracellular domain (ECD) that binds AMH, a transmembrane domain, and an intracel...
Article
Full-text available
Aromatic amine dehydrogenase uses a tryptophan tryptophylquinone (TTQ) cofactor to oxidatively deaminate primary aromatic amines. In the reductive half-reaction, a proton is transferred from the substrate C1 to betaAsp-128 O-2, in a reaction that proceeds by H-tunneling. Using solution studies, kinetic crystallography, and computational simulation...
Article
The hydrogen-transfer reaction catalysed by methylamine dehydrogenase (MADH) with methylamine (MA) as substrate is a good model system for studies of proton tunnelling in enzyme reactions--an area of great current interest--for which atomistic simulations will be vital. Here, we present a detailed analysis of the key deprotonation step of the MADH/...
Article
Proton tunneling dominates the oxidative deamination of tryptamine catalyzed by the enzyme aromatic amine dehydrogenase. For reaction with the fast substrate tryptamine, a H/D kinetic isotope effect (KIE) of 55 +/- 6 has been reported-one of the largest observed in an enzyme reaction. We present here a computational analysis of this proton-transfer...
Article
Full-text available
It is now widely accepted that enzyme-catalysed C-H bond breakage occurs by quantum mechanical tunnelling. This paradigm shift in the conceptual framework for these reactions away from semi-classical transition state theory (TST, i.e. including zero-point energy, but with no tunnelling correction) has been driven over the recent years by experiment...
Article
Full-text available
We present an atomic-level description of the reaction chemistry of an enzyme-catalyzed reaction dominated by proton tunneling. By solving structures of reaction intermediates at near-atomic resolution, we have identified the reaction pathway for tryptamine oxidation by aromatic amine dehydrogenase. Combining experiment and computer simulation, we...
Article
It is now widely accepted that substrate C-H bond breakage by quinoprotein enzymes occurs by quantum mechanical tunneling. This paradigm shift in the conceptual framework for these reactions away from semi-classical transition state theory (i.e., including zero-point energy but with no tunneling correction) has been driven over recent years by expe...
Article
The reasons for the nonlinearity of the Arrhenius plots of gas-phase reactions are analyzed in detail within the frame of conventional canonical transition-state theory and in the absence of tunneling effects. The purpose is to show how the vibrational normal mode frequencies of reactants and the transition state determine the curvature of an Arrhe...
Article
In this paper the first variational transition-state theory rate constant calculation for the OH + CH 3 SH reaction and several isotopic variants involving OD, CH 3 SD, and CD 3 SH is presented. Multidimensional tunneling corrections have been included when necessary. The potential energy surface has been described by low-level calculations at the...
Article
The title reaction has been used as an example to test the importance of using a hindered rotor treatment instead of a harmonic oscillator model for calculating vibrational partition functions corresponding to low-frequency internal rotation modes. First, a normal-mode analysis according to the Ayala and Schlegel's algorithm has been used to identi...
Article
In this paper the first variational transition-state rate constant calculation for the OH + CH 3 COCH 3 f P reaction is presented. The potential energy surface has been described by low level calculations at the B3LYP/ 6-31G* level combined with higher level calculations using the multilevel CBS-RAD technique. Three different reaction pathways have...
Article
 Variational transition state theory including tunneling corrections (as implemented in Polyrate 8.7) and using multilevel energy calculations at the MCCM-CCSD(T)-1sc level for the CH4 + OH reaction and at the MCCM-CCSD(T)-2m level for the CD4 + OH process, reproduces very well the experimental rate constants. However, no single methodology was fou...
Article
Quasi-thermodynamic magnitudes obtained from three different analytical fits to the experimental rate constants of the CH 4 þ OH reaction are compared to the values obtained from theoretical rate constants calculated using canonical variational transition state theory plus multidimensional tunnelling contributions. A right decomposition of DG tot;0...
Article
Full-text available
An attempt was made to calculate the rate constants and their temperature dependence for the reactions CHnD4-n+OH→P, and for the reaction of methane with OD, by means of different multilevel electronic methods including two very recently developed multicoefficient schemes for extrapolating correlated electronic structure calculations (MCSAC and MCC...
Article
Full-text available
In the present work, we have theoretically calculated the rate constants and their temperature dependence for the reactions CH n D 4n OH→P, and for the reaction of methane with OD, by means of variational transition-state theory plus multidimensional tunneling corrections, at the MP-SAC2//MP2/cc-pVTZ/// and CCSDT//MP2/cc-pVTZ/// electronic levels....
Article
Many important bimolecular hydrogen-transfer processes that take place in the atmosphere proceed via a potential energy minimum (hydrogen-bonded complex) that precedes along the minimum energy path the unique saddle point of the reaction, the one corresponding to the hydrogen transfer. It is clear that the one-step low-pressure rate constant of suc...
Article
Hydrogen abstraction from a molecule by OH is an important step in several reaction mechanisms of a key relevance in the chemistry of the atmosphere. The upper limit at 300 K for the rate constant of one of the simplest hydrogen abstraction reactions, HO + HOH f HOH + OH (1), has been experimentally established. This reaction is intrinsicaly intere...

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