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Introduction
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July 2001 - present
Institut de Quimica Avançada de Catalunya
December 1996 - June 2001
Instituto de Investigaciones Químicas y Ambientales de Barcelona
February 1994 - November 1996
Publications
Publications (101)
Chiral 2‐hydroxy‐4‐arylbut‐3‐enoic acid derivatives are important precursors for the synthesis of angiotensin converting enzyme (ACE) inhibitors, such as enalapril, lisinopril, cilapril or benazepril. In this work, we take advantage of the unexplored promiscuous ketoreductase activity of Δ¹‐piperidine‐2‐carboxylate/Δ¹‐pyrroline‐2‐carboxylate reduct...
Chiral 2-hydroxy acids and 2-hydroxy-4-butyrolactone derivatives are structural motifs often found in fine and commodity chemicals. Here, we report a tandem biocatalytic stereodivergent route for the preparation of these compounds using three stereoselective aldolases and two stereocomplementary ketoreductases using simple and achiral starting mate...
Heparin-like macromolecules are widely used in clinics as anticoagulant, antiviral, and anticancer drugs. However, the search of heparin antidotes based on small synthetic molecules to control blood coagulation still remains a challenging task due to the physicochemical properties of this anionic polysaccharide. Here, we use a dynamic combinatorial...
Purpose:
Semaphorin 3A (Sema-3A) is a secreted protein that deflects axons from inappropriate regions and induces neuronal cell death. Intravitreal application of polyclonal antibodies against Sema-3A prevents loss of retinal ganglion cells ensuing from axotomy of optic nerves. This suggested a therapeutic approach for neuroprotection via inhibiti...
Semaphorin 3A (Sema3A) is a cell-secreted protein that participates in the axonal guidance pathways. Sema3A acts as a canonical repulsive axon guidance molecule, inhibiting CNS regenerative axonal growth and propagation. Therefore, interfering with Sema3A signaling is proposed as a therapeutic target for achieving functional recovery after CNS inju...
Three enzymatic routes toward γ-hydroxy-α-amino acids by tandem aldol addition-transamination one-pot two-step reactions are reported. The approaches feature an enantioselective aldol addition of pyruvate to various nonaromatic aldehydes catalyzed by trans-o-hydroxybenzylidene pyruvate hydratase-aldolase (HBPA) from Pseudomonas putida. This affords...
A two‐enzyme cascade reaction plus in situ oxidative decarboxylation for the transformation of readily available canonical and non‐canonical l‐α‐amino acids into 2‐substituted 3‐hydroxycarboxylic acid derivatives is described. The biocatalytic cascade consisted of an oxidative deamination of l‐α‐amino acids by an l‐α‐amino acid deaminase from Cosen...
The congested nature of quaternary carbons hinders their preparation, most notably when stereocontrol is required. Here we report a biocatalytic method for the creation of quaternary carbon centers with broad substrate scope, leading to different compound classes bearing this structural feature. The key step comprises the aldol addition of 3,3-disu...
Dynamic covalent chemistry can be performed on the surface of living cells. In their Communication (DOI: 10.1002/anie.202004745), I. Alfonso et al. describe the Live‐Cell‐Templated Dynamic Combinatorial Chemistry approach for the identification of a strong binder to the glycosaminoglycans of the extracellular matrix of human lung adenocarcinoma cel...
Dynamische kovalente Chemie kann an der Oberfläche von lebenden Zellen durchgeführt werden. In ihrer Zuschrift (DOI: 10.1002/ange.202004745) beschreiben I. Alfonso et al. einen als Live‐Cell‐Templated Dynamic Combinatorial Chemistry bezeichneten Ansatz zur Identifizierung eines starken Binders an die Glykosaminoglykane der extrazellulären Matrix vo...
Whole living cells were used as the template in a dynamic combinatorial chemistry system. The amplified member of the dynamic library showed strong and selective binding to the main glycosaminoglycan of the extracellular matrix of the corresponding cell. This work demonstrates the power of dynamic covalent screening in chemical biology, even in hig...
Dynamic covalent chemistry combines in a single step the screening and synthesis of ligands for biomolecular recognition. In order to do that, a chemical entity is used as template within a dynamic combinatorial library of interconverting species, so that the stronger binders are amplified due to the efficient interaction with the target. Here we e...
Chiral 2-substituted 3-hydroxycarboxylic acid derivatives are valuable building blocks for the preparation of naturally occurring and synthetic biologically active molecules. Current methodologies for the preparation of these compounds are still limited for large-scale production due to the high costs, limited microbial strains, low yields, difficu...
Targeting autophagy is a promising therapeutic strategy for cancer treatment. As a result, the identification of novel autophagy inhibitors is an emerging field of research. Herein, we report the development of a novel AlphaScreen HTS assay that combined with a MS-based assay and a structure-based high-throughput virtual screening have enabled the...
Nitrogen heterocycles are structural motifs found in many bioactive natural products and of utmost importance in pharmaceutical drug development. In this work, a stereoselective synthesis of functionalized N‐heterocycles was accomplished in two steps, comprising the biocatalytic aldol addition of ethanal and simple aliphatic ketones such as propano...
Asymmetric aldol addition of simple aldehydes and ketones to electrophiles is a cornerstone reaction for the synthesis of unusual sugars and chiral building blocks. We investigated D-fructose-6-phosphate aldolase from E. coli (FSA) D6X variants as catalysts for the aldol additions of linear and cyclic non-functionalized aliphatic ketones or ethanal...
Despite heparin being the most widely used macromolecular drug, the design of small‐molecule ligands to modulate its effects has been hampered by the structural properties of this polyanionic polysaccharide. In this work we used a dynamic covalent selection approach to identify a new ligand for heparin, assembled from extremely simple building bloc...
Despite heparin being the most widely used macromolecular drug, the design of small‐molecule ligands to modulate its effects has been hampered by the structural properties of this polyanionic polysaccharide. In this work we used a dynamic covalent selection approach to identify a new ligand for heparin, assembled from extremely simple building bloc...
Strukturgeleitetes Protein-Engineering der Klasse-II-Pyruvat-Aldolase YfaU aus E. coli wird von P. Clapés und Mitarbeitern in ihrer Zuschrift (DOI: 10.1002/ange.201711289) als direkter Weg zu chiralen Bausteinen sowie zu Prolin- und Pyrrolizidin-α-aminosäure-Derivaten beschrieben. Das Bild vergleicht YfaU mit einem Räderwerk, das ein Nukleophil und...
Structure-guided protein engineering of class II pyruvate aldolase YfaU from E. coli is described. In their communication (DOI: 10.1002/anie.201711289) P. Clapés and co-workers report the resulting straightforward access to chiral building blocks and proline and pyrrolizidine α-amino acid derivatives. The picture shows how YfaU works like a timing...
Pyruvate-dependent aldolases exhibit a stringent selectivity for pyruvate, limiting their synthetic potential application, a drawback shared with other existing aldolases. Structure-guided rational protein engineering rendered a 2-keto-3-deoxy-L-rhamnonate aldolase variant, fused with maltose binding protein (MBP-YfaU W23V/L216A), capable to effici...
Pyruvate-dependent aldolases exhibit a stringent selectivity for pyruvate, limiting their synthetic potential application, a drawback shared with other existing aldolases. Structure-guided rational protein engineering rendered a 2-keto-3-deoxy-L-rhamnonate aldolase variant, fused with maltose binding protein (MBP-YfaU W23V/L216A), capable to effici...
New fluorogenic sensors with suitable kinetic parameters and sensitivity have been developed for the determination of sphingosine-1-phosphate lyase activity in cell lysates. The probe RBM148 can be efficiently loaded into cationic liposomes and used to determine S1PL activity in intact cells.
4‐Hydroxy‐2‐keto acid derivatives are versatile building blocks for the synthesis of amino acids, hydroxy carboxylic acids and chiral aldehydes. Pyruvate aldolases are privileged catalysts for a straightforward access to this class of keto acid compounds. In this work, a Class II pyruvate aldolase from Escherichia coli K‐12, 2‐keto‐3‐deoxy‐ l ‐rham...
Intramolecular benzoin reactions catalyzed by benzaldehyde lyase from Pseudomonas fluorescens biovar I (BAL) are reported. The structure of the substrates envisaged for this reaction consists of two benzaldehyde derivatives linked by an alkyl chain. The structural requirements needed to achieve the intramolecular carbon-carbon bond reaction catalyz...
Intramolecular benzoin reactions catalyzed by benzaldehyde lyase from Pseudomonas fluorescens biovar I (BAL) are reported. The structure of the substrates envisaged for this reaction consists of two benzaldehyde derivatives linked by an alkyl chain. The structural requirements needed to achieve the intramolecular carbon–carbon bond reaction catalyz...
A dynamic mixture of stereoisomeric macrocycles derived from glutamic acid displayed a homochiral self-selection when increasing the acetonitrile content of the aqueous mixed medium. The homochiral self-sorting required the anionic form of the side chains and increased at higher temperature, implying an entropic origin. Conformational analysis (NMR...
Amino acids are of paramount importance as chiral building blocks of life, for drug development in modern medicinal chemistry, and for the manufacture of industrial products. In this work, the stereoselective synthesis of (S)- and (R)-2-amino-4-hydroxybutanoic acid was accomplished using a Systems Biocatalysis approach comprising a biocatalytic one...
Two kinds of inhibitors of the PLP-dependent enzyme sphingosine-1-phosphate lyase have been designed and tested on the bacterial (StS1PL) and the human (hS1PL) enzymes. Amino phosphates 1, 12, and 32, mimicking the intermediate aldimines of the catalytic process, were weak inhibitors on both enzyme sources. On the other hand, a series of stereodefi...
A series of potential active-site sphingosine-1-phosphate lyase (S1PL) inhibitors have been designed from scaffolds 1 and 2, arising from virtual screening using the X-ray structures of the bacterial (StS1PL) and the human (hS1PL) enzymes. Both enzymes are very similar at the active site, as confirmed by the similar experimental kinetic constants s...
Semaphorin3A (Sema3A) is a vertebrate-secreted protein that was initially characterized as a repulsive-guidance cue. Semaphorins have crucial roles in several diseases; therefore, the development of Sema3A inhibitors is of therapeutic interest. Sema3A interacts with glycosaminoglycans (GAGs), presumably through its C-terminal basic region. We used...
The preparation of multifunctional chiral molecules can be greatly simplified by adopting a route via the sequential catalytic assembly of achiral building blocks. The catalytic aldol assembly of prebiotic compounds into stereodefined pentoses and hexoses is an as yet unmet challenge. Such a process would be of remarkable synthetic utility and high...
Apoptosis is a biological process relevant to different human diseases that is regulated through protein-protein interactions and complex formation. Peptidomimetic compounds based on linear peptoids and cyclic analogues with different ring sizes have been previously reported as potent apoptotic inhibitors. Among them, the presence of cis/trans conf...
We describe the synthesis of a library of 11,638 N-alkylglycine peptoid trimers in a positional scanning format with adjustment of reaction conditions to account for different reactivity of the monomer building blocks. Evaluation of the library by high-content phenotypic screening for modulators of the cytoskeleton and mitosis resulted in the ident...
A structure‐guided redesign of D ‐fructose‐6‐phosphate aldolase from Escherichia coli (FSA) was devised for improving the acceptor tolerance towards α‐substituted and conformationally constrained aldehydes. FSA A129S/ R134X /A165G/S166G and L107Y/A129G/ R134X /A165G/S166G variants, where X was R , V , P , or S , were the most suited biocatalysts fo...
Dynamic combinatorial libraries are powerful systems for studying adaptive behaviors and relationships, as models of more complex molecular networks. With this aim, we set up a chemically diverse dynamic library of pseudopeptidic macrocycles containing amino-acid side chains with differently charged residues (negative, positive, and neutral). The r...
Four series of C7N aminocyclitols analogs to glucose were synthesized by stereocontrolled epoxide opening of hydroxyl protected forms of the cyclohexane epoxides cyclophellitol and 1,6-epi-cyclophellitol. The resulting hydroxymethyl substituted aminocyclitols were tested as glycosidase inhibitors. Cyclitols having an amino group in alpha configurat...
a,a-Disubstituted a-amino acids are central to biotechnological and biomedical chemical processes for their own sake and as substructures of biologically active molecules for diverse biomedical applications. Structurally, these compounds contain a quaternary stereocenter, which is particularly challenging for stereoselective synthesis. The pyridoxa...
The introduction of aromatic residues connected by a C-C bond into the non-reducing end of carbohydrates
is highly significant for the development of innovative structures with improved binding affinity and selectivity (e.g., C-aril-sLex). In this work, an expedient asymmetric “de novo” synthetic route to new aryl carbohydrate derivatives based on...
α,α-Disubstituted α-amino acids are central to biotechnological and biomedical chemical processes for their own sake and as substructures of biologically active molecules for diverse biomedical applications. Structurally, these compounds contain a quaternary stereocenter, which is particularly challenging for stereoselective synthesis. The pyridoxa...
α,α-Disubstituted α-amino acids are central to biotechnological and biomedical chemical processes for their own sake and as substructures of biologically active molecules for diverse biomedical applications. Structurally, these compounds contain a quaternary stereocenter, which is particularly challenging for stereoselective synthesis. The pyridoxa...
Background
Excessive apoptosis induces unwanted cell death and promotes pathological conditions. Drug discovery efforts aimed at decreasing apoptotic damage initially targeted the inhibition of effector caspases. Although such inhibitors were effective, safety problems led to slow pharmacological development. Therefore, apoptosis inhibition is stil...
A multistep chemoenzymatic synthesis for stereodiverse polyhydroxypipecolic acid analogues, homoiminocyclitols and polyhydroxylated piperidine and pyrrolidine derivatives combining glycine‐dependent aldolases and both D ‐fructose‐6‐phosphate aldolase (FSA) or dihydroxyacetone phosphate (DHAP)‐dependent aldolases is presented. The methodology allowe...
A multistep chemoenzymatic synthesis for stereodiverse polyhydroxypipecolic acid analogues, homoiminocyclitols and polyhydroxylated piperidine and pyrrolidine derivatives combining glycine-dependent aldolases and both d-fructose-6-phosphate aldo-lase (FSA) or dihydroxyacetone phosphate (DHAP)-dependent aldolases is presented. The methodology allowe...
D-Fructose-6-phosphate aldolase (FSA) is a unique catalyst for asymmetric cross-aldol additions of glycolaldehyde. A combination of a structure-guided approach of saturation mutagenesis, site-directed mutagenesis, and computational modeling was applied to construct a set of FSA variants that improved the catalytic efficiency towards glycolaldehyde...
Carbon-carbon bond formation catalyzed by carboligases is finding undeniable increasing acceptance in chemical research and laboratory as well as in large-scale production of polyhydroxylated complex molecules. Aldolases, being highly selective and efficient, offer a green tool to perform asymmetric carbon-carbon bond formation independently or in...
SKI-II has been reported as a dual inhibitor of sphingosine kinases 1 and 2 and has been extensively used to prove the involvement of sphingosine kinases and sphingosine-1-phosphate in cellular processes. Dihydroceramide desaturase (Des1), the last enzyme in the de novo synthesis of ceramide, regulates the balance between dihydroceramides and ceram...
The 1,2,3-triazole ring has recently attracted a renewed interest as a structural scaffold with many applications in different fields. However, very often, the unambiguous assignment of the correct structure is not an easy task, and the development of robust characterization methodologies is needed. Herein, the three possible isomeric forms of disu...
Apoptosis is a biological process relevant to several human diseases that is strongly regulated through protein-protein complex formation. We have previously reported a peptidomimetic compound as potent apoptotic modulator. Structural studies of this compound showed the presence of cis/trans isomers of the exocyclic tertiary amide bond in slow exch...
(25R)-3β-Hydroxy-5α-spirostan-12-one (hecogenin) and 11α-hydroxypregn-4-ene-3,20-dione (11α-hydroxyprogesterone) were used as starting materials for the synthesis of a series of 11- and 12-substituted derivatives of 5ξ-pregnanolone (3α-hydroxy-5α-pregnan-20-one and 3α-hydroxy-5β-pregnan-20-one), the principal neurosteroid acting via γ-aminobutyric...
A chemo-enzymatic strategy for the preparation of 2-aminomethyl derivatives of (2R,3R,4R)-2-(hydroxymethyl)pyrrolidine-3,4-diol (also called 1,4-dideoxy-1,4-imino-d-arabinitol, DAB) and its enantiomer LAB is presented. The synthesis is based on the enzymatic preparation of DAB and LAB followed by the chemical modification of their hydroxymethyl fun...
The synthesis, conformational study and inhibitory properties of diverse indolizidine and quinolizidine iminocyclitols are described. The compounds were chemo-enzymatically synthesized by two-step aldol addition and reductive amination reactions. The aldol addition of dihydroxyacetone phosphate (DHAP) to N-Cbz-piperidine carbaldehyde derivatives ca...
Aldol addition reactions of dihydroxyacetone (DHA) to N-Cbz-amino aldehydes catalyzed by L-rhamnulose-1-phosphate aldolase (RhuA) in the presence of borate buffer are reported. High yields of aldol adduct (e.g. 70-90%) were achieved with excellent (>98 : 2 syn/anti) stereoselectivity for most S or R configured acceptors, which compares favorably to...
The thermosensory transient receptor potential vanilloid 1 channel (TRPV1) is a polymodal receptor activated by physical and chemical stimuli. TRPV1 activity is drastically potentiated by proinflammatory agents released upon tissue damage. Given the pivotal role of TRPV1 in human pain, there is pressing need for improved TRPV1 antagonists, the deve...
The high conformational flexibility of peptoids can generate problems in biomolecular selectivity as a result of undesired off-target interactions. This drawback can be counterbalanced by restricting the original flexibility to a certain extent, thus leading to new peptidomimetics. By starting from the structure of an active peptoid as an apoptosis...
Structure-guided re-design of the acceptor binding site of D-fructose-6-phosphate aldolase from E. coli leads to the construction of FSA A129S/A165G double mutant with an activity between 5- to >900-fold higher than that of wild-type towards N-Cbz-aminoaldehyde derivatives.
A library of aminocyclitols derived from CuAAC reaction between N-propargylaminocyclitol 4 and a series of azides [1-25] is described and tested against GCase. Azides have been chosen from a large collection of potential candidates that has been filtered according to physical and reactivity constraints. A synthetic methodology has been optimized in...
Glucocerebrosidase (GCase, acid β-Glucosidase) hydrolyzes the sphingolipid glucosylceramide into glucose and ceramide. Mutations in this enzyme lead to a lipid metabolism disorder known as Gaucher disease. The design of competitive inhibitors of GCase is a promising field of research for the design of pharmacological chaperones as new therapeutic a...
The aldol addition of unphosphorylated dihydroxyacetone (DHA) to aldehydes catalyzed by L-rhamnulose-1-phosphate aldolase (RhuA), a dihydroxyacetone phosphate-dependent aldolase, is reported. Moreover, a single point mutation in the phosphate binding site of the RhuA wild type, that is, substitution of aspartate for asparagine at position N29, incr...
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
A minimalist active site redesign of the L-fuculose-1-phosphate aldolase from E. coli FucA was envisaged, to extend its tolerance towards bulky and conformationally restricted N-Cbz-amino aldehyde acceptor substrates (Cbz = benzyloxycarbonyl). Various mutants at the active site of the FucA wild type were obtained and screened with seven sterically...
New N-alkylaminocyclitols bearing a 1,2,3-triazole system at different positions of the alkyl chain have been prepared as potential GCase pharmacological chaperones using click chemistry approaches. Among them, compounds 1d and 1e, with the shorter spacer (n = 1) between the alkyltriazolyl system and the aminocyclitol core, were the most active one...
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
The chemoenzymatic synthesis of a collection of pyrrolidine-type iminosugars generated by the aldol addition of dihydroxyacetone phosphate (DHAP) to C-alpha-substituted N-Cbz-2-aminoaldehydes derivatives, catalyzed by DHAP aldolases is reported. L-fuculose-1-phosphate aldolase (FucA) and L-rhamnulose-1-phosphate aldolase (RhuA) from E. coli were us...
Novel aldol addition reactions
of dihydroxyacetone (DHA) and
hydroxyacetone (HA) to a variety of
aldehydes catalyzed by d-fructose-6-
phosphate aldolase (FSA) are presented.
In a chemical-enzymatic cascade reaction
approach, 1-deoxynojirimycin
and 1-deoxymannojirimycin were synthesized
starting from (R)- and (S)-3-
(N-Cbz-amino)-2-hydroxypropanal,...
The paper presents the use of anion-exchange chromatography to separate bioactive cysteine containing catechin conjugates from underivatised polyphenols and oligomeric material. The conjugates were excluded from the anion-exchange resin using a low percentage of organic solvent, enough to eliminate the weak hydrophobic interactions with the matrix....
In the biosynthetic pathway of Spodoptera littoralis sex pheromone, (E,E)-10,12-tetradecadienoic acid is produced from (Z)-11-tetradecenoic acid by desaturation and concomitant migration of the precursor double bond. With the aim of identifying the enzyme involved in this biotransformation, yeast Deltaelo1/Deltaole mutants, which are both elongase...
![Figure 2. Effect of neurosteroid analogues on [ 3 H]flunitrazepam...](profile/Alexander-Kasal/publication/7059475/figure/fig2/AS:549150951055360@1507939197177/Effect-of-neurosteroid-analogues-on-3-Hflunitrazepam-binding-in-primary-cultures-of_Q320.jpg)
A GABA(A) receptor study of several B-nor analogues of allopregnanolone and pregnanolone has been carried out. B-norallopregnanolone (i.e., 3alpha-hydroxy-7-nor-5alpha-pregnan-20-one) was found comparable to allopregnanolone when measured with labeled TBPS. Analogous results were obtained from their effect on neurons in culture: this time, both 3al...
This work examines the influence of N-protecting groups on the conversion and stereoselectivity of dihydroxyacetone phosphate (DHAP) dependent aldolase-catalyzed aldol additions of DHAP to N-protected-3-aminopropanal. Phenylacetyl-(PhAc-), tert-butyloxycarbonyl- (tBoc-) and fluoren-9-ylmethoxycarbonyl- (Fmoc-)-3-aminopropanal were evaluated as subs...
Thymol is a naturally occurring phenolic monoterpene known for its anti-microbial and anti-oxidant properties. It is used in dental practice and in anaesthetic halothane preparations. Recent studies have reported enhanced GABA(A) receptor-operated chloride channel activity and increased binding affinity of [(3)H]flunitrazepam in the presence of thy...
The potential of L-fuculose-1-phosphate aldolase (FucA) as a catalyst for the asymmetric aldol addition of dihydroxyacetone phosphate (DHAP) to N-protected amino aldehydes has been investigated. First, the reaction was studied in both emulsion systems and conventional dimethylformamide (DMF)/H2O (1:4 v/v) mixtures. At 100 mM DHAP, compared with the...
The ingestion of rapeseed oil batches denatured with aniline and illegally refined and distributed by street vendors was responsible for toxic oil syndrome (TOS), an intoxication episode that took place in Spain in 1981, causing over 400 deaths and affecting more than 20,000 people. Despite the intense research efforts carried out to date, the comp...
The potential of dihydroxyacetone phosphate (DHAP)-dependent aldolases to catalyze stereoselective aldol additions is, in many instances, limited by the solubility of the acceptor aldehyde in aqueous/co-solvent mixtures. Herein, we demonstrate the efficiency of emulsion systems as reaction media for the class I fructose-1,6-bisphosphate aldolase (R...
The neurotoxic organochlorine pesticides gamma-hexachlorocyclohexane, alpha-endosulfan and dieldrin induce in mammals a hyperexcitability syndrome accompanied by convulsions. They reduce the GABA-induced Cl(-) flux. The strychnine-sensitive glycine receptor also regulates Cl(-)-flux inhibitory responses. We studied the effects of these compounds on...
The Toxic Oil Syndrome was a massive food-borne intoxication that occurred in Spain in 1981. Epidemiological studies point to 3-(phenylamino)propane-1,2-diol (PAP) derivatives as the putative toxic agents. We report further identification of metabolites cleared in urine of A/J and C57BL/6 mice in which (R)- and (S)-3-(phenylamino)propane-1,2-diol w...
PAP, a very polar substance, is highly metabolized in mice and excreted principally in urine in the form of the 2-hydroxy-3-phenylaminopropanoic acid of each enantiomer. Thus, the major route of PAP elimination in these strains is alkyl chain oxidation. In particular, S-PAP is eliminated principally in the form of that metabolite, whereas R-PAP ena...
Cytochrome c peroxidase (CcP) can bind as many as two cytochrome c (Cc) molecules in an electrostatic complex. The location of the two binding domains on CcP has been probed by photoinduced interprotein electron transfer (ET) between zinc-substituted horse cytochrome c (ZnCc) and CcP with surface charge-reversal mutations and by isothermal titratio...
In May 1981, a massive food-borne intoxication occurred in Spain. The so-called toxic oil syndrome (TOS) was associated with the consumption of aniline-denatured and refined rapeseed oil that was illegally sold as edible olive oil. Fatty acid anilides and fatty acid derivatives of 3-(phenylamino)propane-1,2-diol were detected in oils and implicated...
The three-dimensional structures of two HPII variants, V169C and H392Q, have been determined at resolutions of 1.8 and 2.1 A, respectively. The V169C variant contains a new type of covalent bond between the sulfur atom of Cys(169) and a carbon atom on the imidazole ring of the essential His(128). This variant enzyme has only residual catalytic acti...
The reductively dimethylated derivatives of horse and yeast iso-1-ferricytochromes c have been prepared and characterized for use as NMR probes of the complexes formed by cytochrome c with bovine liver cytochrome b5 and yeast cytochrome c peroxidase. The electrostatic properties and structures of the derivatized cytochromes are not significantly pe...
A new variant of cytochrome-c peroxidase in which the positively charged Arg48 present in the distal heme-binding pocket has been replaced with a Glu residue has been prepared and characterized to explore, in part, the possibility that a negative charge close to the heme could contribute to stabilization of a porphyrin-centered pi-cation radical in...
Treatment of aflatoxin M1 (AFM1) with dimethyldioxirane in an anhydrous mixture of CH2-Cl2 and acetone afforded the corresponding aflatoxin M1 8,9-epoxide (AFM1-E) in practically quantitative yield. This highly reactive intermediate was identified by 1H NMR and characterized by its neat conversion into the corresponding trans-methoxyhydrin derivati...
The presence of six compounds, i.e., the epimeric hydroxyfuro[2,3-b]benzofurans 4, a pair of diastereomers of the hydroxylated tetrahydrofuran 6 and the diastereomeric pair of benzopyran aldehydes 8, was identified in the equilibrium mixture established when hemiacetals 4 were in solution. This identification was carried out by 1H and 13C NMR techn...
A one-pot procedure involving four reaction steps (enolate formation, epoxidn., epoxide opening, and deprotection), constitutes the key process for obtaining the hydroxyfuro[2,3-b]benzofuran moiety present in aflatoxin M1. The above sequential reactions led to the generation of the benzopyran aldehyde I. As expected, this aldehyde underwent equilib...
Anal. of the 1H- and 13C-NMR spectra of the labeled hemiacetal [3a,8a-13C2]-I showed that this compd. exists in soln. in equil. with the benzopyran II . This equil. was exploited for an alternative prepn. of the furo[2,3-b]benzofuran fragment present in aflatoxins. [on SciFinder(R)]
The synthesis and mutagenic activity in the Salmonella/Ames test (TA-98 and TA-100 strains) of an aflatoxin model, i.e., the title furobenzofuran 6 and its 2,3-epoxy derivative 7, are reported. In addition, the mutagenicity exhibited by compounds 6 and 7 has been compared with that obtained from aflatoxin B1 (8) and its 8,9-epoxide 9. Compound 6 wa...
Precocenes I (R = H, R1 = H, Cl, OMe; R = OMe, R1 = OMe, OEt, OCH2CF3) react with dimethyldioxirane to give the 3,4-epoxy derivs. in nearly quant. yields. This procedure constitutes the first direct prepn. of these highly reactive compds. postulated as responsible for the cytotoxic activity of I. [on SciFinder(R)]
The treatment of 2-acetylthiophene with phosphorus pentachloride led, besides other products reported in previous studies, to 2-(2-thienyl)-2-chloroethenephosphonic acid in 16% yield. This compd. was transformed, in the course of purifn. attempts, into 2-(2-thienyl)-2-oxoethanephosphonic acid. Full spectroscopic data for both compds. are provided....
The title yeast suspension is a direct source of a sterol cyclase which is employed for the preparation of lanosterol (IIa) and the ester (IIb).
Questions
Question (1)
I am using molecular docking as starting point to find binding modes, and, if possible, correlate affinities with experimental values, for a series of carbohydrate analogs that act as inhibitors of a glycosidase (ie. aminocyclitols). Despite most of the compounds mainly differ just on their stereochemistry, having identical substituents, some of them showed competitive inhibition while others showed non-competitive inhibition mechanisms (from double-reciprocal plots). This is quite disturbing because, given their similarity, I think it is hard to believe that they are not interacting at the same site, ie. the binding site of the natural substrate, and docking says, indeed, that all of them can bind at that site, implying that all of them would be competitive.
I would appreciate to know about how other people proceeds in such a case.
