Alfredo Torres‐Larios

Universidad Nacional Autónoma de México

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Anne‐Catherine Dock‐Brégeon

Centre National de la Recherche Scientifique

B. Rees

University of British Columbia

Dino Moras

Institut de génétique et de biologie moléculaire et cellulaire

Sergio Enríquez‐Flores

Instituto Nacional de Pediatria

Jesús Oria‐Hernández

Instituto Nacional de Pediatria

Luis G. Brieba

Center for Research and Advanced Studies of the National Polytechnic Institute

Itzhel García‐Torres

Instituto Nacional de Pediatria

Horacio Reyes‐Vivas

Instituto Nacional de Pediatria

J. Caillet

Université Paris Cité

Ruy Pérez‐Montfort

Universidad Nacional Autónoma de México

Cooperative Institutions

Universidad Nacional Autónoma de México

137

Universidad Autónoma de la Ciudad de México

Instituto Politécnico Nacional

Instituto Nacional de Cardiología

Centre National de la Recherche Scientifique

Instituto Nacional de Pediatria

Center for Research and Advanced Studies of the National Polytechnic Institute

Universidad Autónoma Metropolitana

Instituto Tecnológico Superior de Irapuato

Secretaria de Salud

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Structural and Functional Perturbation of Giardia lamblia Triosephosphate Isomerase by Modification of a Non-Catalytic, Non-Conserved Region

PLoS ONE (2013)

Gloria Hernández‐Alcántara Alfredo Torres‐Larios Sergio Enríquez‐Flores Itzhel García‐Torres Adriana Castillo‐Villanueva

Background We have previously proposed triosephosphate isomerase of Giardia lamblia (GlTIM) as a target for rational drug design against giardiasis, one of the most common parasitic infections in humans. Since the enzyme exists in the parasite and the host, selective inhibition is a major challenge because essential regions that could be considered molecular targets are highly conserved. Previous biochemical evidence showed that chemical modification of the non-conserved non-catalytic cysteine 222 (C222) inactivates specifically GlTIM. The inactivation correlates with the physicochemical properties of the modifying agent: addition of a non-polar, small chemical group at C222 reduces the enzyme activity by one half, whereas negatively charged, large chemical groups cause full inactivation. Results In this work we used mutagenesis to extend our understanding of the functional and structural effects triggered by modification of C222. To this end, six GlTIM C222 mutants with side chains having diverse physicochemical characteristics were characterized. We found that the polarity, charge and volume of the side chain in the mutant amino acid differentially alter the activity, the affinity, the stability and the structure of the enzyme. The data show that mutagenesis of C222 mimics the effects of chemical modification. The crystallographic structure of C222D GlTIM shows the disruptive effects of introducing a negative charge at position 222: the mutation perturbs loop 7, a region of the enzyme whose interactions with the catalytic loop 6 are essential for TIM stability, ligand binding and catalysis. The amino acid sequence of TIM in phylogenetic diverse groups indicates that C222 and its surrounding residues are poorly conserved, supporting the proposal that this region is a good target for specific drug design. Conclusions The results demonstrate that it is possible to inhibit species-specifically a ubiquitous, structurally highly conserved enzyme by modification of a non-conserved, non-catalytic residue through long-range perturbation of essential regions.

Triosephosphate isomerase

10.1371/journal.pone.0069031

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Citations (25)

The E104D mutation increases the susceptibility of human triosephosphate isomerase to proteolysis. Asymmetric cleavage of the two monomers of the homodimeric enzyme

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics (2013)

De Ji Alfredo Torres‐Larios Guillermo Mendoza‐Hernández Sergio Enríquez‐Flores Adriana Castillo‐Villanueva

Proteolysis

Triosephosphate isomerase

Wild type

Cleavage (geology)

10.1016/j.bbapap.2013.08.012

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Citations (16)

Structural Basis of Human Triosephosphate Isomerase Deficiency

Journal of Biological Chemistry (2008)

Claudia Rodríguez-Almazán Rodrigo Arreola David Rodríguez‐Larrea Beatriz Aguirre‐López Marietta Tuena de Gómez‐Puyou

Human triosephosphate isomerase deficiency is a rare autosomal disease that causes premature death of homozygous individuals. The most frequent mutation that leads to this illness is in position 104, which involves a conservative change of a Glu for Asp. Despite the extensive work that has been carried out on the E104D mutant enzyme in hemolysates and whole cells, the molecular basis of this disease is poorly understood. Here, we show that the purified, recombinant mutant enzyme E104D, while exhibiting normal catalytic activity, shows impairments in the formation of active dimers and low thermostability and monomerizes under conditions in which the wild type retains its dimeric form. The crystal structure of the E104D mutant at 1.85 A resolution showed that its global structure was similar to that of the wild type; however, residue 104 is part of a conserved cluster of 10 residues, five from each subunit. An analysis of the available high resolution structures of TIM dimers revealed that this cluster forms a cavity that possesses an elaborate conserved network of buried water molecules that bridge the two subunits. In the E104D mutant, a disruption of contacts of the amino acid side chains in the conserved cluster leads to a perturbation of the water network in which the water-protein and water-water interactions that join the two monomers are significantly weakened and diminished. Thus, the disruption of this solvent system would stand as the underlying cause of the deficiency.

Triosephosphate isomerase

Basis (linear algebra)

10.1074/jbc.m802145200

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Citations (82)

Crystal Structure of a bacterial RNase P holoenzyme in complex with tRNA and in the presence of 5' leader

Nicholas J. Reiter A. Ostermanm Alfredo Torres‐Larios Kerren K. Swinger T. Pan

10.2210/pdb3okb/pdb

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Structure of Staphylococcus aureus threonyl-tRNA synthetase complexed with an analogue of threonyl adenylate

Alfredo Torres‐Larios R. Sankaranarayanan B. Rees Anne‐Catherine Dock‐Brégeon Dino Moras

10.2210/pdb1nyq/pdb

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Achieving Error-Free TranslationThe Mechanism of Proofreading of Threonyl-tRNA Synthetase at Atomic Resolution

Molecular Cell (2004)

Anne‐Catherine Dock‐Brégeon B. Rees Alfredo Torres‐Larios Gilbert Bey J. Caillet

Proofreading

Aminoacylation

Amino Acyl-tRNA Synthetases

10.1016/s1097-2765(04)00591-x

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Citations (9)

Crystal structure of Arabidopsis thaliana cytosolic triosephosphate isomerase C218D mutant

Pedro Jiménez‐Sandoval Corina Díaz‐Quezada Alfredo Torres‐Larios Luis G. Brieba

Triosephosphate isomerase

10.2210/pdb6nxs/pdb

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Estudio de las interacciones entre las subunidades ASA del brazo periférico de la ATP sintasa mitocondrial de Polytomella sp

Héctor Vicente Miranda Astudillo Araceli Cano-Estrada Miriam Vázquez‐Acevedo Alfredo Torres‐Larios Diego González‐Halphen

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The modular structure of Escherichia coli threonyl‐tRNA synthetase as both an enzyme and a regulator of gene expression

Molecular Microbiology (2003)

J. Caillet Teresa Nogueira Benoı̂t Masquida Flore Winter M. Graffe

Summary In addition to its role in tRNA aminoacylation, Escherichia coli threonyl‐tRNA synthetase is a regulatory protein which binds a site, called the operator, located in the leader of its own mRNA and inhibits translational initiation by competing with ribosome binding. This work shows that the two essential steps of regulation, operator recognition and inhibition of ribosome binding, are performed by different domains of the protein. The catalytic and the C‐terminal domain of the protein are involved in binding the two anticodon arm‐like structures in the operator whereas the N‐terminal domain of the enzyme is responsible for the competition with the ribosome. This is the first demonstration of a modular structure for a translational repressor and is reminiscent of that of transcriptional regulators. The mimicry between the operator and tRNA, suspected on the basis of previous experiments, is further supported by the fact that identical regions of the synthetase recognize both the operator and the tRNA anticodon arm. Based on these results, and recent structural data, we have constructed a computer‐derived molecular model for the operator‐threonyl‐tRNA synthetase complex, which sheds light on several essential aspects of the regulatory mechanism.

T arm

Operator (biology)

EF-Tu

Ribosomal binding site

10.1046/j.1365-2958.2003.03364.x

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Citations (31)

Chitinase ChiA74 from Bacillus thuringiensis

Estefania O. Juárez-Hernández Luis G. Brieba Alfredo Torres‐Larios Pedro Jiménez‐Sandoval José E. Barboza‐Corona

Bacillus thuringiensis

Chitinase

10.2210/pdb6bt9/pdb

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Citations (0)