Biomedical subjects

Rui Alves

Publications and source records attributed to Rui Alves.

10 recordsLinked to original sources

PubMed2007

Cooperativity and saturation in biochemical networks: a saturable formalism using Taylor series approximations.

Cooperative and saturable systems are common in molecular biology. Nevertheless, common canonical formalisms for kinetic modeling that are theoretically well justified do not have a saturable form. Modeling and fitting data from saturable systems are widely done using Hill-like equations. In practice, there is no theoretical justification for the generalized use of these equations, other than their ability to fit experimental data. Thus it is important to find a canonical formalism that is (a) theoretically well supported, (b) has a saturable functional form, and (c) can be justifiably applicable to any biochemical network. Here we derive such a formalism using Taylor approximations in a special transformation space defined by power-inverses and logarithms of power-inverses. This formalism is generalized for processes with n-variables, leading to a useful mathematical representation for molecular biology: the Saturable and Cooperative Formalism (SC formalism). This formalism provides an appropriate representation that can be used for modeling processes with cooperativity and saturation. We also show that the Hill equation can be seen as a special case within this formalism. Parameter estimation for the SC formalism requires information that is also necessary to build Power-Law models, Metabolic Control Analysis descriptions or (log)linear and Lin-log models. In addition, the saturation fraction of the relevant processes at the operating point needs to be considered. The practical use of the SC formalism for modeling is illustrated with a few examples. Similar models are built using different formalisms and compared to emphasize advantages and limitations of the different approaches.

Algorithms↗

PubMed2006

Use of physiological constraints to identify quantitative design principles for gene expression in yeast adaptation to heat shock.

BACKGROUND: Understanding the relationship between gene expression changes, enzyme activity shifts, and the corresponding physiological adaptive response of organisms to environmental cues is crucial in explaining how cells cope with stress. For example, adaptation of yeast to heat shock involves a characteristic profile of changes to the expression levels of genes coding for enzymes of the glycolytic pathway and some of its branches. The experimental determination of changes in gene expression profiles provides a descriptive picture of the adaptive response to stress. However, it does not explain why a particular profile is selected for any given response. RESULTS: We used mathematical models and analysis of in silico gene expression profiles (GEPs) to understand how changes in gene expression correlate to an efficient response of yeast cells to heat shock. An exhaustive set of GEPs, matched with the corresponding set of enzyme activities, was simulated and analyzed. The effectiveness of each profile in the response to heat shock was evaluated according to relevant physiological and functional criteria. The small subset of GEPs that lead to effective physiological responses after heat shock was identified as the result of the tuning of several evolutionary criteria. The experimentally observed transcriptional changes in response to heat shock belong to this set and can be explained by quantitative design principles at the physiological level that ultimately constrain changes in gene expression. CONCLUSION: Our theoretical approach suggests a method for understanding the combined effect of changes in the expression of multiple genes on the activity of metabolic pathways, and consequently on the adaptation of cellular metabolism to heat shock. This method identifies quantitative design principles that facilitate understating the response of the cell to stress.

Adaptation, Physiological↗

PubMed2006

Tools for kinetic modeling of biochemical networks.

The number of software packages for kinetic modeling of biochemical networks continues to grow. Although most packages share a common core of functionality, the specific capabilities and user interfaces of different packages mean that choosing the best package for a given task is not trivial. We compare 12 software packages with respect to their functionality, reliability, efficiency, user-friendliness and compatibility. Although most programs performed reliably in all numerical tasks tested, SBML compatibility and the set-up of multicompartmentalization are problematic in many packages. For simple models, GEPASI seems the best choice for non-expert users. For large-scale models, environments such as Jarnac/JDesigner are preferable, because they allow modular implementation of models. Virtual Cell is the most versatile program and provides the simplest and clearest functionality for setting up multicompartmentalization.

Biochemistry↗

PubMed2005

Evidence of selection for low cognate amino acid bias in amino acid biosynthetic enzymes.

If the enzymes responsible for biosynthesis of a given amino acid are repressed and the cognate amino acid pool suddenly depleted, then derepression of these enzymes and replenishment of the pool would be problematic, if the enzymes were largely composed of the cognate amino acid. In the proverbial "Catch 22", cells would lack the necessary enzymes to make the amino acid, and they would lack the necessary amino acid to make the needed enzymes. Based on this scenario, we hypothesize that evolution would lead to the selection of amino acid biosynthetic enzymes that have a relatively low content of their cognate amino acid. We call this the "cognate bias hypothesis". Here we test several implications of this hypothesis directly using data from the proteome of Escherichia coli. Several lines of evidence show that low cognate bias is evident in 15 of the 20 amino acid biosynthetic pathways. Comparison with closely related Salmonella typhimurium shows similar results. Comparison with more distantly related Bacillus subtilis shows general similarities as well as significant differences in the detailed profiles of cognate bias. Thus, selection for low cognate bias plays a significant role in shaping the amino acid composition for a large class of cellular proteins.

Amino Acids↗

PubMed2004

Predictive reconstruction of the mitochondrial iron-sulfur cluster assembly metabolism. II. Role of glutaredoxin Grx5.

Grx5 is a Saccharomyces cerevisiae glutaredoxin involved in iron-sulfur cluster (FeSC) biogenesis. Previous work suggests that Grx5 is involved in regulating protein cysteine glutathionylation, prompting several questions about the systemic role of Grx5. First, is the regulation of mixed protein-glutathione disulfide bridges in FeSC biosynthetic proteins by Grx5 sufficient to account for the observed phenotypes of the Deltagrx5 mutants? If so, does Grx5 regulate the oxidation state of mixed protein-glutathione disulfide bridges in FeSC biogenesis in general? Alternatively, can the Deltagrx5 mutant phenotypes be explained if Grx5 acts on just one or a few of the FeSC biogenesis proteins?In the first part of this article, we address these questions by building and analyzing a mathematical model of FeSC biosynthesis. We show that, independent of the tested parameter values, the dynamic behavior observed in cells depleted of Grx5 can only be qualitatively reproduced if Grx5 acts by regulating the initial assembly of FeSC in scaffold proteins. This can be achieved by acting on the cysteine desulfurase (Nfs1) activity and/or on scaffold functionality. In the second part of this article, we use structural bioinformatics methods to evaluate the possibility of interaction between Grx5 and proteins involved in FeSC biogenesis. Based on such methods, our results indicate that the proteins with which Grx5 is more likely to interact are consistent with the kinetic modeling results.Thus, our theoretical studies, combined with known Grx5 biochemistry, suggest that Grx5 acts on FeSC biosynthesis by regulating the redox state of important cysteine residues in Nfs1 and/or in the scaffold proteins where FeSC initially assemble.

Carbon-Sulfur Lyases↗

PubMed2004

Predictive reconstruction of the mitochondrial iron-sulfur cluster assembly metabolism: I. The role of the protein pair ferredoxin-ferredoxin reductase (Yah1-Arh1).

Adrenodoxin reductase homologue (Arh1) and yeast adrenodoxin homologue (Yah1) are essential Saccharomyces cerevisiae mitochondrial proteins involved in heme A biosynthesis and in iron-sulfur cluster (FeSC) assembly. Although the role of Arh1 and Yah1 in heme A biosynthesis is fairly well established, their systemic role on FeSC synthesis is not well understood. Also, while it is thought that the reductase Arh1 provides electrons for the ferredoxin Yah1, two hybrid experiments do not show interaction between the two proteins. In the first part of this article, we use structural bioinformatics methods to evaluate the possibility of interaction between Arh1 and Yah1. Using protein model building and docking algorithms, we predict a complex between Arh1 and Yah1 that is similar to that of their bovine homologues (adrenodoxin reductase-adrenodoxin), suggesting that Arh1 can indeed reduce Yah1. The predicted complex allows us to suggest point mutations to either molecule that could hinder Arh1-Yah1 interaction and test the role of Arh1 as the reductase for Yah1. In the second part of this article, we investigate the physiological role of Arh1-Yah1 on FeSC assembly by deriving alternative mathematical models of the process, based on published information. Comparing the dynamical behavior of each model with that observed in reported experiments emphasizes the importance of Arh1-Yah1 providing electrons for in situ FeSC repair. Only when this mode of action of either of the two proteins in FeSC synthesis is considered can previously reported results be reproduced.

Adrenodoxin↗

PubMed2004

[Pancreas transplantation].

A clinic case of simultaneous pancreas/kidney transplantation on a type 1 diabetic patient is described. A six years follow-up was made with both organs functionating and a good quality of live. Then the authors make a review of the available surgical techniques, indications and complications of this form of treatment. A comparison between the Portuguese and the International experience was discussed.

Adult↗

PubMed2003

Comparative analysis of prototype two-component systems with either bifunctional or monofunctional sensors: differences in molecular structure and physiological function.

Signal transduction by a traditional two-component system involves a sensor protein that recognizes a physiological signal, autophosphorylates and transfers its phosphate, and a response regulator protein that receives the phosphate, alters its affinity toward specific target proteins or DNA sequences and causes change in metabolic activity or gene expression. In some cases the sensor protein, when unphosphorylated, has a positive effect upon the rate of dephosphorylation of the regulator protein (bifunctional sensor), whereas in other cases it has no such effect (monofunctional sensor). In this work we identify structural and functional differences between these two designs. In the first part of the paper we use sequence data for two-component systems from several organisms and homology modelling techniques to determine structural features for response regulators and for sensors. Our results indicate that each type of reference sensor (bifunctional and monofunctional) has a distinctive structural feature, which we use to make predictions regarding the functionality of other sensors. In the second part of the paper we use mathematical models to analyse and compare the physiological function of systems that differ in the type of sensor and are otherwise equivalent. Our results show that a bifunctional sensor is better than a monofunctional sensor both at amplifying changes in the phosphorylation level of the regulator caused by signals from the sensor and at attenuating changes caused by signals from small phosphodonors. Cross-talk to or from other two-component systems is better suppressed if the transmitting sensor is monofunctional, which is the more appropriate design when such cross-talk represents pathological noise. Cross-talk to or from other two-component systems is better amplified if the transmitting sensor is bifunctional, which is the more appropriate design when such cross-talk represents a physiological signal. These results provide a functional rationale for the selection of each design that is consistent with available experimental evidence for several two-component systems.

Bacterial Proteins↗

PubMed2002

Evolution of enzymes in metabolism: a network perspective.

Several models have been proposed to explain the origin and evolution of enzymes in metabolic pathways. Initially, the retro-evolution model proposed that, as enzymes at the end of pathways depleted their substrates in the primordial soup, there was a pressure for earlier enzymes in pathways to be created, using the later ones as initial template, in order to replenish the pools of depleted metabolites. Later, the recruitment model proposed that initial templates from other pathways could be used as long as those enzymes were similar in chemistry or substrate specificity. These two models have dominated recent studies of enzyme evolution. These studies are constrained by either the small scale of the study or the artificial restrictions imposed by pathway definitions. Here, a network approach is used to study enzyme evolution in fully sequenced genomes, thus removing both constraints. We find that homologous pairs of enzymes are roughly twice as likely to have evolved from enzymes that are less than three steps away from each other in the reaction network than pairs of non-homologous enzymes. These results, together with the conservation of the type of chemical reaction catalyzed by evolutionarily related enzymes, suggest that functional blocks of similar chemistry have evolved within metabolic networks. One possible explanation for these observations is that this local evolution phenomenon is likely to cause less global physiological disruptions in metabolism than evolution of enzymes from other enzymes that are distant from them in the metabolic network.

Databases, Protein↗

PubMedDate not supplied

[Diabetic nephropathy. Study protocol for pre-kidney transplantation].

Between May 1990 and October 1998, 67 diabetic patients with end-stage renal disease, on dialysis, were submitted to a standardized protocol in order to assess the coexistence and degree of other diabetic and nondiabetic complications that could affect transplantation. Some of the results were analysed. Type 2 diabetic patients had more abnormal results on the lower limbs doppler ultrasound and on the lower limbs arteriography than type 1 (p < 0.05). Type 2 diabetic patients had more cardiovascular complications so the decision to transplant should be taken on a case by case basis.

Adult↗