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At least 721 records · Page 40Linked to original sources

A novel pathway to enzyme deactivation: the cutinase model.

Cutinase in aqueous solution at pH 4.5 deactivates following a parallel pathway. At 53 degrees C, 88% of the cutinase molecules are in the unfolded conformation, which can aggregate with a reaction order of 3 if the protein concentration is high (>/=12 microM). The aggregates show a sixfold increase in size as determined by dynamic light scattering. This aggregation process is the first phase observed during a deactivation experiment; however, after significant cutinase depletion and maturation of the aggregates, a first-order step starts to dominate and a second phase independent of the protein concentration is observed. Kinetic partitioning between aggregation and first-order irreversible changes of the unfolded conformation can occur during enzyme deactivation when the equilibrium between the native and the unfolded conformation is shifted and kept toward the unfolded conformation.

Carboxylic Ester Hydrolases↗

Protein side-chain motion and hydration in proton-transfer pathways. Results for cytochrome p450cam.

Proton-transfer reactions form an integral part of bioenergetics and enzymatic catalysis. The identification of proton-conducting pathways inside a protein is a key to understanding the mechanisms of biomolecular proton transfer. Proton pathways are modeled here as hydrogen bonded networks of proton-conducting groups, including proton-exchanging groups of amino acid side chains and bound water molecules. We focus on the identification of potential proton-conducting pathways inside a protein of known structure. However, consideration of the static structure alone is often not sufficient to detect suitable proton-transfer paths, leading, for example, from the protein surface to the active site buried inside the protein. We include dynamic fluctuations of amino acid side chains and water molecules into our analysis. To illustrate the method, proton transfer into the active site of cytochrome P450cam is studied. The cooperative rotation of amino acids and motion of water molecules are found to connect the protein surface to the molecular oxygen. Our observations emphasize the intrinsic dynamical nature of proton pathways where critical connections in the network may be transiently provided by mobile groups.

Camphor 5-Monooxygenase↗

Can cycle power predict sprint running performance?

A major criticism of present models of the energetics and mechanics of sprint running concerns the application of estimates of parameters which seem to be adapted from measurements of running during actual competitions. This study presents a model which does not perpetuate this solecism. Using data obtained during supra-maximal cycle ergometer tests of highly trained athletes, the kinetics of the anaerobic and aerobic pathways were modelled. Internal power wasted in the acceleration and deceleration of body limbs and the power necessary to overcome air friction was calculated from data in the literature. Assuming a mechanical efficiency as found during submaximal cycling, a power equation was constructed which also included the power necessary to accelerate the body at the start of movement. The differential equation thus obtained was solved through simulation. The model appeared to predict realistic times at 100 m (10.47 s), 200 m (19.63 s) and 400 m (42.99 s) distances. By comparison with other methods it is argued that power equations of locomotion should include the concept of mechanical efficiency.

Aerobiosis↗

From folding theories to folding proteins: a review and assessment of simulation studies of protein folding and unfolding.

Beginning with simplified lattice and continuum "minimalist" models and progressing to detailed atomic models, simulation studies have augmented and directed development of the modern landscape perspective of protein folding. In this review we discuss aspects of detailed atomic simulation methods applied to studies of protein folding free energy surfaces, using biased-sampling free energy methods and temperature-induced protein unfolding. We review studies from each on systems of particular experimental interest and assess the strengths and weaknesses of each approach in the context of "exact" results for both free energies and kinetics of a minimalist model for a beta-barrel protein. We illustrate in detail how each approach is implemented and discuss analysis methods that have been developed as components of these studies. We describe key insights into the relationship between protein topology and the folding mechanism emerging from folding free energy surface calculations. We further describe the determination of detailed "pathways" and models of folding transition states that have resulted from unfolding studies. Our assessment of the two methods suggests that both can provide, often complementary, details of folding mechanism and thermodynamics, but this success relies on (a) adequate sampling of diverse conformational regions for the biased-sampling free energy approach and (b) many trajectories at multiple temperatures for unfolding studies. Furthermore, we find that temperature-induced unfolding provides representatives of folding trajectories only when the topology and sequence (energy) provide a relatively funneled landscape and "off-pathway" intermediates do not exist.

Models, Molecular↗

mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt.

Stimulation of the insulin and insulin-like growth factor I (IGF-I) receptor activates the phosphoinositide-3-kinase/Akt/mTOR pathway causing pleiotropic cellular effects including an mTOR-dependent loss in insulin receptor substrate-1 expression leading to feedback down-regulation of signaling through the pathway. In model systems, tumors exhibiting mutational activation of phosphoinositide-3-kinase/Akt kinase, a common event in cancers, are hypersensitive to mTOR inhibitors, including rapamycin. Despite the activity in model systems, in patients, mTOR inhibitors exhibit more modest antitumor activity. We now show that mTOR inhibition induces insulin receptor substrate-1 expression and abrogates feedback inhibition of the pathway, resulting in Akt activation both in cancer cell lines and in patient tumors treated with the rapamycin derivative, RAD001. IGF-I receptor inhibition prevents rapamycin-induced Akt activation and sensitizes tumor cells to inhibition of mTOR. In contrast, IGF-I reverses the antiproliferative effects of rapamycin in serum-free medium. The data suggest that feedback down-regulation of receptor tyrosine kinase signaling is a frequent event in tumor cells with constitutive mTOR activation. Reversal of this feedback loop by rapamycin may attenuate its therapeutic effects, whereas combination therapy that ablates mTOR function and prevents Akt activation may have improved antitumor activity.

Cell Line, Tumor↗

Application of a generalized MWC model for the mathematical simulation of metabolic pathways regulated by allosteric enzymes.

In our effort to elucidate the systems biology of the model organism, Escherichia coli, we have developed a mathematical model that simulates the allosteric regulation for threonine biosynthesis pathway starting from aspartate. To achieve this goal, we used kMech, a Cellerator language extension that describes enzyme mechanisms for the mathematical modeling of metabolic pathways. These mechanisms are converted by Cellerator into ordinary differential equations (ODEs) solvable by Mathematica. In this paper, we describe a more flexible model in Cellerator, which generalizes the Monod, Wyman, Changeux (MWC) model for enzyme allosteric regulation to allow for multiple substrate, activator and inhibitor binding sites. Furthermore, we have developed a model that describes the behavior of the bifunctional allosteric enzyme aspartate Kinase I-Homoserine Dehydrogenase I (AKI-HDHI). This model predicts the partition of enzyme activities in the steady state which paves a way for a more generalized prediction of the behavior of bifunctional enzymes.

Algorithms↗

Application of a generalized MWC model for the mathematical simulation of metabolic pathways regulated by allosteric enzymes.

In our effort to elucidate the systems biology of the model organism, Escherichia coli, we have developed a mathematical model that simulates the allosteric regulation for threonine biosynthesis pathway starting from aspartate. To achieve this goal, we used kMech, a Cellerator language extension that describes enzyme mechanisms for the mathematical modeling of metabolic pathways. These mechanisms are converted by Cellerator into ordinary differential equations (ODEs) solvable by Mathematica. In this paper, we describe a more flexible model in Cellerator, which generalizes the Monod, Wyman, Changeux (MWC) model for enzyme allosteric regulation to allow for multiple substrate, activator and inhibitor binding sites. Furthermore, we have developed a model that describes the behavior of the bifunctional allosteric enzyme aspartate kinase I-homoserine dehydrogenase I (AKI-HDHI). This model predicts the partition of enzyme activities in the steady state which paves the way for a more generalized prediction of the behavior of bifunctional enzymes.

Algorithms↗

The retinoids and cancer prevention mechanisms.

Carcinogenesis is a multistep process that converts normal cells into malignant cells. Once transformed, malignant cells acquire the ability to invade and metastasize, leading to clinically evident disease. During this continuum from normal to metastatic cells, carcinogenic steps can be arrested or reversed through pharmacological treatments, known as cancer chemoprevention. Chemoprevention strategies represent therapeutic interventions at early stages of carcinogenesis, before the onset of invasive cancer. Effective chemoprevention should reduce or avoid the clinical consequences of overt malignancies by treating early neoplastic lesions before development of clinically apparent signs or symptoms. Preclinical, clinical, and epidemiological data provide considerable support for cancer chemoprevention as an attractive therapeutic strategy. This clinical approach was validated in the recent tamoxifen randomized trial, demonstrating that a selective estrogen receptor modulator reduces the risk of breast cancer in women at high risk for this malignancy. Derivatives of vitamin A, the retinoids, have reported activity in treating specific premalignant lesions and reducing incidence of second primary tumors in patients with prior head and neck, lung or liver cancers. Whether the retinoids will prevent primary cancers at these sites is not yet known. Notably, a carotenoid (beta-carotene) was shown as inactive in primary prevention of lung cancers in high-risk individuals. This underscores the need for relevant in vitro models to identify pathways signaling chemopreventive effects. These models should assess the activity of candidate chemoprevention agents before the conduct of large and costly prevention trials. An improved understanding of cancer prevention mechanisms should aid in the discovery of new therapeutic targets and chemoprevention agents. Ideally, these agents should have tolerable clinical toxicities suitable for chronic administration to individuals at high risk for developing primary or second cancers. This article reviews what is now known from clinical and preclinical studies about the retinoids as cancer prevention agents.

Animals↗

An assessment of the role of the inhibitory gamma subunit of the retinal cyclic GMP phosphodiesterase and its effect on the p42/p44 mitogen-activated protein kinase pathway in animal and cellular models of pulmonary hypertension.

1. We have previously reported that the inhibitory gamma subunit of the rod photoreceptor type 6 cyclic GMP phosphodiesterase (PDEgamma) is expressed in nonretinal tissues and is involved in the stimulation of the p42/p44 mitogen-activated protein kinase (MAPK) pathway by growth factors and G-protein-coupled receptor agonists. We have now investigated whether PDEgamma plays a role in modulating chronic hypoxic-dependent mitogenic signalling pathways in pulmonary smooth muscle from rats with pulmonary hypertension (PHT). 2. We show for the first time that PDEgamma is expressed in rat main, first, intrapulmonary and resistance pulmonary arteries. Moreover, its expression is increased in all the arteries to varying extents by chronic hypoxia. The extent of the increased expression of PDEgamma is correlated with an enhanced activation of p42/p44 MAPK in these vessels. 3. We also report that PDEgamma translation from mRNA transcript is increased in cultured human pulmonary artery smooth muscle cells subjected to chronic hypoxia for 14 days. This was correlated with hypoxic-dependent increase in p42/p44 MAPK activation. 4. In conclusion, our studies identify for the first time a major chronic hypoxic-dependent change in the phenotypic expression of an intermediate protein regulating mitogenic signalling in pulmonary arteries. This may have a significant effect on arterial remodelling in PHT. Future studies will focus on strategies designed to knockout rod PDEgamma to assess whether this rescues rats from chronic hypoxic-dependent changes in arterial remodelling and PHT.

3',5'-Cyclic-GMP Phosphodiesterases↗

An in vitro model of pericardial tissue healing.

INTRODUCTION: A previous study in our laboratory showed that a flap of fresh autologous pericardium bisecting the aorta of sheep retracted and became fibrotic. Histologic analyses suggested that activated cells within the pericardium contributed to the retraction of the implant. Here we report the development of an in vitro model to investigate the effects of serum on cellular proliferation and cell-mediated tissue contraction. METHODS: Sections of living and ethanol-treated sheep pericardium were incubated with 0.5%, 5%, 10%, 20%, and 50% serum in medium for up to 8 days and evaluated for cellular proliferation and tissue contraction. These serum-stimulated events were further evaluated in the presence of Mitomycin C, Cytochalasin B and D, Aphidicolin, AraC, and Cycloheximide. RESULTS: Cellular proliferation and cell-mediated tissue contraction were induced by serum in a dose-dependent manner. Expression of PCNA was suppressed in the presence of Cytochalasin B, Cytochalasin D, Aphidicolin, and AraC. Tissue contraction was prevented by Cycloheximide. Mitomycin C inhibited both proliferation and tissue contraction. Ethanol-treated tissue, which was absent of living cells, did not respond to stimulation with serum. CONCLUSIONS: An in vitro model was developed to study the responses of cells within pericardial tissues to stimulation by serum. In this model, serum induced cellular proliferation and tissue contraction. Different chemical inhibitors independently modulated these serum-stimulated events. Pre-existing cells within pericardial tissues might respond to stimulus through differential pathways. This model may help to develop methods to make autologous pericardium a clinically useful biomaterial.

Animals↗

Enterocutaneous Fistula-Associated Sepsis and Mortality: Development and Validation of a Multimodal Artificial Intelligence Prediction Model.

BACKGROUND: Predicting enterocutaneous fistula (ECF)-associated sepsis and mortality poses significant challenges in digital health care due to the disease's complexity and heterogeneous clinical manifestations. Current approaches that rely on single-modal data or traditional scoring systems often fail to capture the intricate immune-inflammatory dynamics and multisystem involvement in patients with ECF. OBJECTIVE: This study aims to develop an artificial intelligence (AI)-driven multimodal fusion model integrating clinical, imaging, and transcriptomic data for early prediction of ECF-associated sepsis and 28-day mortality, addressing the limitations of conventional single-dimensional models. METHODS: This study leveraged publicly available datasets (Medical Information Mart for Intensive Care III [MIMIC-III], electronic Intensive Care Unit [eICU], and The Cancer Genome Atlas) to construct a multimodal framework. Clinical parameters were processed using Extreme Gradient Boosting, abdominal imaging features were extracted via convolutional neural networks, and transcriptomic profiles were analyzed with variational autoencoders. A Transformer-based fusion network was employed for joint prediction and validated through cross-validation and external testing. Key features were identified using Shapley Additive Explanations and Local Interpretable Model-Agnostic Explanations interpretability algorithms, while immune regulatory mechanisms were explored via weighted gene co-expression network analysis. RESULTS: The multimodal model achieved an area under the curve (AUC) of 0.89 for predicting sepsis and 28-day mortality, outperforming unimodal models (clinical-only model, AUC 0.72, and imaging-only model, AUC 0.78). Critical predictors included Sequential Organ Failure Assessment score, lactate levels, intra-abdominal free fluid on imaging, and immunoregulatory genes (programmed death-ligand 1 [PD-L1] and indoleamine 2,3-dioxygenase 1 [IDO1]). Mechanistic analysis revealed distinct immune reprogramming in patients with sepsis, characterized by increased regulatory T cells and M2 macrophages, along with downregulated cluster of differentiation 8+ (CD8+) T cells. CONCLUSIONS: This multimodal AI model offers an innovative digital solution in medical informatics, enabling precise early risk stratification for ECF-associated sepsis. By integrating multisource data and providing interpretable insights into immune-inflammatory pathways, the model enhances health care quality for patients with ECF and paves the way for personalized intervention strategies.

Humans↗

Choline import into chloroplasts limits glycine betaine synthesis in tobacco: analysis of plants engineered with a chloroplastic or a cytosolic pathway.

The biosynthesis of the osmoprotectant glycine betaine (GlyBet) is a target for metabolic engineering to enhance stress resistance in crops. Certain plants synthesize GlyBet in chloroplasts via a two-step oxidation of choline (Cho). In previous work, a chloroplastic GlyBet synthesis pathway was inserted into tobacco (which lacks GlyBet) by expressing spinach choline monooxygenase (CMO). The transformants had low CMO enzyme activity, and produced little GlyBet (less than or = 70 nmol g(-1) fresh wt). In this study, transformants with up to 100-fold higher CMO activity showed no further increase in GlyBet. In contrast, tobacco expressing a cytosolic GlyBet synthesis pathway accumulated significantly more GlyBet (430 nmol g(-1) fresh wt), suggesting that subcellular localization influences pathway flux. Modeling of the labeling kinetics of Cho metabolites observed when [14C]Cho was supplied to engineered plants demonstrated that Cho import into chloroplasts indeed limits the flux to GlyBet in the chloroplastic pathway. A high-activity Cho transporter in the chloroplast envelope may therefore be an integral part of the GlyBet synthesis pathway in species that accumulate GlyBet naturally, and hence a target for future engineering.

Alcohol Oxidoreductases↗

Pathway evolution, structurally speaking.

Small-molecule metabolism forms the core of the metabolic processes of all living organisms. As early as 1945, possible mechanisms for the evolution of such a complex metabolic system were considered. The problem is to explain the appearance and development of a highly regulated complex network of interacting proteins and substrates from a limited structural and functional repertoire. By permitting the co-analysis of phylogeny and metabolism, the combined exploitation of pathway and structural databases, as well as the use of multiple-sequence alignment search algorithms, sheds light on this problem. Much of the current research suggests a chemistry-driven 'patchwork' model of pathway evolution, but other mechanisms may play a role. In the future, as metabolic structure and sequence space are further explored, it should become easier to trace the finer details of pathway development and understand how complexity has evolved.

Amino Acid Sequence↗

A compartmental model of zinc metabolism in adult men used to study effects of three levels of dietary copper.

The effect of dietary copper level on zinc metabolism in five healthy adult men was studied using compartmental modeling. The subjects were fed one level of dietary zinc (11.2 +/- 1.6 mg/day) and three levels of dietary copper (1.68, 0.785, and 7.52 mg/day). The stable isotope tracers 70Zn and 67Zn were administered intravenously (3 times) and orally (4 times), respectively. Plasma, urinary, and fecal 67Zn and 70Zn levels were measured. An existing model of zinc metabolism was used as a basis for our model. Model rate constants were modified to simulate multiple oral and intravenous doses of stable isotope tracers given during the 90-day study. Most rate constant changes occurred in the absorption and excretion pathways. The model predicted that movement of zinc through the gastrointestinal tract increased when the highest level of copper was fed and the urinary zinc excretion rate tended to increase. The fractional rate constant representing absorption of zinc decreased slightly when the highest level of copper was fed. Total body zinc was predicted to be approximately 2,000 mg, with 95% in tissues other than the liver, red blood cells, or plasma and approximately 2.25% in the blood (with 95% of that in the red blood cells), which follows expected zinc masses within the body and those predicted by previous models.

Adult↗

Biologic modification of animal models of intervertebral disc degeneration.

Intervertebral disc degeneration is a chronic process that can become manifest in clinical disorders such as idiopathic low back pain, sciatica, disc herniation, spinal stenosis, and myelopathy. The limited available treatment options (including discectomy and spinal fusion) for these and other disabling conditions that arise from intervertebral disc degeneration are highly invasive, achieve limited success, and only address acute symptoms while doing nothing to halt the process of degeneration. Although the precise pathophysiology of intervertebral disc degeneration has yet to be clearly delineated, the progressive decline in aggrecan, the primary proteoglycan of the nucleus pulposus, appears to be a final common pathway. Animal models as well as in vitro studies of the process of disc degeneration have yielded many potentially useful targets for the reversal of disc degeneration. One current research trend is the use of established animal models of disc degeneration to study the role of therapeutic modalities in reversing the process of degeneration, often with use of the delivery of genes or gene products that influence the anabolic and catabolic pathways of the disc. This article reviews the ability of gene-product delivery systems and gene therapy to alter biologic processes in animal models of disc degeneration and examines future trends in this field.

Animals↗

The population genetics of alleles affecting enzyme activity.

It is possible to predict the population genetics of allozymes by assuming that fitness is proportional to flux through a biochemical pathway. The model presented here extends previous work by incorporating two additional features of biological realism. Firstly, that more than one biochemical route may exist between any two metabolites. The major routes have been identified as the classical biochemical pathways but in the event of a mutation blocking a major route, minor routes become significant. These minor routes are named "bypass fluxes" and have profound effects on the population genetics of allozymes. Secondly, recent work has suggested that a metabolic cost is associated with enzyme synthesis; this will constitute an additional selective pressure on alleles which affect the amount of enzyme synthesized. The model generates a fitness curve which predicts the fitness associated with any level of enzyme activity. It can utilize data on null or near-null, structural or regulatory, mutations in the presence or absence of bypass fluxes. When data from natural populations of Drosophila are investigated, it is concluded that selection pressures acting on enzyme variants may be much higher than previously thought.

Animals↗

Comparative mechanisms of vitamin B6-catalyzed beta-decarboxylation and beta-dephosphonylation in model systems.

Reaction pathways and mechanisms of vitamin B6-catalyzed beta-decarboxylation and beta-dephosphonylation of aminocarboxylic and aminophosphonic acids in model systems are compared. It was found that both reactions require prior transamination of an aldimine intermediate to a ketimine. For ketimines having carboxylate or phosphonate groups substituted on the beta-carbon atoms of the keto acid residue, there is a hydrogen ion or metal ion-activated covalent bond pathway which involves a shift of electron pairs toward the coordinated ketimine nitrogen, leading to beta-gamma, C-C or C-P bond fission and release of carbon dioxide or metaphosphate, respectively. Comparison of these reactions indicates that beta-decarboxylation is 10(6) faster than the corresponding dephosphonylation reaction. Since only a few studies of vitamin B6-catalyzed dephosphonylation have been carried out, suggestions are made for further studies with substrates designed to elucidate the reaction mechanisms involved.

Amino Acids↗