Computational modeling of genome-scale metabolic models is an effective approach for designing new therapeutics targeting dysregulated cancer metabolism by identifying metabolic enzymes crucial for satisfying metabolic goals of cancer cells, but nearly all previous studies neglect the existence of metabolic demands other than biomass synthesis and trade-offs between these contradicting metabolic demands.
Full Answer
What is a genome-scale metabolic model?
Genome-Scale Metabolic Models (GEMs) are a network-based tool that collect all known metabolic information of a biological system, including the genes, enzymes, reactions, associated gene-protein-reaction (GPR) rules, and metabolites [ 12 ].
Can genome-scale metabolic modelling predict biomarkers and therapeutic targets for neuropsychiatric disorders?
Moolamalla S.T.R., Vinod P.K. Genome-scale metabolic modelling predicts biomarkers and therapeutic targets for neuropsychiatric disorders. Comput. Biol. Med. 2020;125:103994. doi: 10.1016/j.compbiomed.2020.103994.
What can metabolic models tell us about cell function?
Metabolic models are currently used to elucidate, comprehend, analyze, optimize, and even discover new cell functions when the studied organisms are subjected to different conditions [ 124, 125 ].
Can dynamic metabolic models address macromolecular expression?
For example, dynamic metabolic models have been successfully used to characterize growth dynamics, time-dependent cycles, and organelle crosstalk [ 21 ]. On the other hand, the integration of additional biological layers to GEMs allowed addressing macromolecular expression.
What is genome-scale metabolic model?
A genome-scale metabolic model (GEM) is a mathematical representation of the metabolism for an organism and it provides extensive gene–reaction–metabolite connectivity via two matrices: the S matrix for associating metabolites to reactions and the rxnGeneMat matrix associating reactions to corresponding enzymes and ...
What is the metabolic theory of cancer?
A fundamental doctrine of cancer metabolism theory is that cancer cells are glycolytic, meaning they consume more glucose and produce more lactate than normal cells.
What is genome-scale metabolic network reconstruction?
Genome-scale metabolic reconstruction A metabolic reconstruction provides a highly mathematical, structured platform on which to understand the systems biology of metabolic pathways within an organism.
What is a genomic scale?
Genome-scale metabolic models (GEMs) computationally describe gene-protein-reaction associations for entire metabolic genes in an organism, and can be simulated to predict metabolic fluxes for various systems-level metabolic studies.
What is metabolic cancer treatment?
WHAT IS METABOLIC THERAPY? Cancer cells need sugar for replication. Metabolic therapy involves using a group of drugs called metabolic inhibitors. These metabolic inhibitors interrupt the production of energy in the cancer cells rendering them more sensitive to other cancer fighting approaches.
Is cancer genetic or metabolic?
The NCI website states, “Cancer is a genetic disease—that is, it is caused by changes to genes that control the way our cells function, especially how they grow and divide.” The cancer drug industry and the NIH both consider cancer to be a genetic disease.
What is metabolic network analysis?
Metabolic network analysis is a tool for investigating the features that identify the topology of a metabolic network and the relative activities of its individual branches.
How does metabolic engineering work?
Classical metabolic engineering changes cell metabolism by changing its pathway enzyme(s) or regulatory protein(s) using recombinant DNA technology, thus improving the productivity and yield of an industrial fermentation product or producing novel biochemical compounds.
What is Cobra toolbox?
The COnstraint-Based Reconstruction and Analysis Toolbox is a MATLAB software suite for quantitative prediction of cellular and multicellular biochemical networks with constraint-based modelling.
Does genome include RNA?
What is a genome? A genome is the complete set of DNA (or RNA in RNA viruses) of an organism. It is sufficient to build and maintain that organism. Each nucleated cell in the body contains this same set of genetic material.
What is metabolic network in biology?
Definition. Metabolic networks are interconnected pathways of biochemical reactions within living cells through which building blocks or compounds necessary for cellular functioning are assembled (anabolism) or energy and matter are produced by breaking down biomolecules (catabolism).
What is an in silico genome?
In biology and other experimental sciences, an in silico experiment is one performed on computer or via computer simulation. The phrase is pseudo-Latin for 'in silicon' (in Latin it would be in silicio), referring to silicon in computer chips.
Does cancer have cellular metabolism?
Abstract. Cancer cells have fundamentally altered cellular metabolism that is associated with their tumorigen icity and malignancy . In addition to the widely studied Warburg effect, several new key metabolic alterations in cancer have been established over the last decade, leading to the recognition that altered tumor metabolism is one ...
Is the metabolic network the best characterized cellular network?
Encouragingly, while the metabolic network is highly interconnected and complex, it is at the same time probably the best characterized cellular network. Following, this review discusses the challenges that genome-scale modeling of cancer metabolism has been facing.
What is cancer reprogramming?
Cancer is a neoplastic disease, where cells are reprogrammed to avoid the checkpoints in control of nutrient supply, growth, aging, death and dissemination ( Hanahan and Weinberg, 2011 ). This is often caused by genetic events, e.g. mutations and copy number alterations, affecting the cell's signaling system. Cancer cells develop the ability to rapidly evolve, by acquired genomic instability. This allows the cancer cells to adapt to new environments allowing it to metastasize, to evade the immune system and resist cancer treatments. Aberrant energy metabolism is involved in many human diseases ( Sangar et al., 2012) and reprogramming energy metabolism is an emerging hallmark of cancer ( Hanahan and Weinberg, 2011 ).
Why are GEMs important for cancer?
Cancer GEMs have transcended from the early focus on model reconstruction towards applications, through bottom up simulation as well as top down data analysis. GEMs are excellent frameworks to formalize and reconcile biological knowledge from multiple fields and studies, and thanks to their strict mathematical language they force explicit definitions of biological hypothesis with quantitative, verifiable predictions. Cancer is a heterogeneous disease with expression in both the mechanical and information processing dimension. It is therefore desirable to extend GEMs to include as many mechanical processes of the cell as possible, without introducing to much ambiguity and loss of precision, e.g. protein translation, cell division and membrane potential. Similarly it is important to construct an interface between models of signaling and GEMs to enforce a strict mechanistic interpretation of biological circuits and to highlight the limitations of our current knowledge.
What is the scientific activity currently conducted on human GEMs?
The scientific activity currently conducted on human GEMs may been divided into: 1) the reconstruction of the metabolic network, 2) In Silico Knockouts studies, 3) the use of the network as scaffold for analysis of throughput data and 4) for quantitative predictions of exchange fluxes using FBA (for a summary see Table 1 ).
What are the components of cancer cells?
Cancer cells consist primarily of proteins, lipids and polynucleotides, in similarity with most cells from lean tissues ( Keibler et al., 2016 ). Many amino acids are essential, meaning that they cannot be synthesized by human cells, and therefore amino acid derived carbon constitutes up to 80% of the carbon in cell lines ( Hosios et al., 2016 ). Amongst the non-essential amino acids only 6 could be replaced by de novo synthesis without severely affecting proliferation of lung cancer cell lines ( Hosios et al., 2016 ). Amino acids may also be derived from extracellular proteins through macropinocytosis and proteolytic degradation. Inhibiting macropinocytosis reduced the growth in tumor xenografts and extracellular protein may be used in place of glutamine when growing cell lines ( Commisso et al., 2013 ). The ability to utilize external protein appears to be dependent on KRAS signaling. Branched chain Amino Acids (BCAA) are used as nitrogen sources for non-essential amino acid synthesis, and the transamination step in BCCA metabolism is upregulated in glioblastoma ( Tönjes et al., 2013 ).
Why are GEMs used in medicine?
Many drugs aim to rewire the user's metabolism in a beneficial way and GEMs may therefore be an aid in the engineering of drugs. Cancer specific models may be used to determine if a patient is expected to respond to a specific drug treatment.