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7.18D: Repression of Anabolic Pathways - Biology

7.18D: Repression of Anabolic Pathways - Biology


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Repression of anabolic pathways is regulated by altering transcription rates.

LEARNING OBJECTIVES

Differentiate between inducible and repressible systems in gene regulation

Key Points

  • Regulation of transcription controls when transcription occurs and how much RNA is created.
  • Gene regulation is either controlled by an inducible system or a repressible system.
  • In prokaryotes, regulation of transcription is needed for the cell to quickly adapt to the ever-changing outer environment.

Key Terms

  • anabolic pathways: Anabolism describes the set of metabolic pathways that construct molecules from smaller units.
  • transcription: The synthesis of RNA under the direction of DNA.
  • gene: A unit of heredity; a segment of DNA or RNA that is transmitted from one generation to the next. It carries genetic information such as the sequence of amino acids for a protein.

Repression of anabolic pathways is regulated by altering transcription rates. Transcriptional regulation is the change in gene expression levels by altering transcription rates.

Regulation of transcription controls when transcription occurs and how much RNA is created. Transcription of a gene by RNA polymerase can be regulated by at least five mechanisms:

  • Specificity factors alter the specificity of RNA polymerase for a given promoter or set of promoters, making it more or less likely to bind to them (i.e. sigma factors used in prokaryotic transcription).
  • Repressors bind to non-coding sequences on the DNA strand that are close to or overlapping the promoter region, impeding RNA polymerase’s progress along the strand, thus impeding the expression of the gene.
  • General transcription factors position RNA polymerase at the start of a protein -coding sequence and then release the polymerase to transcribe the mRNA.
  • Activators enhance the interaction between RNA polymerase and a particular promoter, encouraging the expression of the gene. Activators do this by increasing the attraction of RNA polymerase for the promoter, through interactions with subunits of the RNA polymerase or indirectly by changing the structure of the DNA.
  • Enhancers are sites on the DNA helix that are bound to by activators in order to loop the DNA bringing a specific promoter to the initiation complex.

Regulatory protein is a term used in genetics to describe a protein involved in regulating gene expression. Such proteins are usually bound to a DNA binding site which is sometimes located near the promoter although this is not always the case. Sites of DNA sequences where regulatory proteins bind are called enhancer sequences. Regulatory proteins are often needed to be bound to a regulatory binding site to switch a gene on (activator) or to shut off a gene (repressor). Generally, as the organism grows more sophisticated, its cellular protein regulation becomes more complicated and, indeed, some human genes can be controlled by many activators and repressors working together.

In prokaryotes, regulation of transcription is needed for the cell to quickly adapt to the ever-changing outer environment. The presence or the quantity and type of nutrients determines which genes are expressed; in order to do that, genes must be regulated in some fashion. In prokaryotes, repressors bind to regions called operators that are generally located downstream from and near the promoter (normally part of the transcript). Activators bind to the upstream portion of the promoter, such as the CAP region (completely upstream from the transcript). A combination of activators, repressors and rarely enhancers (in prokaryotes) determines whether a gene is transcribed.

Gene regulation can be summarized as how genes respond: inducible systems or repressible systems. An inducible system is off unless there is the presence of some molecule (called an inducer) that allows for gene expression. The molecule is said to “induce expression. ” The manner in which this happens is dependent on the control mechanisms as well as differences between prokaryotic and eukaryotic cells. A repressible system is on except in the presence of some molecule (called a corepressor) that suppresses gene expression. The molecule is said to “repress expression. ” The manner in which this happens is dependent on the control mechanisms as well as differences between prokaryotic and eukaryotic cells.

For example, when E. coli bacteria are subjected to heat stress, the σ32 subunit of its RNA polymerase changes in such a way that the enzyme binds to a specialized set of promoters that precede genes for heat-shock response proteins.

Another example is when a cell contains a surplus amount of the amino acid tryptophan, the acid binds to a specialized repressor protein (tryptophan repressor). The binding changes the structural conformity of the repressor such that it binds to the operator region for the operon that synthesizes tryptophan, preventing their expression and thus suspending production. This is a form of negative feedback.

In bacteria, the lac repressor protein blocks the synthesis of enzymes that digest lactose when there is no lactose to feed on. When lactose is present, it binds to the repressor, causing it to detach from the DNA strand.


What is the difference between Induction and Repression?

The synthesis of an enzyme in response to a substance (substrate) is called turning on or induction. A structural gene is induced to transcribe an mRNA and then the mRNA translates a protein.

Genes, whose expressions are regulated in this manner, are called inducible genes and their products, if enzymes, are inducible enzymes. The substrate is known as an inducer.

Generally speaking, enzymes of the catabolic pathways are inducible).Inducible Operon model, (a) The repressor alone forms an activated dimer, which binds to the operator inhibiting the RNA polymerase binding to the promoter, thereby inhibiting the expression (transcription) of the structural genes, (b) The repressor, in the presence of an inducer (lactose) forms repressor-inducer complex.

This complex forms an inactivated dimer, which does not bind to the operator. The RNA polymerase binds to the promoter, thereby bringing about the expression of the structural genes.

Conversely, when the expression of a gene is turned off in response to a substance, the process is called repression. The genes, whose expression is regulated in this manner, are called repressible genes and the enzymes, repressible enzymes. The repressing substance is known as the co-repressor. The enzymes of anabolic pathways are repressible. Induction and repression occur at the level of transcription.

Repressible Operon model, (a) the repressor, in the presence of a co-repressor (tryptophan) forms a repressor-corepressor complex.

This complex forms an activated dimer, which binds to the promoter, thereby inhibiting the expression of the structural genes (b) The repressor alone forms an inactivated dimer, which does not bind to the promoter, thereby bringing about the expression of the structural genes.


Repression of Anabolic Pathways

Repression of anabolic pathways is regulated by altering transcription rates.

Learning Objective

Differentiate between inducible and repressible systems in gene regulation

Key Points

    • Regulation of transcription controls when transcription occurs and how much RNA is created. regulation is either controlled by an inducible system or a repressible system.
    • In prokaryotes, regulation of transcription is needed for the cell to quickly adapt to the ever-changing outer environment.

    Terms

    A unit of heredity a segment of DNA or RNA that is transmitted from one generation to the next. It carries genetic information such as the sequence of amino acids for a protein.

    The synthesis of RNA under the direction of DNA.

    Anabolism describes the set of metabolic pathways that construct molecules from smaller units.

    Full Text

    Repression of anabolic pathways is regulated by altering transcription rates. Transcriptional regulation is the change in gene expression levels by altering transcription rates.

    Regulation of transcription controls when transcription occurs and how much RNA is created. Transcription of a gene by RNA polymerase can be regulated by at least five mechanisms:

    • Specificity factors alter the specificity of RNA polymerase for a given promoter or set of promoters, making it more or less likely to bind to them (i.e. sigma factors used in prokaryotic transcription).
    • Repressors bind to non-coding sequences on the DNA strand that are close to or overlapping the promoter region, impeding RNA polymerase's progress along the strand, thus impeding the expression of the gene.
    • General transcription factors position RNA polymerase at the start of a protein-coding sequence and then release the polymerase to transcribe the mRNA.
    • Activators enhance the interaction between RNA polymerase and a particular promoter, encouraging the expression of the gene. Activators do this by increasing the attraction of RNA polymerase for the promoter, through interactions with subunits of the RNA polymerase or indirectly by changing the structure of the DNA.
    • Enhancers are sites on the DNA helix that are bound to by activators in order to loop the DNA bringing a specific promoter to the initiation complex.

    Regulatory protein is a term used in genetics to describe a protein involved in regulating gene expression. Such proteins are usually bound to a DNA binding site which is sometimes located near the promoter although this is not always the case. Sites of DNA sequences where regulatory proteins bind are called enhancer sequences. Regulatory proteins are often needed to be bound to a regulatory binding site to switch a gene on (activator) or to shut off a gene (repressor). Generally, as the organism grows more sophisticated, its cellular protein regulation becomes more complicated and, indeed, some human genes can be controlled by many activators and repressors working together.

    In prokaryotes, regulation of transcription is needed for the cell to quickly adapt to the ever-changing outer environment. The presence or the quantity and type of nutrients determines which genes are expressed in order to do that, genes must be regulated in some fashion. In prokaryotes, repressors bind to regions called operators that are generally located downstream from and near the promoter (normally part of the transcript). Activators bind to the upstream portion of the promoter, such as the CAP region (completely upstream from the transcript). A combination of activators, repressors and rarely enhancers (in prokaryotes) determines whether a gene is transcribed.

    Gene regulation can be summarized as how genes respond: inducible systems or repressible systems. An inducible system is off unless there is the presence of some molecule (called an inducer) that allows for gene expression. The molecule is said to "induce expression. " The manner in which this happens is dependent on the control mechanisms as well as differences between prokaryotic and eukaryotic cells. A repressible system is on except in the presence of some molecule (called a corepressor) that suppresses gene expression. The molecule is said to "repress expression. " The manner in which this happens is dependent on the control mechanisms as well as differences between prokaryotic and eukaryotic cells.

    For example, when E. coli bacteria are subjected to heat stress, the σ32 subunit of its RNA polymerase changes in such a way that the enzyme binds to a specialized set of promoters that precede genes for heat-shock response proteins.

    Another example is when a cell contains a surplus amount of the amino acid tryptophan, the acid binds to a specialized repressor protein (tryptophan repressor) . The binding changes the structural conformity of the repressor such that it binds to the operator region for the operon that synthesizes tryptophan, preventing their expression and thus suspending production. This is a form of negative feedback.


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    Repressors Biology for Majors I

    • When tryptophan is plentiful, two tryptophan molecules bind the repressor protein at the operator sequence
    • This physically blocks the RNA polymerase from transcribing the tryptophan genes
    • When tryptophan is absent, the repressor protein does not bind to the operator and the genes are transcribed.

    Repression of Women: What Does Biology Tell Us

    • Repression of women by men has been a feature of history and fact of today
    • By repression, one means restricted or unfair access to social, physical, political or financial assets.

    Difference Between Induction and Repression

    Definition of Repression The repression of operon facilitates the cessation of the enzyme synthesis at the appropriate level of particular amino acid. For instance, tryptophan is an amino acid whose supply can repress the production of tryptophan synthesizing enzymes.

    Repression of Women: What Does Biology Tell Us

    • Repression of women by men has been a feature of history and fact of today
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    Repression as a Defense Mechanism

    Repression is the unconscious blocking of unpleasant emotions, impulses, memories, and thoughts from your conscious mind. Introduced by Sigmund Freud, the purpose of this defense mechanism is to try to minimize feelings of guilt and anxiety.

    The lac operon (article) Khan Academy

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    • The lac repressor is a protein that represses (inhibits) transcription of the lac operon. It does this by binding to the operator, which partially overlaps with the promoter
    • When bound, the lac repressor gets in RNA polymerase's way and keeps it from transcribing the …

    Gene repression definition of gene repression by Medical

    • Gene repression the deactivation of an active gene that causes a shut-down of TRANSCRIPTION. see OPERON MODEL
    • Collins Dictionary of Biology, 3rd ed

    7.18D: Repression of Anabolic Pathways

    • Repression of anabolic pathways is regulated by altering transcription rates. Transcriptional regulation is the change in gene expression levels by altering transcription rates
    • Regulation of transcription controls when transcription occurs and how much RNA is created.

    Repression Definition & Facts Britannica

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    • Repression, in psychoanalytic theory, the exclusion of distressing memories, thoughts, or feelings from the conscious mind
    • Often involving sexual or aggressive urges or painful childhood memories, these unwanted mental contents are pushed into the unconscious mind.

    Regulation of Gene Expression: Transcriptional Repression

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    • By studying the lac operon found in E
    • Coli bacteria, biologists learned about gene regulation and the processes of repression and induction
    • Repression is a decrease in gene expression

    Catabolite repression definition of catabolite

    REPRESSION of certain INDUCIBLE ENZYME systems by the presence of specific carbon sources, such as GLUCOSE, that the organism prefers to metabolize.

    What is the difference between Induction and Repression

    • Induction and repression occur at the level of transcription
    • Repressible Operon model, (a) the repressor, in the presence of a co-repressor (tryptophan) forms a repressor-corepressor complex
    • This complex forms an activated dimer, which binds to the promoter, thereby inhibiting the expression of the structural genes (b) The repressor alone

    Enzyme Induction and Repression Encyclopedia.com

    • Enzyme repression is when the repressor molecules prevent the manufacture of an enzyme
    • Repression typically operates by feedback inhibition
    • For example, if the end product of a series of enzyme-catalyzed reactions is a particular amino acid, that amino acid acts as the repressor molecule to further production
    • Often the repressor will combine

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    Transcription factors (article) Khan Academy

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    • Transcription factors are proteins that help turn specific genes "on" or "off" by binding to nearby DNA
    • Transcription factors that are activators boost a gene's transcription
    • Repressors decrease transcription
    • Groups of transcription factor binding sites called enhancers and silencers can turn a gene on/off in specific parts of the body.

    Catabolite repression definition

    Biology Glossary search by EverythingBio.com Repression (inactivation) of certain sugar-metabolizing operons (eg lac) in favour of glucose utilization when glucose is the predominant carbon source in the environment of the cell.

    Freudian Repression: Definition & Overview

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    • Repression refers to the ego's efforts to subconsciously keep anxious thoughts and impulses out of our awareness and keep them buried and hidden
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    16.2A: The trp Operon: A Repressor Operon

    • The trp Operon: A Repressor Operon
    • Coli need amino acids to survive
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    • Coli can ingest from the environment
    • Coli can also synthesize tryptophan using enzymes that are encoded by five genes
    • These five genes are next to each other in what is called the tryptophan (trp) operon.

    Activation and repression at the heart of human RNA

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    • A marked difference in the structures of human and S
    • Cerevisiae RPC6 is the presence of the 4Fe–4S cluster at the C terminus of human RPC6

    Regulation of Enzyme Activity by

    • ADVERTISEMENTS: In connection with the tryptophan operon, that an excess of tryptophan can cause a repression of the genes of this operon, leading to an arrest of the synthesis of the enzymes required for the formation of tryptophan
    • Beside this possibility of repression, there is very often feedback inhibition, i.e
    • The possibility for an essential […]

    Repression Definition of Repression by Merriam-Webster

    • Repression definition is - the action or process of repressing : the state of being repressed
    • How to use repression in a sentence.

    Biology and The Oppression of Women by Aly E Medium

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    (PDF) Catabolite Repression Definition What is

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    • Catabolite Repression Explanation
    • Catabolite repression or carbon catabolite repression is a crucial part of global control system of microorganisms particularly bacteria
    • Through catabolite repression the microorganisms can adapt quickly and easily to a preferred energy and carbon source first.

    Activators and Inducers Biology for Majors I

    • Lactose Operon: An Inducer Operon
    • The third type of gene regulation in prokaryotic cells occurs through inducible operons, which have proteins that bind to activate or repress transcription depending on the local environment and the needs of the cell.The lac operon is a typical inducible operon.As mentioned previously, E
    • Coli is able to use other sugars as energy sources when glucose

    Repression vs. Suppression – What’s the Difference

    • Suppression and repression are two similar nouns, and there meaning sometimes overlap
    • Suppression refers to stoppage or blockage, like in the context of bleeding or police tactics
    • Repression means inhibition, like in sociological or psychological contexts
    • The distinction may be small, but it is important.

    Systems biology approach reveals that overflow metabolism

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    • Coli shown by proteomic, transcriptomic and metabolomic levels coupled to two-phase acetate accumulation: acetate overflow metabolism in E

    What is meant by a repressible operon

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    • Repressible operon are proteins that inhibits gene transcription
    • In case of trp operon is repressed in the presence of tryptophan.

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    Yeast Carbon Catabolite Repression Microbiology and

    • SUMMARY Glucose and related sugars repress the transcription of genes encoding enzymes required for the utilization of alternative carbon sources some of these genes are also repressed by other sugars such as galactose, and the process is known as catabolite repression
    • The different sugars produce signals which modify the conformation of certain proteins that, in turn, directly or through a

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    Solution for What is catabolic repression? How glucose concentration regulate catabolic repression of lac operon?


    Discussion

    In this study, we aimed to identify the mechanisms underlying E. coli’s coordinated response to different metabolic limitations. From the large-scale quantification of metabolic fluxes, metabolites, and proteins, in genetically implemented catabolic and anabolic limitations, we identify two mechanisms that facilitate the global as well as local coordination of metabolic activity (Fig 4). First, a global gene regulatory program coordinates the expression of catabolism and anabolism, largely through the activity of a single transcription factor, Crp. This regulatory program however does not exactly match protein levels to the required flux changes for many reactions. Second, the mismatches between protein and flux changes are adjusted locally through passive changes in enzyme saturation. These findings provide insights on mechanistic implementations of global resource allocation predicted previously by the phenomenological theory of bacterial growth control (Appendix Text 4 and Appendix Figs S17–S19).

    Figure 4. Schematic summary of mechanisms implementing the global coordination of metabolism identified in this study

    Coordination in the expression of catabolic and anabolic proteins is achieved by a single transcription factor, Crp, which directly induces catabolic proteins and indirectly represses anabolic proteins under catabolic limitation, through the competition for scarce expression machinery capacity (mechanism 1, see also Box 1). This approximate gene regulatory program is further adjusted locally through changes in metabolite concentrations, which alter each enzyme’s saturation. At a given enzyme concentration, high substrate concentration (= high enzyme saturation, symbolized by large S) leads to a high reaction rate (symbolized by a thick horizontal arrow). Conversely, low substrate concentration (small S) reduces the reaction rate (thin horizontal arrow).

    Our results suggest that Crp exerts its effect on catabolic and anabolic proteins through both direct and indirect regulation: Catabolic proteins are directly induced by Crp under catabolic limitation, while anabolic protein expression is repressed indirectly. Conversely, Crp induction of catabolic proteins is reduced under anabolic limitation (due to increased 2-oxoglutarate (You et al, 2013 )), while anabolic protein expression is indirectly increased, exhibiting similar behaviors as the constitutive (i.e., unregulated) reporters. Importantly, the indirect mode of regulation reported here has broad implications beyond the coordination of catabolism and anabolism by Crp. A common approach to identify the targets of a transcriptional regulator is to identify genes whose expression changes upon its deletion (e.g., Wang et al, 2018 ). Our results suggest that deletion of transcriptional regulators, in particular global regulators, may also affect the expression of non-target genes, thus confounding the regulatory networks resulting from such efforts. Nevertheless, this indirect regulation of non-Crp targeted genes can be overridden by additional designated regulation, as exemplified by the regulation of the ribosomal proteome fraction, which maintains its strict dependency on growth rate in both of the imposed limitations (Appendix Fig S9). Future studies may use this work as a starting point to identify the regulatory mechanisms responsible for overriding the indirect regulation by Crp in other proteome fractions, e.g., those which do not change expression across either catabolic or anabolic limitations (Hui et al, 2015 ).

    How this indirect mode of regulation is achieved mechanistically is currently unclear. In principle, this mechanism could be the result of competition for limited capacity of expression machinery at the transcription or translation level (Box 1). The proposed models yield the same result at the proteome level, and identifying whether any of these—or alternative—models are responsible for this indirect mode of regulation is left for future studies.

    Box 1. Two plausible mechanisms of indirect repression of non-Crp targets by the transcriptional activator Crp

    Although gene expression and enzyme saturation accounted for about 50% of the observed flux changes in a simple multiplicative model for both limitations, many flux changes could not be explained simply by these two mechanisms alone. For example, most glutamate-dependent transamination reactions—in which the amination of a metabolite is coupled to the deamination of glutamate to 2-oxoglutarate (see Appendix Fig S1C)—were poorly accounted for by changes in protein and substrate concentrations alone, resulting in regulation coefficients far from 1 (see IlvE as example in Fig 3C, bottom row). A possible explanation is that these reactions are affected by concerted changes in both substrate and product concentrations (Hackett et al, 2016 ). Although the lack of complete metabolite and proteome data for many reactions does not allow us to assess the impact of reaction products across a large number of reactions, our results already suggest that the glutamate-dependent transamination reactions show a massive shift in the ratio of 2-oxoglutarate (reaction product of most transamination reactions) to glutamate (reaction substrate) under anabolic limitation, causing a “thermodynamic choke-point” (Appendix Fig S16). In contrast, transamination reactions which use fumarate instead of 2-oxoglutarate as a product (and aspartate instead of glutamate as a substrate) are explained well by gene expression and enzyme saturation (see ArgG in Appendix Fig S15 as an example). Importantly, these findings also suggest a possible physiological rationale for the increased protein concentration of anabolic proteins despite a decrease in the net flux: Increasing the concentration of the catalyzing enzyme is an effective way to increase the net flux in a thermodynamically choked reaction involving high exchange flux (Noor et al, 2014 ). Therefore, by increasing the expression of transaminases in the anabolic limitation, cells can counter the reduction in driving force resulting from 2-oxoglutarate accumulation. Future studies, with broader metabolome coverage, may explore the importance of such changes in thermodynamic driving force in more detail.

    Overall, the findings reported in this study point to a common theme, in which E. coli largely relies on simple heuristics, or “rules of thumb” to cope with environmental and genetic changes (Tversky & Kahneman, 1974 Towbin et al, 2017 ). Instead of specifically adjusting its gene expression program to meet exactly the imposed metabolic demands, the coordination of metabolic activity in E. coli is achieved by an approximate global gene regulatory response, which sets the system roughly in the desired direction. This response is further adjusted locally through changes in enzyme saturation. However, the downside of such a simple regulatory program is that it effectively makes each reaction involved more expensive (since enzymes are being expressed at higher levels than needed strictly to maintain the desired metabolic flux), with a potential cost to the steady-state growth rate (Scott et al, 2010 Hui et al, 2015 O’Brien et al, 2016 ).

    While the approximate (or suboptimal) regulation of protein expression is widespread in bacteria (Price et al, 2013 Towbin et al, 2017 ), it appears to be at odds with numerous laboratory-based evolutionary studies (e.g., LaCroix et al, 2015 ), showing that even small differences in fitness (i.e., growth rate) are selected against. One previously proposed explanation (Price et al, 2013 ) is that cells have not evolved to cope with the artificial laboratory environments they are subjected to, which is particularly true for the genetically implemented limitations used in this study. Nevertheless, a recent study, which quantified the global proteome allocation of wild-type E. coli strains growing on various carbon sources (resulting in different degrees of catabolic limitation), found an inverse relationship between catabolic and anabolic proteome sectors that is consistent with our findings (Schmidt et al, 2016 ). Future studies may examine whether natural anabolic limitations similarly exert an effect on E. coli’s proteome allocation that is consistent with our genetically implement anabolic limitation.

    A more parsimonious explanation of the difference between the degree of optimization manifested by the laboratory-evolved and natural strains is that the simple regulatory programs emerged from an evolutionary trade-off: Given the multitude of environments that cells could encounter, it is simply infeasible to have a dedicated optimized program for each environment that is also consistent across conditions (Shoval et al, 2012 Keren et al, 2013 Price et al, 2013 ). Consequently, cells may rather rely on using the “rule of thumb” as a heuristic guide to coarsely allocate the proteome according to a few signals (Chubukov et al, 2014 ). A good illustration of this strategy is the proteome response to anabolic limitation: If cells cannot identify the exact reaction responsible for the reduction in anabolic capacity (in this case, it is ultimately the reduced glutamate synthesis that slows down transamination reactions), or if it cannot fix the problem (the “optimal solution” would be to upregulate just the transaminases), the best alternative may be an across-the-board increase in the expression of anabolic proteins (which include all the transaminases). Importantly, proteome allocation within this mode of response can be easily coordinated and optimized (You et al, 2013 Hui et al, 2015 ). Future research will reveal the prevalence and nature of this type of simple regulatory strategies underlying microbial responses to complex environmental challenges.


    Contents

    Catabolite repression was extensively studied in Escherichia coli. E. coli grows faster on glucose than on any other carbon source. For example, if E. coli is placed on an agar plate containing only glucose and lactose, the bacteria will use glucose first and lactose second. When glucose is available in the environment, the synthesis of β-galactosidase is under repression due to the effect of catabolite repression caused by glucose. The catabolite repression in this case is achieved through the utilization of phosphotransferase system.

    An important enzyme from the phosphotransferase system called Enzyme II A (EIIA) plays a central role in this mechanism. There are different catabolite-specific EIIA in a single cell, even though different bacterial groups have specificities to different sets of catabolites. In enteric bacteria one of the EIIA enzymes in their set is specific for glucose transport only. When glucose levels are high inside the bacteria, EIIA mostly exists in its unphosphorylated form. This leads to inhibition of adenylyl cyclase and lactose permease, therefore cAMP levels are low and lactose can not be transported inside the bacteria.

    Once the glucose is all used up, the second preferred carbon source (i.e. lactose) has to be used by bacteria. Absence of glucose will "turn off" catabolite repression. When glucose levels are low, the phosphorylated form of EIIA accumulates and consequently activates the enzyme adenylyl cyclase, which will produce high levels of cAMP. cAMP binds to catabolite activator protein (CAP) and together they will bind to a promoter sequence on the lac operon. However, this is not enough for the lactose genes to be transcribed. Lactose must be present inside the cell to remove the lactose repressor from the operator sequence (transcriptional regulation). When these two conditions are satisfied, it means for the bacteria that glucose is absent and lactose is available. Next, bacteria start to transcribe the lac operon and produce β-galactosidase enzymes for lactose metabolism. The example above is a simplification of a complex process. Catabolite repression is considered to be a part of global control system and therefore it affects more genes rather than just lactose gene transcription. [1] [2]

    Gram positive bacteria such as Bacillus subtilis have a cAMP-independent catabolite repression mechanism controlled by catabolite control protein A (CcpA). In this alternative pathway CcpA negatively represses other sugar operons so they are off in the presence of glucose. It works by the fact that Hpr is phosphorylated by a specific mechanism, when glucose enters through the cell membrane protein EIIC, and when Hpr is phosphoralated it can then allow CcpA to block transcription of the alternative sugar pathway operons at their respective cre sequence binding sites. Note that E. coli has a similar cAMP-independent catabolite repression mechanism that utilizes a protein called catabolite repressor activator (Cra).


    MTORC1 signaling and the metabolic control of cell growth

    mTOR [mechanistic target of rapamycin] is a serine/threonine protein kinase that, as part of mTORC1 (mTOR complex 1), acts as an important molecular connection between nutrient signals and the metabolic processes indispensable for cell growth. While there has been pronounced interest in the upstream mechanisms regulating mTORC1, the full range of downstream molecular targets through which mTORC1 signaling stimulates cell growth is only recently emerging. It is now evident that mTORC1 promotes cell growth primarily through the activation of key anabolic processes. Through a diverse set of downstream targets, mTORC1 promotes the biosynthesis of macromolecules, including proteins, lipids, and nucleotides to build the biomass underlying cell, tissue, and organismal growth. Here, we focus on the metabolic functions of mTORC1 as they relate to the control of cell growth. As dysregulated mTORC1 underlies a variety of human diseases, including cancer, diabetes, autoimmune diseases, and neurological disorders, understanding the metabolic program downstream of mTORC1 provides insights into its role in these pathological states.

    Current address: Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.


    Hiroyuki Okano and Sheng Hui: These authors contributed equally to this work.

    Affiliations

    Department of Physics, University of California at San Diego, La Jolla, 92093-0374, California, USA

    Conghui You, Hiroyuki Okano, Sheng Hui, Minsu Kim & Terence Hwa

    Division of Biological Sciences, Section of Molecular Biology, University of California at San Diego, La Jolla, 92093, California, USA

    Conghui You, Hiroyuki Okano, Zhongge Zhang, Carl W. Gunderson & Terence Hwa

    Center for Theoretical Biological Physics, University of California at San Diego, La Jolla, 92093-0374, California, USA

    State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing, 100871, China

    Department of Physics and Center for Synthetic Microbiology, University of Marburg, 35032 Marburg, Germany

    Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, 46202, Indiana, USA