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Time and Demand are Two Critical Dimensions of Immunometabolism: The Process of Macrophage Activation and the Pentose Phosphate Pathway.

Nagy C, Haschemi A - Front Immunol (2015)

Bottom Line: This perspective article starts by presenting an early attempt to investigate the physiology of inflammation, in order to illustrate one of the basic concepts of immunometabolism, wherein an adapted metabolism of infiltrating immune cells affects tissue function and inflammation.In the last section, we will provide information on how the pentose phosphate pathway may be of importance to provide both nucleotide precursors and redox-equivalents, and speculate how carbon-scrambling events in the non-oxidative pentose phosphate pathway might be regulated within cells by demand.We conclude that the adapted metabolism of inflammation is specific in respect to the effector-function and appears as a well-orchestrated event, dynamic by nature, and based on a functional interplay of signaling- and metabolic-pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine (KILM), Medical University of Vienna , Vienna , Austria.

ABSTRACT
A process is a function of time; in immunometabolism, this is reflected by the stepwise adaptation of metabolism to sustain the bio-energetic demand of an immune-response in its various states and shades. This perspective article starts by presenting an early attempt to investigate the physiology of inflammation, in order to illustrate one of the basic concepts of immunometabolism, wherein an adapted metabolism of infiltrating immune cells affects tissue function and inflammation. We then focus on the process of macrophage activation and aim to delineate the factor time within the current molecular context of metabolic-rewiring important for adapting primary carbohydrate metabolism. In the last section, we will provide information on how the pentose phosphate pathway may be of importance to provide both nucleotide precursors and redox-equivalents, and speculate how carbon-scrambling events in the non-oxidative pentose phosphate pathway might be regulated within cells by demand. We conclude that the adapted metabolism of inflammation is specific in respect to the effector-function and appears as a well-orchestrated event, dynamic by nature, and based on a functional interplay of signaling- and metabolic-pathways.

No MeSH data available.


The function and regulation of the non-oxidative PPP. (A) represents a simplified model, which illustrates how transketolase (TK) and transaldolase (TALDO) may interconvert carbohydrate-phosphates of three to seven carbon-atoms in length (C3P to C7P) without the need of energy (carbon-scrambling) to account for the cellular demand, which in part defines cell function (indicated by the symbol f (x)). In (B), we theoretically evaluate the regulatory effect of Shpk-derived sedoheptulose 7-phosphate ([C7P]Shpk) on non-oxPPP flux in the presence of TK and TALDO. Flux through the non-oxPPP, by its reversible reactions, is dependent on the stoichiometry of the reactants (indicated by green arrowheads). In contrast to TK- and TALDO-derived S7P, the phosphorylation of free sedoheptulose to S7P by Shpk requires energy in form of ATP. Assuming a constant contribution by Shpk, this additional source of S7P may therefore act as a thermodynamic buffer, which can be actively regulated to induce a non-equilibrium. In theory, perturbation of Shpk can either increase the resistance (increased [C7P]Shpk) or lower it (decreased [C7P]Shpk) to support shunting through the non-oxPPP. However, in the presence of TK or TALDO, an increased [C7P]Shpk will promote the incorporation of glycolytic-G3P into the PPP. This model further illustrates that non-oxPPP flux-direction is also dependent on the demand of respective molecules (indicated by red arrowheads).
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Figure 2: The function and regulation of the non-oxidative PPP. (A) represents a simplified model, which illustrates how transketolase (TK) and transaldolase (TALDO) may interconvert carbohydrate-phosphates of three to seven carbon-atoms in length (C3P to C7P) without the need of energy (carbon-scrambling) to account for the cellular demand, which in part defines cell function (indicated by the symbol f (x)). In (B), we theoretically evaluate the regulatory effect of Shpk-derived sedoheptulose 7-phosphate ([C7P]Shpk) on non-oxPPP flux in the presence of TK and TALDO. Flux through the non-oxPPP, by its reversible reactions, is dependent on the stoichiometry of the reactants (indicated by green arrowheads). In contrast to TK- and TALDO-derived S7P, the phosphorylation of free sedoheptulose to S7P by Shpk requires energy in form of ATP. Assuming a constant contribution by Shpk, this additional source of S7P may therefore act as a thermodynamic buffer, which can be actively regulated to induce a non-equilibrium. In theory, perturbation of Shpk can either increase the resistance (increased [C7P]Shpk) or lower it (decreased [C7P]Shpk) to support shunting through the non-oxPPP. However, in the presence of TK or TALDO, an increased [C7P]Shpk will promote the incorporation of glycolytic-G3P into the PPP. This model further illustrates that non-oxPPP flux-direction is also dependent on the demand of respective molecules (indicated by red arrowheads).

Mentions: The non-oxPPP relies on transketolase (TK) and TALDO catalyzed reversible transfer of keto-groups to various aldose acceptors. TK uses thiamine pyrophosphate as cofactor to transfer two carbon (C2)-units, while TALDO can transfer C3-units by forming Schiff base intermediates (75, 76). Thereby, this pathway interconverts carbohydrate-phosphates of different chain length (C3P to C7P), without the need of energy in form of ATP (carbon scrambling, Figure 2A). The regulation of non-oxPPP is complex due to its reversible nature and still not fully understood. The flux-rate and its direction are generally thought to depend on thermodynamics, which impose a major constraint on the structure of metabolic pathways (77). However, the recent identification of Shpk indicates additional regulatory mechanism, which was previously not considered (Figure 2B) (78). In contrast to TK or TALDO, Shpk is reported to be regulated differently during LPS- and IL-4 induced polarization (21). LPS stimulation leads to a rapid down-regulation of Shpk mRNA in the early phase of macrophage activation in mice and humans likewise and in vitro as well as in vivo. In contrast to LPS, IL-4 stimulation maintains or even slightly increases Shpk levels (21). Counterbalancing LPS-induced down-regulation of Shpk by overexpression in a macrophage cell line resulted in an accumulation of pentose phosphates and an imbalance of the cellular redox system, as indicated by the accumulation of oxidized redox couples as well as blunted LPS-induced intracellular superoxide production (21). In theory, Shpk, by the formation of rate-limiting S7P, should increase the shunting of glycolysis-derived G3P into the non-oxPPP (78) and regulate oxPPP activity through the formation or recycling of pentose phosphates (79). So far, we have no confirmed mode-of-action, how Shpk activity actually regulates carbon-flux through the non-oxPPP, and no information on its activity and local distribution during macrophage activation. Therefore, we can only speculate on the consequences of Shpk regulation for the process of metabolic-adaptation (Figure 2B). Shpk-derived S7P may act as a thermodynamic buffer to support a stable non-equilibrium, which drives (low S7P) or inhibits (high S7P) carbon-flux through the non-oxPPP. However, flux-direction seems to be determined by demand and by the presence of TK and TALDO (Figure 2B). In addition to that, high S7P levels can directly modulate glycolytic flux through the inhibition of hexose phosphate isomerase, as well as by competitively inhibiting fructose 6-phosphate (F6P) phosphorylation by PFK (80, 81). Therefore, the consequences of Shpk regulation appear as strictly context dependent, which is defined by the demand of metabolites (i.e., C5P) and the presence or absence of other enzymes. We know that Shpk only partially colocalizes with G6PD in the cytoplasm of cells, which points out that there are instances where the ox- and the non-oxPPP are coupled to and uncoupled from each other (21). Information on the function of TK and TALDO in the process of macrophage activation is rare; however, both enzymes were tightly linked to oxidative stress-defense in other cell types (82–84). Notably, yeast seems to lack a Shpk homolog but utilizes a specific sedoheptulose–bisphosphatase [dephosphorylates sedoheptulose 1,7-bisphosphate (S1,7bP) to S7P] for riboneogenesis when the demand for nucleotide precursors is high (85). S1,7bP was previously reported to also exists in rat liver tissue (86, 87); however, there appear to be some major differences in the architecture of heptose metabolism (heptolysis) between fungi and vertebrates (78, 85).


Time and Demand are Two Critical Dimensions of Immunometabolism: The Process of Macrophage Activation and the Pentose Phosphate Pathway.

Nagy C, Haschemi A - Front Immunol (2015)

The function and regulation of the non-oxidative PPP. (A) represents a simplified model, which illustrates how transketolase (TK) and transaldolase (TALDO) may interconvert carbohydrate-phosphates of three to seven carbon-atoms in length (C3P to C7P) without the need of energy (carbon-scrambling) to account for the cellular demand, which in part defines cell function (indicated by the symbol f (x)). In (B), we theoretically evaluate the regulatory effect of Shpk-derived sedoheptulose 7-phosphate ([C7P]Shpk) on non-oxPPP flux in the presence of TK and TALDO. Flux through the non-oxPPP, by its reversible reactions, is dependent on the stoichiometry of the reactants (indicated by green arrowheads). In contrast to TK- and TALDO-derived S7P, the phosphorylation of free sedoheptulose to S7P by Shpk requires energy in form of ATP. Assuming a constant contribution by Shpk, this additional source of S7P may therefore act as a thermodynamic buffer, which can be actively regulated to induce a non-equilibrium. In theory, perturbation of Shpk can either increase the resistance (increased [C7P]Shpk) or lower it (decreased [C7P]Shpk) to support shunting through the non-oxPPP. However, in the presence of TK or TALDO, an increased [C7P]Shpk will promote the incorporation of glycolytic-G3P into the PPP. This model further illustrates that non-oxPPP flux-direction is also dependent on the demand of respective molecules (indicated by red arrowheads).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
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Figure 2: The function and regulation of the non-oxidative PPP. (A) represents a simplified model, which illustrates how transketolase (TK) and transaldolase (TALDO) may interconvert carbohydrate-phosphates of three to seven carbon-atoms in length (C3P to C7P) without the need of energy (carbon-scrambling) to account for the cellular demand, which in part defines cell function (indicated by the symbol f (x)). In (B), we theoretically evaluate the regulatory effect of Shpk-derived sedoheptulose 7-phosphate ([C7P]Shpk) on non-oxPPP flux in the presence of TK and TALDO. Flux through the non-oxPPP, by its reversible reactions, is dependent on the stoichiometry of the reactants (indicated by green arrowheads). In contrast to TK- and TALDO-derived S7P, the phosphorylation of free sedoheptulose to S7P by Shpk requires energy in form of ATP. Assuming a constant contribution by Shpk, this additional source of S7P may therefore act as a thermodynamic buffer, which can be actively regulated to induce a non-equilibrium. In theory, perturbation of Shpk can either increase the resistance (increased [C7P]Shpk) or lower it (decreased [C7P]Shpk) to support shunting through the non-oxPPP. However, in the presence of TK or TALDO, an increased [C7P]Shpk will promote the incorporation of glycolytic-G3P into the PPP. This model further illustrates that non-oxPPP flux-direction is also dependent on the demand of respective molecules (indicated by red arrowheads).
Mentions: The non-oxPPP relies on transketolase (TK) and TALDO catalyzed reversible transfer of keto-groups to various aldose acceptors. TK uses thiamine pyrophosphate as cofactor to transfer two carbon (C2)-units, while TALDO can transfer C3-units by forming Schiff base intermediates (75, 76). Thereby, this pathway interconverts carbohydrate-phosphates of different chain length (C3P to C7P), without the need of energy in form of ATP (carbon scrambling, Figure 2A). The regulation of non-oxPPP is complex due to its reversible nature and still not fully understood. The flux-rate and its direction are generally thought to depend on thermodynamics, which impose a major constraint on the structure of metabolic pathways (77). However, the recent identification of Shpk indicates additional regulatory mechanism, which was previously not considered (Figure 2B) (78). In contrast to TK or TALDO, Shpk is reported to be regulated differently during LPS- and IL-4 induced polarization (21). LPS stimulation leads to a rapid down-regulation of Shpk mRNA in the early phase of macrophage activation in mice and humans likewise and in vitro as well as in vivo. In contrast to LPS, IL-4 stimulation maintains or even slightly increases Shpk levels (21). Counterbalancing LPS-induced down-regulation of Shpk by overexpression in a macrophage cell line resulted in an accumulation of pentose phosphates and an imbalance of the cellular redox system, as indicated by the accumulation of oxidized redox couples as well as blunted LPS-induced intracellular superoxide production (21). In theory, Shpk, by the formation of rate-limiting S7P, should increase the shunting of glycolysis-derived G3P into the non-oxPPP (78) and regulate oxPPP activity through the formation or recycling of pentose phosphates (79). So far, we have no confirmed mode-of-action, how Shpk activity actually regulates carbon-flux through the non-oxPPP, and no information on its activity and local distribution during macrophage activation. Therefore, we can only speculate on the consequences of Shpk regulation for the process of metabolic-adaptation (Figure 2B). Shpk-derived S7P may act as a thermodynamic buffer to support a stable non-equilibrium, which drives (low S7P) or inhibits (high S7P) carbon-flux through the non-oxPPP. However, flux-direction seems to be determined by demand and by the presence of TK and TALDO (Figure 2B). In addition to that, high S7P levels can directly modulate glycolytic flux through the inhibition of hexose phosphate isomerase, as well as by competitively inhibiting fructose 6-phosphate (F6P) phosphorylation by PFK (80, 81). Therefore, the consequences of Shpk regulation appear as strictly context dependent, which is defined by the demand of metabolites (i.e., C5P) and the presence or absence of other enzymes. We know that Shpk only partially colocalizes with G6PD in the cytoplasm of cells, which points out that there are instances where the ox- and the non-oxPPP are coupled to and uncoupled from each other (21). Information on the function of TK and TALDO in the process of macrophage activation is rare; however, both enzymes were tightly linked to oxidative stress-defense in other cell types (82–84). Notably, yeast seems to lack a Shpk homolog but utilizes a specific sedoheptulose–bisphosphatase [dephosphorylates sedoheptulose 1,7-bisphosphate (S1,7bP) to S7P] for riboneogenesis when the demand for nucleotide precursors is high (85). S1,7bP was previously reported to also exists in rat liver tissue (86, 87); however, there appear to be some major differences in the architecture of heptose metabolism (heptolysis) between fungi and vertebrates (78, 85).

Bottom Line: This perspective article starts by presenting an early attempt to investigate the physiology of inflammation, in order to illustrate one of the basic concepts of immunometabolism, wherein an adapted metabolism of infiltrating immune cells affects tissue function and inflammation.In the last section, we will provide information on how the pentose phosphate pathway may be of importance to provide both nucleotide precursors and redox-equivalents, and speculate how carbon-scrambling events in the non-oxidative pentose phosphate pathway might be regulated within cells by demand.We conclude that the adapted metabolism of inflammation is specific in respect to the effector-function and appears as a well-orchestrated event, dynamic by nature, and based on a functional interplay of signaling- and metabolic-pathways.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine (KILM), Medical University of Vienna , Vienna , Austria.

ABSTRACT
A process is a function of time; in immunometabolism, this is reflected by the stepwise adaptation of metabolism to sustain the bio-energetic demand of an immune-response in its various states and shades. This perspective article starts by presenting an early attempt to investigate the physiology of inflammation, in order to illustrate one of the basic concepts of immunometabolism, wherein an adapted metabolism of infiltrating immune cells affects tissue function and inflammation. We then focus on the process of macrophage activation and aim to delineate the factor time within the current molecular context of metabolic-rewiring important for adapting primary carbohydrate metabolism. In the last section, we will provide information on how the pentose phosphate pathway may be of importance to provide both nucleotide precursors and redox-equivalents, and speculate how carbon-scrambling events in the non-oxidative pentose phosphate pathway might be regulated within cells by demand. We conclude that the adapted metabolism of inflammation is specific in respect to the effector-function and appears as a well-orchestrated event, dynamic by nature, and based on a functional interplay of signaling- and metabolic-pathways.

No MeSH data available.