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In silico experimentation with a model of hepatic mitochondrial folate metabolism.

Nijhout HF, Reed MC, Lam SL, Shane B, Gregory JF, Ulrich CM - Theor Biol Med Model (2006)

Bottom Line: We investigate: the control of the direction of the mitochondrial and cytosolic serine hydroxymethyltransferase (SHMT) reactions, the role of the mitochondrial bifunctional enzyme, the role of the glycine cleavage system, the effects of variations in serine and glycine inputs, and the effects of methionine and protein loading.The model reproduces many experimental findings and gives new insights into the underlying properties of mitochondrial folate metabolism.Particularly interesting is the remarkable stability of formate production in the mitochondria in the face of large changes in serine and glycine input.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, Duke University, Durham, NC 27708, USA. hfn@duke.edu

ABSTRACT

Background: In eukaryotes, folate metabolism is compartmentalized and occurs in both the cytosol and the mitochondria. The function of this compartmentalization and the great changes that occur in the mitochondrial compartment during embryonic development and in rapidly growing cancer cells are gradually becoming understood, though many aspects remain puzzling and controversial.

Approach: We explore the properties of cytosolic and mitochondrial folate metabolism by experimenting with a mathematical model of hepatic one-carbon metabolism. The model is based on known biochemical properties of mitochondrial and cytosolic enzymes. We use the model to study questions about the relative roles of the cytosolic and mitochondrial folate cycles posed in the experimental literature. We investigate: the control of the direction of the mitochondrial and cytosolic serine hydroxymethyltransferase (SHMT) reactions, the role of the mitochondrial bifunctional enzyme, the role of the glycine cleavage system, the effects of variations in serine and glycine inputs, and the effects of methionine and protein loading.

Conclusion: The model reproduces many experimental findings and gives new insights into the underlying properties of mitochondrial folate metabolism. Particularly interesting is the remarkable stability of formate production in the mitochondria in the face of large changes in serine and glycine input. The model shows that in the presence of the bifunctional enzyme (as in embryonic tissues and cancer cells), the mitochondria primarily support cytosolic purine and pyrimidine synthesis via the export of formate, while in adult tissues the mitochondria produce serine for gluconeogenesis.

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Change in the steady-state concentrations of selected metabolites and steady-state velocities of selected reactions when the GDC reaction is eliminated.
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Figure 4: Change in the steady-state concentrations of selected metabolites and steady-state velocities of selected reactions when the GDC reaction is eliminated.

Mentions: In order to study the contribution of the GDC reaction, we set its velocity to zero in the model and calculated the percentage change in concentrations and fluxes at the new steady state (Figure 4). Because the GDC reaction is turned off, the concentration of 5,10-CH2-THF in the mitochondria drops dramatically, which lowers the flux through the MTD, MTCH, and FTS reactions. Thus, much less formate is produced in the mitochondria and therefore the rate of export of formate to the cytosol declines to about 50% of its former value. Because of the reduced supply of formate, the concentration of cytosolic 10f-THF goes down. This has two effects. First, fewer purines are produced and second, the net flux from 10f-THF to 5,10-CH2-THF reverses so that the net flux is from 5,10-CH2-THF to 10f-THF. This reduces the cytosolic concentration of 5,10-CH2-THF, which causes thymidine synthesis to drop. It also makes the concentration of 5mTHF drop, which causes the homocysteine concentration to rise. The decline in [5mTHF] releases the inhibition of GNMT, which draws down [SAM].


In silico experimentation with a model of hepatic mitochondrial folate metabolism.

Nijhout HF, Reed MC, Lam SL, Shane B, Gregory JF, Ulrich CM - Theor Biol Med Model (2006)

Change in the steady-state concentrations of selected metabolites and steady-state velocities of selected reactions when the GDC reaction is eliminated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1713227&req=5

Figure 4: Change in the steady-state concentrations of selected metabolites and steady-state velocities of selected reactions when the GDC reaction is eliminated.
Mentions: In order to study the contribution of the GDC reaction, we set its velocity to zero in the model and calculated the percentage change in concentrations and fluxes at the new steady state (Figure 4). Because the GDC reaction is turned off, the concentration of 5,10-CH2-THF in the mitochondria drops dramatically, which lowers the flux through the MTD, MTCH, and FTS reactions. Thus, much less formate is produced in the mitochondria and therefore the rate of export of formate to the cytosol declines to about 50% of its former value. Because of the reduced supply of formate, the concentration of cytosolic 10f-THF goes down. This has two effects. First, fewer purines are produced and second, the net flux from 10f-THF to 5,10-CH2-THF reverses so that the net flux is from 5,10-CH2-THF to 10f-THF. This reduces the cytosolic concentration of 5,10-CH2-THF, which causes thymidine synthesis to drop. It also makes the concentration of 5mTHF drop, which causes the homocysteine concentration to rise. The decline in [5mTHF] releases the inhibition of GNMT, which draws down [SAM].

Bottom Line: We investigate: the control of the direction of the mitochondrial and cytosolic serine hydroxymethyltransferase (SHMT) reactions, the role of the mitochondrial bifunctional enzyme, the role of the glycine cleavage system, the effects of variations in serine and glycine inputs, and the effects of methionine and protein loading.The model reproduces many experimental findings and gives new insights into the underlying properties of mitochondrial folate metabolism.Particularly interesting is the remarkable stability of formate production in the mitochondria in the face of large changes in serine and glycine input.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biology, Duke University, Durham, NC 27708, USA. hfn@duke.edu

ABSTRACT

Background: In eukaryotes, folate metabolism is compartmentalized and occurs in both the cytosol and the mitochondria. The function of this compartmentalization and the great changes that occur in the mitochondrial compartment during embryonic development and in rapidly growing cancer cells are gradually becoming understood, though many aspects remain puzzling and controversial.

Approach: We explore the properties of cytosolic and mitochondrial folate metabolism by experimenting with a mathematical model of hepatic one-carbon metabolism. The model is based on known biochemical properties of mitochondrial and cytosolic enzymes. We use the model to study questions about the relative roles of the cytosolic and mitochondrial folate cycles posed in the experimental literature. We investigate: the control of the direction of the mitochondrial and cytosolic serine hydroxymethyltransferase (SHMT) reactions, the role of the mitochondrial bifunctional enzyme, the role of the glycine cleavage system, the effects of variations in serine and glycine inputs, and the effects of methionine and protein loading.

Conclusion: The model reproduces many experimental findings and gives new insights into the underlying properties of mitochondrial folate metabolism. Particularly interesting is the remarkable stability of formate production in the mitochondria in the face of large changes in serine and glycine input. The model shows that in the presence of the bifunctional enzyme (as in embryonic tissues and cancer cells), the mitochondria primarily support cytosolic purine and pyrimidine synthesis via the export of formate, while in adult tissues the mitochondria produce serine for gluconeogenesis.

Show MeSH
Related in: MedlinePlus