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A mathematical model of the folate cycle: new insights into folate homeostasis.

Publication ,  Journal Article
Nijhout, HF; Reed, MC; Budu, P; Ulrich, CM
Published in: The Journal of biological chemistry
December 2004

A mathematical model is developed for the folate cycle based on standard biochemical kinetics. We use the model to provide new insights into several different mechanisms of folate homeostasis. The model reproduces the known pool sizes of folate substrates and the fluxes through each of the loops of the folate cycle and has the qualitative behavior observed in a variety of experimental studies. Vitamin B(12) deficiency, modeled as a reduction in the V(max) of the methionine synthase reaction, results in a secondary folate deficiency via the accumulation of folate as 5-methyltetrahydrofolate (the "methyl trap"). One form of homeostasis is revealed by the fact that a 100-fold up-regulation of thymidylate synthase and dihydrofolate reductase (known to occur at the G(1)/S transition) dramatically increases pyrimidine production without affecting the other reactions of the folate cycle. The model also predicts that an almost total inhibition of dihydrofolate reductase is required to significantly inhibit the thymidylate synthase reaction, consistent with experimental and clinical studies on the effects of methotrexate. Sensitivity to variation in enzymatic parameters tends to be local in the cycle and inversely proportional to the number of reactions that interconvert two folate substrates. Another form of homeostasis is a consequence of the nonenzymatic binding of folate substrates to folate enzymes. Without folate binding, the velocities of the reactions decrease approximately linearly as total folate is decreased. In the presence of folate binding and allosteric inhibition, the velocities show a remarkable constancy as total folate is decreased.

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Published In

The Journal of biological chemistry

DOI

EISSN

1083-351X

ISSN

0021-9258

Publication Date

December 2004

Volume

279

Issue

53

Start / End Page

55008 / 55016

Related Subject Headings

  • Vitamin B 12 Deficiency
  • Up-Regulation
  • Time Factors
  • Thymidylate Synthase
  • Tetrahydrofolates
  • Tetrahydrofolate Dehydrogenase
  • Models, Theoretical
  • Models, Chemical
  • Models, Biological
  • Methotrexate
 

Citation

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Nijhout, H. F., Reed, M. C., Budu, P., & Ulrich, C. M. (2004). A mathematical model of the folate cycle: new insights into folate homeostasis. The Journal of Biological Chemistry, 279(53), 55008–55016. https://doi.org/10.1074/jbc.m410818200
Nijhout, H Frederik, Michael C. Reed, Paula Budu, and Cornelia M. Ulrich. “A mathematical model of the folate cycle: new insights into folate homeostasis.The Journal of Biological Chemistry 279, no. 53 (December 2004): 55008–16. https://doi.org/10.1074/jbc.m410818200.
Nijhout HF, Reed MC, Budu P, Ulrich CM. A mathematical model of the folate cycle: new insights into folate homeostasis. The Journal of biological chemistry. 2004 Dec;279(53):55008–16.
Nijhout, H. Frederik, et al. “A mathematical model of the folate cycle: new insights into folate homeostasis.The Journal of Biological Chemistry, vol. 279, no. 53, Dec. 2004, pp. 55008–16. Epmc, doi:10.1074/jbc.m410818200.
Nijhout HF, Reed MC, Budu P, Ulrich CM. A mathematical model of the folate cycle: new insights into folate homeostasis. The Journal of biological chemistry. 2004 Dec;279(53):55008–55016.

Published In

The Journal of biological chemistry

DOI

EISSN

1083-351X

ISSN

0021-9258

Publication Date

December 2004

Volume

279

Issue

53

Start / End Page

55008 / 55016

Related Subject Headings

  • Vitamin B 12 Deficiency
  • Up-Regulation
  • Time Factors
  • Thymidylate Synthase
  • Tetrahydrofolates
  • Tetrahydrofolate Dehydrogenase
  • Models, Theoretical
  • Models, Chemical
  • Models, Biological
  • Methotrexate