Biopolym. Cell. 2014; 30(2):149-156.
Bioinformatics
Mathematical modeling of folate-related processes
in human placenta
- Institute of Molecular Biology and Genetics, NAS of Ukraine
150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03680
Abstract
Aim. Description the folate-related processes in the human placenta using the stoichiometric model and investigation the system’s behavior under various conditions. Methods. The model is based on the stoichiometry of the reactions of the folate-related processes at steady state conditions and constructed using CellNetAnalyzer. Behavior of the system is described by elementary flux modes and control-effective fluxes depending on the activity of methylenetetrahydrofolate reductase and methionine synthase and input methionine flux. Results. Change in methylenetetrahydrofolate reductase activity causes a decrease in fluxes through the main routes of homocysteine elimination and increases the need for 5-methyltetrahydrofolate. Methionine synthase inactivation reduces 5-methyltetrahydrofolate consumption and increases the flux through the taurine syn-thesis. Lack of methionine leads to increased 5-methyltetrahydrofolate consumption, reduced homocysteine concentration and reduces the fluxes through the methionine cycle. Conclusions. Analysis of model functioning has shown the compliance of system’s functioning changes with the clinic parameters. There is evidence that the homocysteine level as a marker of folate-related processes functioning of is not sufficient to justify the therapy.
Keywords: folate-related processes, stoichiometric model, elementary flux mode, control-effective fluxes
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References
[1]
Mykytenko DO, Tymchenko OI. Prevalence of polymorphism of methylentetrahydropholatreductase gene among parturients of Kiev region. Medical Perspectives. 2009. 14(3):100–104.
[2]
Tymchenko OI, Lynchak OV, Mykytenko DO, Pol'ka OO, Pokanevych TM. Nervous system congenital pathology: the prevalence of nervous tube defects and possibilities of folic acid in prevention of its development. J. Pediatrics, Obstetrics and Gynecology. 2010; 72(1):18–24.
[3]
Kalhan SC, Marczewski SE. Methionine, homocysteine, one carbon metabolism and fetal growth. Rev Endocr Metab Disord. 2012; 13(2):109–19.
[4]
Martsenyuk OP, Obolenska MYu, Romanets KL, Huppertz B. Effect of homocysteine on the structure and functions of human placenta trophoblast. Ukr Biokhim Zh. 2009. 81(5):40–49.
[5]
Nijhout HF, Reed MC, Budu P, Ulrich CM. A mathematical model of the folate cycle: new insights into folate homeostasis. J Biol Chem. 2004; 279(53):55008–16.
[6]
Ulrich CM, Neuhouser M, Liu AY, Boynton A, Gregory JF 3rd, Shane B, James SJ, Reed MC, Nijhout HF. Mathematical modeling of folate metabolism: predicted effects of genetic polymorphisms on mechanisms and biomarkers relevant to carcinogenesis. Cancer Epidemiol Biomarkers Prev. 2008; 17(7):1822–31.
[7]
Finkelstein JD, Martin JJ, Harris BJ. Methionine metabolism in mammals. The methionine-sparing effect of cystine. J Biol Chem. 1988; 263(24):11750–4.
[8]
Tibbetts AS, Appling DR. Compartmentalization of Mammalian folate-mediated one-carbon metabolism. Annu Rev Nutr. 2010; 30:57–81.
[9]
Engel SM, Olshan AF, Siega-Riz AM, Savitz DA, Chanock SJ. Polymorphisms in folate metabolizing genes and risk for spontaneous preterm and small-for-gestational age birth. Am J Obstet Gynecol. 2006; 195(5):1231.e1–11.
[10]
Schuster S, Fell DA, Dandekar T. A general definition of metabolic pathways useful for systematic organization and analysis of complex metabolic networks. Nat Biotechnol. 2000;18(3): 326–32.
[11]
Gagneur J, Klamt S. Computation of elementary modes: a unifying framework and the new binary approach. BMC Bioinformatics. 2004; 5:175.
[12]
Cakir T, Tacer CS, Ulgen KO. Metabolic pathway analysis of enzyme-deficient human red blood cells. Biosystems. 2004;78 (1–3):49–67.
[13]
Stelling J, Klamt S, Bettenbrock K, Schuster S, Gilles ED. Metabolic network structure determines key aspects of functionality and regulation. Nature. 2002; 420(6912):190–3.
[14]
Obolenskaya MYu, Rodriges RR, Martsenyuk OP. Folate-related processes in human placenta: gene expression, aminothiols, proliferation and apoptosis. Ukr Biokhim Zh. 2011. 83(1): 5–17.
[15]
Rodriguez RR, Lushchyk IS, Obolenska MYu. Stoichiometric model of folate-dependent metabolism of one-carbon units in human placenta. Ukr Biokhim Zh. 2012; 84(4): 20–31.
[16]
Battaglia FC, Regnault TR. Placental transport and metabolism of amino acids. Placenta. 2001; 22(2–3): 145–61.
[17]
Sastre J, Pallardo FV, Vina J. Glutathione. The Handbook of Environmental Chemistry. Springer, 2005; Vol. 20: 91–108.
[18]
Gasparovic J, Raslova K, Basistova Z, Zacharova M, Wsolova L, Avdicova M, Blazicek P, Lietava J, Sivakova D. Effect of C677T methylenetetrahydrofolate reductase gene polymorphism on plasma homocysteine levels in ethnic groups. Physiol Res. 2004; 53(2):215–8.
[19]
Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP, Rozen R. A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet. 1995; 10(1): 111–3.
[20]
Martseniuk OP, Mishlanova Sh, Romanets' KL, Tepliuk NM, Obolens'ka MYu. The level of low molecular thiols and folate in human placenta. Ukr Biokhim Zh. 2009; 81(4): 94–104.
[21]
Bailey LB, Gregory JF 3rd. Polymorphisms of methylenetetrahydrofolate reductase and other enzymes: metabolic significance, risks and impact on folate requirement. J Nutr. 1999; 129 (5):919–22.
[22]
Mislanova C, Martsenyuk O, Huppertz B, Obolenskaya M. Placental markers of folate-related metabolism in preeclampsia. Reproduction. 2011; 142(3):467–76.
[23]
Watkins D, Ru M, Hwang HY, Kim CD, Murray A, Philip NS, Kim W, Legakis H, Wai T, Hilton JF, Ge B, Dore C, Hosack A, Wilson A, Gravel RA, Shane B, Hudson TJ, Rosenblatt DS. Hyperhomocysteinemia due to methionine synthase deficiency, cblG: structure of the MTR gene, genotype diversity, and recognition of a common mutation, P1173L. Am J Hum Genet. 2002;71(1):143–53.
[24]
Rosenblatt D, Fenton W. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill, 2001; 3933 p.
[25]
Swanson DA, Liu ML, Baker PJ, Garrett L, Stitzel M, Wu J, Harris M, Banerjee R, Shane B, Brody LC. Targeted disruption of the methionine synthase gene in mice. Mol Cell Biol. 2001; 21(4):1058–65.
[26]
Gulati S, Baker P, Li YN, Fowler B, Kruger W, Brody LC, Banerjee R. Defects in human methionine synthase in cblG patients. Hum Mol Genet. 1996; 5(12):1859–65.
[27]
O'Leary VB, Mills JL, Pangilinan F, Kirke PN, Cox C, Conley M, Weiler A, Peng K, Shane B, Scott JM, Parle-McDermott A, Molloy AM, Brody LC; Members of the Birth Defects Research Group. Analysis of methionine synthase reductase polymorphisms for neural tube defects risk association. Mol Genet Metab. 2005; 85 (3):220–7.
[28]
Mykytenko DO, Tymchenko OI, Mykytenko OP. Association of methlylentetrahydrofolate reductase polymorphisms with pathology of pregnant and fetus at the kyiv region. Collection of scientific works of staff members of NMAPE named after P. L. Shupyk. 2009; 18(4): 21–31.
[29]
Huang YC, Chang SJ, Chiu YT, Chang HH, Cheng CH. The status of plasma homocysteine and related B-vitamins in healthy young vegetarians and nonvegetarians. Eur J Nutr. 2003; 42(2): 84–90.
[30]
Hung CJ, Huang PC, Lu SC, Li YH, Huang HB, Lin BF, Chang SJ, Chou HF. Plasma homocysteine levels in Taiwanese vegetarians are higher than those of omnivores. J Nutr. 2002; 132(2): 152–8.
[31]
Mann NJ, Li D, Sinclair AJ, Dudman NP, Guo XW, Elsworth GR, Wilson AK, Kelly FD. The effect of diet on plasma homocysteine concentrations in healthy male subjects. Eur J Clin Nutr. 1999; 53(11):895–9.