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Cell-Specific Expression of Enzymes for Serine Biosynthesis and Glutaminolysis in Farm Animals

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Amino Acids in Nutrition and Health

Abstract

During the peri-implantation period, conceptuses [embryo and placental membranes, particularly the trophectoderm (Tr)] of farm animals (e.g., sheep and pigs) rapidly elongate from spherical to tubular to filamentous forms. In concert with Tr outgrowth during conceptus elongation, the Tr of sheep and pig conceptuses attaches to the endometrial luminal epithelium (LE) to initiate placentation. In sheep, binucleate cells (BNCs) begin to differentiate from the mononuclear trophectoderm cells and migrate to the endometrial LE to form syncytial plaques. These events require Tr cells to expend significant amounts of energy to undergo timely and extensive proliferation, migration and fusion. It is likely essential that conceptuses optimally utilize multiple biosynthetic pathways to convert molecules such as glucose, fructose, and glutamine (components of histotroph transport by sheep and pig endometria into the uterine lumen), into ATP, amino acids, ribose, hexosamines and nucleotides required to support early conceptus development and survival. Elongating and proliferating conceptus Tr cells potentially act, in a manner similar to cancer cells, to direct carbon generated from glucose and fructose away from the TCA cycle for utilization in branching pathways of glycolysis, including the pentose phosphate pathway, one-carbon metabolism, and hexosamine biosynthesis. The result is a limited availability of pyruvate for maintaining the TCA cycle within mitochondria, and Tr cells replenish TCA cycle metabolites via a process known as anaplerosis, primarily through glutaminolysis to convert glutamine into TCA cycle intermediates. Here we describe the cell-specific expression of enzymes required for serine biosynthesis, one-carbon metabolism and glutaminolysis at the uterine-placental interface of sheep and pigs, and propose that these biosynthetic pathways are essential to support early placental development including Tr elongation, cell migration, cell fusion and implantation by ovine and porcine conceptuses.

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Abbreviations

3-PG:

3-phosphoglycerate

BNC:

binucleate cells

GE:

glandular epithelium

GLUD:

glutamate dehydrogenase

LE:

luminal epithelium

PHGDH:

phosphoglyceride dehydrogenase

PHP:

3-phosphohydoypyruvate

PSAT:

phophoserine aminotransferase

PSPH:

phosphoserine phosphatase

SAM:

S-adenosylmethionine

SHMT:

serine hydroxymethyltransferase

SLC:

solute carrier

TCA:

tricarboxylic acid

THF:

tetrahydrofolate

Tr:

trophectoderm

α-KG:

α-ketoglutarate

References

  • Altman BJ, Stine ZE, Dang CV (2016) From Krebs to clinic: glutamine metabolism to cancer therapy. Nat Rev Cancer 16:619–634

    Article  CAS  Google Scholar 

  • Andrejeva G, Rathmell JC (2017) Similarities and distinctions of cancer and immune metabolism in inflammation and tumors. Cell Metab 26:49–70

    Article  CAS  Google Scholar 

  • Bazer FW, Johnson GA (2014) Pig blastocyst-uterine interactions. Differentiation 87:52–65

    Article  CAS  Google Scholar 

  • Bazer FW, Seo H, Johnson GA, Wu G (2020) One-carbon metabolism and development of the conceptus during pregnancy: Lessons from studies with sheep and pigs. Adv Exp Med Biol 1285:1–15

    Google Scholar 

  • Cluntun AA, Lukey MJ, Cerione RA, Locasale JW (2017) Glutamine metabolism in cancer: understanding the heterogeneity. Trends Cancer 3:169–180

    Article  CAS  Google Scholar 

  • Cruys B, Wong BW, Kuchnio A, Verdegem D, Cantelmo AR, Conradi LC, Vandekeere S, Bouché A, Cornelissen I, Vinckier S, Merks RM, Dejana E, Gerhardt H, Dewerchin M, Bentley K, Carmeliet P (2016) Glycolytic regulation of cell rearrangement in angiogenesis. Nat Commun 7:12240

    Article  CAS  Google Scholar 

  • DeBerardinis RJ, Chandel NS (2016) Fundamentals of cancer metabolism. Sci Adv 2(5):e1600200

    Article  Google Scholar 

  • DeBerardinis RJ, Mancuso A, Daikhin E, Nissim I, Yudkoff M, Wehrli S, Thompson CB (2007) Beyond aerobic glycolysis: transformed cells can engage in glutamine metabolism that exceeds the requirement for protein and nucleotide synthesis. Proc Natl Acad Sci U S A 104:19345–19350

    Article  CAS  Google Scholar 

  • Fischer HE, Bazer FW, Fields MJ (1985) Steroid metabolism by endometrial and conceptus tissues during early pregnancy and pseudopregnancy in gilts. J Reprod Fertil 75:69–78

    Article  CAS  Google Scholar 

  • Gao H, Wu G, Spencer TE, Johnson GA, Li X, Bazer FW (2009a) Select nutrients in the ovine uterine lumen. I. Amino acids, glucose, and ions in uterine lumenal flushings of cyclic and pregnant ewes. Biol Reprod 80:86–93

    Article  CAS  Google Scholar 

  • Gao H, Wu G, Spencer TE, Johnson GA, Bazer FW (2009b) Select nutrients in the ovine uterine lumen. ii. glucose transporters in the uterus and peri-implantation conceptuses. Biol Reprod 80:94–104

    Article  CAS  Google Scholar 

  • Geisert RD, Brookbank JW, Roberts RM, Bazer FW (1982) Establishment of pregnancy in the pig. II. Cellular remodelling of the porcine blastocysts during elongation of day 12 of pregnancy. Biol Reprod 27:941–955

    Article  CAS  Google Scholar 

  • Gross MI, Demo SD, Dennison JB, Chen L, Chernov-Rogan T, Goyal B, Janes JR, Laidig GJ, Lewis ER, Li J, Mackinnon AL, Parlati F, Rodriguez ML, Shwonek PJ, Sjogren EB, Stanton TF, Wang T, Yang J, Zhao F, Bennett MK (2014) Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol Cancer Ther 13:890–901

    Article  CAS  Google Scholar 

  • Hou YQ, He WL, Hu SD, Wu G (2019) Composition of polyamines and amino acids in plant-source foods for human consumption. Amino Acids 51:1153-1165

    Google Scholar 

  • Kim J, Song G, Wu G, Bazer FW (2012) Functional roles of fructose. Proc Natl Acad Sci U S A 109:E1619–E1628

    Article  CAS  Google Scholar 

  • Kim J, Song G, Wu G, Gao H, Johnson GA, Bazer FW (2013) Arginine, leucine, and glutamine stimulate proliferation of porcine trophectoderm cells through the MTOR-RPS6K-RPS6-EIF4EBP1 signal transduction pathway. Biol Reprod 88:113

    PubMed  Google Scholar 

  • Kung HN, Marks JR, Chi JT (2011) Glutamine synthetase is a genetic determinant of cell type-specific glutamine independence in breast epithelia. PLoS Genet 7(8):e1002229

    Article  CAS  Google Scholar 

  • Kwon H, Spencer TE, Bazer FW, Wu G (2003) Developmental changes of amino acids in ovine fetal fluids. Biol Reprod 68:1813–1820

    Article  CAS  Google Scholar 

  • Li P, Wu G (2020) Composition of amino acids and related nitrogenous nutrients in feedstuffs for animal diets. Amino Acids 52:523-542

    Google Scholar 

  • Lin G, Li DF, Wang JJ, Bazer FW, Wu G (2013) Stimulation of pentose cycle activity in porcine trophectoderm cells by L-glutamine, but not L-arginine. Amino Acids 45:603–604

    Google Scholar 

  • Locasale JW, Grassian AR, Melman T, Lyssiotis CA, Mattaini KR, Bass AJ, Heffron G, Metallo CM, Muranen T, Sharfi H, Sasaki AT, Anastasiou D, Mullarky E, Vokes NI, Sasaki M, Beroukhim R, Stephanopoulos G, Ligon AH, Meyerson M, Richardson AL, Chin L, Wagner G, Asara JM, Brugge JS, Cantley LC, Vander Heiden MG (2011) Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nat Genet 43:869–874

    Article  CAS  Google Scholar 

  • Nilsson R, Jain M, Madhusudhan N, Sheppard NG, Strittmatter L, Kampf C, Huang J, Asplund A, Mootha VK (2014) Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer. Nat Commun 5:3128

    Article  Google Scholar 

  • O’Neill LA, Kishton RJ, Rathmell J (2016) A guide to immunometabolism for immunologists. Nat Rev Immunol 16:553–565

    Article  Google Scholar 

  • Pavlova NN, Thompson CB (2016) The emerging hallmarks of cancer metabolism. Cell Metab 23:27–47

    Article  CAS  Google Scholar 

  • Perry JS, Heap RB, Amoroso EC (1973) Steroid hormone production by pig blastocysts. Nature 245:45–47

    Article  CAS  Google Scholar 

  • Possemato R, Marks KM, Shaul YD, Pacold ME, Kim D, Birsoy K, Sethumadhavan S, Woo HK, Jang HG, Jha AK, Chen WW, Barrett FG, Stransky N, Tsun ZY, Cowley GS, Barretina J, Kalaany NY, Hsu PP, Ottina K, Chan AM, Yuan B, Garraway LA, Root DE, Mino-Kenudson M, Brachtel EF, Driggers EM, Sabatini DM (2011) Functional genomics reveal that the serine synthesis pathway is essential in breast cancer. Nature 476:346–350

    Article  CAS  Google Scholar 

  • Rathmell JC, Vander Heiden MG, Harris MH, Frauwirth KA, Thompson CB (2000) In the absence of extrinsic signals, nutrient utilization by lymphocytes is insufficient to maintain either cell size or viability. Mol Cell 6:683–692

    Article  CAS  Google Scholar 

  • Ron-Harel N, Santos D, Ghergurovich JM, Sage PT, Reddy A, Lovitch SB, Dephoure N, Satterstrom FK, Sheffer M, Spinelli JB, Gygi S, Rabinowitz JD, Sharpe AH, Haigis MC (2016) Mitochondrial biogenesis and proteome remodeling promote one-carbon metabolism for T cell activation. Cell Metab 24:104–117

    Article  CAS  Google Scholar 

  • Song G, Bailey DW, Dunlap KA, Burghardt RC, Spencer TE, Bazer FW, Johnson GA (2010) Cathepsin B, cathepsin L and cystatin C in the porcine uterus and placenta: potential roles in endometrial/placental remodeling and in fluid-phase transport of proteins secreted by uterine epithelia across placental areolae and neonatal gut. Biol Reprod 82:854–864

    Article  CAS  Google Scholar 

  • Wang T, Marquardt C, Foker J (1976) Aerobic glycolysis during lymphocyte proliferation. Nature 261:702–705

    Article  CAS  Google Scholar 

  • Wang X, Li D, Wu G, Bazer FW (2016) Functional roles of fructose: crosstalk between O-linked glycosylation and phosphorylation of Akt-TSC2-MTOR cell signaling cascade in ovine trophectoderm cells. Biol Reprod 95(5):102

    Article  Google Scholar 

  • Wooding FB, Burton GJ (2008) Chapter 6: comparative placentation: structure, function and evolution. In: Synepitheliochorial placentation: ruminants (ewe and cow). Springer, Heidelberg, pp 133–144

    Chapter  Google Scholar 

  • Wu G (2013) Amino acids: biochemistry and nutrition. CRC Press, Boca Raton

    Book  Google Scholar 

  • Wu G (2018) Principles of animal nutrition. CRC Press, Boca Raton

    Google Scholar 

  • Wu G, Bazer FW, Tuo W (1995) Developmental changes of free amino acid concentrations in fetal fluids of pigs. J Nutr 125:2859–2868

    Article  CAS  Google Scholar 

  • Wu G, Bazer FW, Tuo W, Flynn SP (1996) Unusual abundance of arginine and ornithine in porcine allantoic fluid. Biol Reprod 54:1261–1265

    Article  CAS  Google Scholar 

  • Wu G, Bazer FW, Johnson GA, Knabe DA, Burghardt RC, Spencer TE, Li XL, Wang JJ (2011) Important roles for L-glutamine in swine nutrition and production. J Anim Sci 89:2017–2030

    Article  CAS  Google Scholar 

  • Yang L, Moss T, Mangala LS, Marini J, Zhao H, Wahlig S, Armaiz-Pena G, Jiang D, Achreja A, Win J, Roopaimoole R, Rodriguez-Aguayo C, Mercado-Uribe I, Lopez-Berestein G, Liu J, Tsukamoto T, Sood AK, Ram PT, Nagrath D (2014) Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer. Mol Syst Biol 10:728

    Article  Google Scholar 

  • Yang L, Venneti S, Nagrath D (2017) Glutaminolysis: a hallmark of cancer metabolism. Annu Rev Biomed Eng 19:163–194

    Article  CAS  Google Scholar 

  • Zavy MT, Clark WR, Sharp DC, Roberts RM, Bazer FW (1982) Comparison of glucose, fructose, ascorbic acid and glucosephosphate isomerase enzymatic activity in uterine flushings from nonpregnant and pregnant gilts and pony mares. Biol Reprod 27:1147–1158

    Article  CAS  Google Scholar 

  • Zhu YH, Li TT, Huang SM, Wang W, Dai ZL, Feng CP, Wu G, Wang JJ (2018) Maternal L-glutamine supplementation during late-gestation improves intrauterine growth restriction-induced intestinal dysfunction in piglets. Amino Acids 50:1289–1299

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Work in our laboratories was supported by Agriculture and Food Research Initiative Competitive Grants (No. 2016-67015-24958 and 2018-67015-28093) from the USDA National Institute of Food and Agriculture.

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Correspondence to Heewon Seo .

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Seo, H., Johnson, G.A., Bazer, F.W., Wu, G., McLendon, B.A., Kramer, A.C. (2021). Cell-Specific Expression of Enzymes for Serine Biosynthesis and Glutaminolysis in Farm Animals. In: Wu, G. (eds) Amino Acids in Nutrition and Health. Advances in Experimental Medicine and Biology, vol 1285. Springer, Cham. https://doi.org/10.1007/978-3-030-54462-1_2

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