title: Serine biosynthesis with one carbon catabolism and the glycine cleavage system represents a novel pathway for ATP generation.
abstract: Previous experimental evidence indicates that some cancer cells have an alternative glycolysis pathway with net zero ATP production, implying that upregulation of glycolysis in these cells may not be related to the generation of ATP. Here we use a genome-scale model of human cell metabolism to investigate the potential metabolic alterations in cells using net zero ATP glycolysis. We uncover a novel pathway for ATP generation that involves reactions from serine biosynthesis, one-carbon metabolism and the glycine cleavage system, and show that the pathway is transcriptionally upregulated in an inducible murine model of Myc-driven liver tumorigenesis. This pathway has a predicted two-fold higher flux rate in cells using net zero ATP glycolysis than those using standard glycolysis and generates twice as much ATP with significantly lower rate of lactate - but higher rate of alanine secretion. Thus, in cells using the standard - or the net zero ATP glycolysis pathways a significant portion of the glycolysis flux is always associated with ATP generation, and the ratio between the flux rates of the two pathways determines the rate of ATP generation and lactate and alanine secretion during glycolysis.
authors.affiliation: Division of Bioinformatics and Surveillance, Department of Radiation Oncology, The Cancer Institute of New Jersey and University of Medicine and Dentistry of New Jersey, Robert-Wood Johnson Medical School, New Brunswick, New Jersey, United States of America. vazqueal@umdnj.edu
authors.forename: Alexei
authors.initials: A
authors.lastname: Vazquez
authors.forename: Elke K
authors.initials: EK
authors.lastname: Markert
authors.forename: Zoltán N
authors.initials: ZN
authors.lastname: Oltvai
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis*; D000818:Animals; D002244:Carbon / Q000378:metabolism*; D049109:Cell Proliferation; D005998:Glycine / Q000378:metabolism*; D006019:Glycolysis; D007700:Kinetics; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D012694:Serine / Q000096:biosynthesis*; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: D012694:Serine; D002244:Carbon; D000255:Adenosine Triphosphate; D005998:Glycine
references.citation: Biochem J. 1995 Jun 15;308 ( Pt 3):761-7
references.pmid: 8948430
references.citation: Exp Cell Res. 1959 Jun;17(3):490-8
references.pmid: 13672205
references.citation: Biosci Rep. 1981 Feb;1(2):101-6
references.pmid: 6794659
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 2;105(48):18782-7
references.pmid: 19033189
references.citation: Science. 2010 Sep 17;329(5998):1492-9
references.pmid: 20847263
references.citation: J Physiol. 2008 Jan 1;586(1):35-44
references.pmid: 17901124
references.citation: Nucleic Acids Res. 2005 Jun 10;33(10):3390-400
references.pmid: 15951512
references.citation: PLoS Comput Biol. 2008 Oct;4(10):e1000195
references.pmid: 18846199
references.citation: J Cell Biol. 1966 Jun;29(3):507-23
references.pmid: 5962940
references.citation: Nucleic Acids Res. 2002 Jan 1;30(1):47-9
references.pmid: 11752250
references.citation: Clin Physiol Funct Imaging. 2002 May;22(3):226-32
references.pmid: 12076351
references.citation: Med Sci Sports. 1979 Winter;11(4):338-44
references.pmid: 530025
references.citation: Cancer Res. 2008 Jul 15;68(14):5812-9
references.pmid: 18632635
references.citation: J Appl Physiol (1985). 1992 Nov;73(5):2004-10
references.pmid: 1474078
references.citation: Mol Biosyst. 2007 Sep;3(9):598-603
references.pmid: 17700859
references.citation: J Biol Chem. 1972 Apr 10;247(7):1965-71
references.pmid: 5016638
references.citation: Nature. 2008 Mar 13;452(7184):230-3
references.pmid: 18337823
references.citation: PLoS Biol. 2010 Oct 19;8(10):e1000514
references.pmid: 21049082
references.citation: Proc Natl Acad Sci U S A. 2007 Jul 31;104(31):12663-8
references.pmid: 17652176
references.citation: Cancer Res. 1955 Dec;15(11):715-8
references.pmid: 13270262
references.citation: J Clin Invest. 2008 Dec;118(12):3835-7
references.pmid: 19033652
references.citation: Int J Biochem Cell Biol. 2011 Jul;43(7):969-80
references.pmid: 20156581
references.citation: Breast Cancer Res Treat. 2011 Jan;125(2):421-30
references.pmid: 20352489
references.citation: Nature. 1976 Jun 24;261(5562):702-5
references.pmid: 934318
references.citation: Genome Biol. 2003;4(10):R69
references.pmid: 14519204
references.citation: Proc Natl Acad Sci U S A. 2009 Jun 30;106(26):10632-7
references.pmid: 19520830
references.citation: Proc Natl Acad Sci U S A. 1989 Mar;86(5):1583-7
references.pmid: 2922400
references.citation: Oncogene. 2009 Jul 9;28(27):2485-91
references.pmid: 19448666
references.citation: Science. 2009 May 22;324(5930):1029-33
references.pmid: 19460998
references.citation: Nat Genet. 2011 Jul 31;43(9):869-74
references.pmid: 21804546
references.citation: Biochem J. 1978 Sep 15;174(3):703-9
references.pmid: 310305
references.citation: Proc Natl Acad Sci U S A. 2011 May 24;108(21):8674-9
references.pmid: 21555572
references.citation: Immunity. 2003 Mar;18(3):343-54
references.pmid: 12648452
references.citation: PLoS One. 2011 Apr 29;6(4):e19538
references.pmid: 21559344
references.citation: J Biol Chem. 2004 Dec 31;279(53):55008-16
references.pmid: 15496403
references.citation: J Theor Biol. 1992 Feb 21;154(4):421-54
references.pmid: 1593896
references.citation: Biotechnol Bioeng. 1990 Jun 20;36(2):191-7
references.pmid: 18595067
references.citation: Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
references.pmid: 16199517
references.citation: BMC Syst Biol. 2010 May 06;4:58
references.pmid: 20459610
references.citation: Biotechnol Prog. 2005 Jan-Feb;21(1):112-21
references.pmid: 15903248
references.citation: Wound Repair Regen. 2003 Nov-Dec;11(6):504-9
references.pmid: 14617293
references.citation: Nature. 2011 Aug 18;476(7360):346-50
references.pmid: 21760589
references.citation: Proc Natl Acad Sci U S A. 1983 Jan;80(2):622-6
references.pmid: 6572909
references.citation: BMC Bioinformatics. 2010 Apr 29;11:213
references.pmid: 20426874
references.citation: PLoS Comput Biol. 2011 Mar;7(3):e1002018
references.pmid: 21423717
references.citation: Am J Physiol Lung Cell Mol Physiol. 2010 Oct;299(4):L513-22
references.pmid: 20675437
references.citation: Am J Physiol Endocrinol Metab. 2001 May;280(5):E761-9
references.pmid: 11287359
references.citation: Cell Metab. 2011 Jul 6;14(1):131-42
references.pmid: 21723511
references.citation: J Invest Dermatol. 1993 Jun;100(6):834-40
references.pmid: 8496624
references.citation: Science. 1956 Feb 24;123(3191):309-14
references.pmid: 13298683