Glycolysis and gluconeogenesis (short map)
D-Glucose is the major energy source for mammalian cells
as well as an important substrate for protein and lipid synthesis. Mammalian cells take
up D-Glucose from extracellular fluid into the cell through
two families of structurally related glucose transporters. Solute carrier family 2
(facilitated glucose transporter), member 4 (GLUT4) is one
such transporters. It mediates bidirectional and energy-independent process of glucose
transport in most tissues and cells [1], [2].
The first step of D-Glucose conversion is its immediate
phosphorylation to
alpha-D-Glucose-6-phosphate by
the family of hexokinases: Hexokinase 1 (HXK1) [3], [4], [5], Hexokinase 2 (HXK2)
[3], [6], Hexokinase 3 (HXK3)
[3], [7], and Glucokinase (hexokinase 4)
HXK4 [3], [8]. The reverse reaction
takes place in gluconeogenesis and plays a crucial role in maintaining
D-Glucose homeostasis. Solute carrier family 37
(glucose-6-phosphate transporter), member 4 (G6PT1)
translocates
alpha-D-Glucose-6-phosphate
from the cytoplasm into the lumen of the endoplasmic reticulum [9], [10] where Glucose-6-phosphatase, catalytic subunit
(G6PT) hydrolyses the
alpha-D-Glucose-6-phosphate
into D-Glucose and phosphate [10], [11].
Alpha-D-Glucose-6-phosphate
is further converted to Beta-D-Fructose
6-phosphate by Glucose phosphate isomerase
(GPI) [12], [13], [14].
Then, phosphofructokinases (Phosphofructokinase, muscle -
PFKM, Phosphofructokinase, platelet -
PFKP, Phosphofructokinase, liver -
PFKL) attach the second phosphate group to Beta-D-Fructose
6-phosphate resulting in formation of Beta-D-Fructose
1,6-bisphosphate [15], [16], [17].
Beta-D-Fructose 1,6-bisphosphate is further hydrolyzed by
important gluconeogenic enzymes Fructose-1,6-bisphosphatase 1 (F16P)
and Fructose-1,6-bisphosphatase 2 (F16Q) to
Beta-D-Fructose 6-phosphate and phosphate [18], [19].
Vertebrate aldolases exist as three isozymes with different tissue distributions and
kinetics: Aldolase A, fructose-bisphosphate (ALDOA) (muscle
and red blood cell), Aldolase B, fructose-bisphosphate
(ALDOB) (liver, kidney, and small intestine), and Aldolase C
fructose-bisphosphate (ALDOC) (brain and neuronal tissue).
These are ubiquitous enzymes that catalyze the reversible aldol cleavage of
Beta-D-Fructose 1,6-bisphosphate (and also
D-Fructose-1-phosphate) to Dihydroxyacetone
phosphate and either (D)-Glyceraldehyde
3-phosphate or Glyceraldehyde, respectively
[20], [21], [22]. Dihydroxyacetone
phosphate is further reversibly isomerized to
(D)-Glyceraldehyde 3-phosphate by Triosephosphate isomerase
1 (TPI1) [23], [24].
(D)-Glyceraldehyde 3-phosphate is metabolized to
3-Phospho-(D)-glyceroyl phosphate by
glyceraldehyde-3-phosphate dehydrogenases (G3P1, G3P2, G3PT)
[25], [26], [27]. Enzymes Phosphoglycerate kinase 1
(PGK1), Phosphoglycerate kinase 2
(PGK2) catalyze the reversible transfer of a phosphoryl
group from 3-Phospho-(D)-glyceroyl phosphate to
ADP which results in formation of D-Glycerate
3-phosphate [28], [29], [30].
D-Glycerate 3-phosphate is enzymatically converted into
2-Phospho-(D)-glyceric acid by phosphoglycerate mutase that
has several isoforms: Phosphoglycerate mutase 1 (brain) -
PGAM1, Phosphoglycerate mutase 2 (muscle) -
PGAM2, Phosphoglycerate mutase family 3 - PGAM3,
and by a multifunctional enzyme 2,3-Bisphosphoglycerate mutase
(PMGE) [31], [32], [33], [34], [35]. After releasing water, catalyzed by Enolase 1,
(alpha), (ENO1), Enolase 3 (beta, muscle) (ENO3), Enolase 2
(gamma, neuronal) (ENO2)
Phosphoenolpyruvate is formed [36], [37], [38]. Then it is converted to Pyruvic
acid by Pyruvate kinase, liver and RBC
(KPYR) [39], [40] and
Pyruvate kinase, muscle (PKM2)
[41], [42].
Pyruvate carboxylase (PYC) converts Pyruvic
acid to 2-Oxo-succinic acid [43], [44] that is reversibly reduced by Malate dehydrogenase 1, NAD (soluble)
(MDH1) and Malate dehydrogenase 2, NAD
(mitochondrial) (MDH2) to
(S)-Malic acid [45], [46], [47], [48]and is metabolized back to
Phosphoenolpyruvate by Phosphoenolpyruvate carboxykinase 2
(mitochondrial) (PPCKM) [49], [50]
and Phosphoenolpyruvate carboxykinase 1 (soluble) (PPCKC)
[51], [52].
References:
- Wood IS, Trayhurn P
Glucose transporters (GLUT and SGLT): expanded families of sugar transport proteins.
The British journal of nutrition 2003 Jan;89(1):3-9
- Zhao FQ, Keating AF
Functional properties and genomics of glucose transporters.
Current genomics 2007 Apr;8(2):113-28
- Lowes W, Walker M, Alberti KG, Agius L
Hexokinase isoenzymes in normal and cirrhotic human liver: suppression of glucokinase in cirrhosis.
Biochimica et biophysica acta 1998 Jan 8;1379(1):134-42
- Aleshin AE, Zeng C, Bourenkov GP, Bartunik HD, Fromm HJ, Honzatko RB
The mechanism of regulation of hexokinase: new insights from the crystal structure of recombinant human brain hexokinase complexed with glucose and glucose-6-phosphate.
Structure (London, England : 1993) 1998 Jan 15;6(1):39-50
- Aleshin AE, Zeng C, Bartunik HD, Fromm HJ, Honzatko RB
Regulation of hexokinase I: crystal structure of recombinant human brain hexokinase complexed with glucose and phosphate.
Journal of molecular biology 1998 Sep 18;282(2):345-57
- Vestergaard H, Bj?rbaek C, Hansen T, Larsen FS, Granner DK, Pedersen O
Impaired activity and gene expression of hexokinase II in muscle from non-insulin-dependent diabetes mellitus patients.
The Journal of clinical investigation 1995 Dec;96(6):2639-45
- Sebastian S, Edassery S, Wilson JE
The human gene for the type III isozyme of hexokinase: structure, basal promoter, and evolution.
Archives of biochemistry and biophysics 2001 Nov 1;395(1):113-20
- Takeda J, Gidh-Jain M, Xu LZ, Froguel P, Velho G, Vaxillaire M, Cohen D, Shimada F, Makino H, Nishi S
Structure/function studies of human beta-cell glucokinase. Enzymatic properties of a sequence polymorphism, mutations associated with diabetes, and other site-directed mutants.
The Journal of biological chemistry 1993 Jul 15;268(20):15200-4
- Labrune P
Glycogen storage disease type I: indications for liver and/or kidney transplantation.
European journal of pediatrics 2002 Oct;161 Suppl 1:S53-5
- Han SH, Ki CS, Lee JE, Hong YJ, Son BK, Lee KH, Choe YH, Lee SY, Kim JW
A novel mutation (A148V) in the glucose 6-phosphate translocase (SLC37A4) gene in a Korean patient with glycogen storage disease type 1b.
Journal of Korean medical science 2005 Jun;20(3):499-501
- Bandsma RH, Smit GP, Kuipers F
Disturbed lipid metabolism in glycogen storage disease type 1.
European journal of pediatrics 2002 Oct;161 Suppl 1:S65-9
- Davies C, Muirhead H, Chirgwin J
The structure of human phosphoglucose isomerase complexed with a transition-state analogue.
Acta crystallographica. Section D, Biological crystallography 2003 Jun;59(Pt 6):1111-3
- Cakir T, Tacer CS, Ulgen KO
Metabolic pathway analysis of enzyme-deficient human red blood cells.
Bio Systems 2004 Dec;78(1-3):49-67
- Funasaka T, Yanagawa T, Hogan V, Raz A
Regulation of phosphoglucose isomerase/autocrine motility factor expression by hypoxia.
The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2005 Sep;19(11):1422-30
- Levanon D, Danciger E, Dafni N, Bernstein Y, Elson A, Moens W, Brandeis M, Groner Y
The primary structure of human liver type phosphofructokinase and its comparison with other types of PFK.
DNA (Mary Ann Liebert, Inc.) 1989 Dec;8(10):733-43
- Sakakibara R, Okudaira T, Fujiwara K, Kato M, Hirata T, Yamanaka S, Naito M, Fukasawa M
Tissue distribution of placenta-type 6-phosphofructo- 2-kinase/fructose-2,6-bisphosphatase.
Biochemical and biophysical research communications 1999 Apr 2;257(1):177-81
- Hannemann A, Jandrig B, Gaunitz F, Eschrich K, Bigl M
Characterization of the human P-type 6-phosphofructo-1-kinase gene promoter in neural cell lines.
Gene 2005 Jan 31;345(2):237-47
- Tillmann H, Stein S, Liehr T, Eschrich K
Structure and chromosomal localization of the human and mouse muscle fructose-1,6-bisphosphatase genes.
Gene 2000 Apr 18;247(1-2):241-53
- Herzog B, Waltner-Law M, Scott DK, Eschrich K, Granner DK
Characterization of the human liver fructose-1,6-bisphosphatase gene promoter.
The Biochemical journal 2000 Oct 15;351 Pt 2:385-92
- Yao DC, Tolan DR, Murray MF, Harris DJ, Darras BT, Geva A, Neufeld EJ
Hemolytic anemia and severe rhabdomyolysis caused by compound heterozygous mutations of the gene for erythrocyte/muscle isozyme of aldolase, ALDOA(Arg303X/Cys338Tyr).
Blood 2004 Mar 15;103(6):2401-3
- Esposito G, Santamaria R, Vitagliano L, Ieno L, Viola A, Fiori L, Parenti G, Zancan L, Zagari A, Salvatore F
Six novel alleles identified in Italian hereditary fructose intolerance patients enlarge the mutation spectrum of the aldolase B gene.
Human mutation 2004 Dec;24(6):534
- Arakaki TL, Pezza JA, Cronin MA, Hopkins CE, Zimmer DB, Tolan DR, Allen KN
Structure of human brain fructose 1,6-(bis)phosphate aldolase: linking isozyme structure with function.
Protein science : a publication of the Protein Society 2004 Dec;13(12):3077-84
- Olah J, Orosz F, Keseru GM, Kovari Z, Kovacs J, Hollan S, Ovadi J
Triosephosphate isomerase deficiency: a neurodegenerative misfolding disease.
Biochemical Society transactions 2002 Apr;30(2):30-8
- Guallar V, Jacobson M, McDermott A, Friesner RA
Computational modeling of the catalytic reaction in triosephosphate isomerase.
Journal of molecular biology 2004 Mar 12;337(1):227-39
- Mercer WD, Winn SI, Watson HC
Twinning in crystals of human skeletal muscle D-glyceraldehyde-3-phosphate dehydrogenase.
Journal of molecular biology 1976 Jun 14;104(1):277-83
- Welch JE, Brown PL, O'Brien DA, Magyar PL, Bunch DO, Mori C, Eddy EM
Human glyceraldehyde 3-phosphate dehydrogenase-2 gene is expressed specifically in spermatogenic cells.
Journal of andrology 2000 Mar-Apr;21(2):328-38
- Yamaji R, Chatani E, Harada N, Sugimoto K, Inui H, Nakano Y
Glyceraldehyde-3-phosphate dehydrogenase in the extracellular space inhibits cell spreading.
Biochimica et biophysica acta 2005 Nov 30;1726(3):261-71
- McCarrey JR, Thomas K
Human testis-specific PGK gene lacks introns and possesses characteristics of a processed gene.
Nature 1987 Apr 2-8;326(6112):501-5
- Huang IY, Welch CD, Yoshida A
Complete amino acid sequence of human phosphoglycerate kinase. Cyanogen bromide peptides and complete amino acid sequence.
The Journal of biological chemistry 1980 Jul 10;255(13):6412-20
- Shetty S, Ganachari M, Liu MC, Azghani A, Muniyappa H, Idell S
Regulation of urokinase receptor expression by phosphoglycerate kinase is independent of its catalytic activity.
American journal of physiology. Lung cellular and molecular physiology 2005 Oct;289(4):L591-8
- Joulin V, Garel MC, Le Boulch P, Valentin C, Rosa R, Rosa J, Cohen-Solal M
Isolation and characterization of the human 2,3-bisphosphoglycerate mutase gene.
The Journal of biological chemistry 1988 Oct 25;263(30):15785-90
- Fokina KV, Dainyak MB, Nagradova NK, Muronetz VI
A study on the complexes between human erythrocyte enzymes participating in the conversions of 1,3-diphosphoglycerate.
Archives of biochemistry and biophysics 1997 Sep 15;345(2):185-92
- Hadjigeorgiou GM, Kawashima N, Bruno C, Andreu AL, Sue CM, Rigden DJ, Kawashima A, Shanske S, DiMauro S
Manifesting heterozygotes in a Japanese family with a novel mutation in the muscle-specific phosphoglycerate mutase (PGAM-M) gene.
Neuromuscular disorders : NMD 1999 Oct;9(6-7):399-402
- Betran E, Wang W, Jin L, Long M
Evolution of the phosphoglycerate mutase processed gene in human and chimpanzee revealing the origin of a new primate gene.
Molecular biology and evolution 2002 May;19(5):654-63
- Repiso A, Perez de la Ossa P, Aviles X, Oliva B, Junca J, Oliva R, Garcia E, Vives-Corrons JL, Carreras J, Climent F
Red blood cell phosphosphoglycerate mutase. Description of the first human BB isoenzyme mutation.
Haematologica 2003 Mar;88(3):ECR07
- Wevers RA, Jacobs AA, Hommes OR
A bioluminescent assay for enolase (EC 4.2.1.11) activity in human serum and cerebrospinal fluid.
Clinica chimica acta; international journal of clinical chemistry 1983 Dec 15;135(2):159-68
- Verma M, Kurl RN
Human lung enolase: cloning and sequencing of cDNA and its inducibility with dexamethasone.
Biochemistry and molecular biology international 1993 Jun;30(2):293-303
- Bonner JA, Sloan JA, Rowland KM Jr, Klee GG, Kugler JW, Mailliard JA, Wiesenfeld M, Krook JE, Maksymiuk AW, Shaw EG, Marks RS, Perez EA
Significance of neuron-specific enolase levels before and during therapy for small cell lung cancer.
Clinical cancer research : an official journal of the American Association for Cancer Research 2000 Feb;6(2):597-601
- Tani K, Fujii H, Nagata S, Miwa S
Human liver type pyruvate kinase: complete amino acid sequence and the expression in mammalian cells.
Proceedings of the National Academy of Sciences of the United States of America 1988 Mar;85(6):1792-5
- Zanella A, Fermo E, Bianchi P, Valentini G
Red cell pyruvate kinase deficiency: molecular and clinical aspects.
British journal of haematology 2005 Jul;130(1):11-25
- Takenaka M, Noguchi T, Sadahiro S, Hirai H, Yamada K, Matsuda T, Imai E, Tanaka T
Isolation and characterization of the human pyruvate kinase M gene.
European journal of biochemistry / FEBS 1991 May 23;198(1):101-6
- Dombrauckas JD, Santarsiero BD, Mesecar AD
Structural basis for tumor pyruvate kinase M2 allosteric regulation and catalysis.
Biochemistry 2005 Jul 12;44(27):9417-29
- Scrutton MC, White MD
Prufication and properties of human liver pyruvate carboxylase.
Biochemical medicine 1974 Mar;9(3):217-92
- Jitrapakdee S, Walker ME, Wallace JC
Functional expression, purification, and characterization of recombinant human pyruvate carboxylase.
Biochemical and biophysical research communications 1999 Dec 20;266(2):512-7
- Mazo A, Forner A, Domenech C, Busquets M, Gelpi JL, Cortes A
Comparative analysis of the reduction of oxaloacetate by human hepatoma and normal liver extracts.
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 1990;11(3):120-8
- Fernandez CA, Des Rosiers C
Modeling of liver citric acid cycle and gluconeogenesis based on 13C mass isotopomer distribution analysis of intermediates.
The Journal of biological chemistry 1995 Apr 28;270(17):10037-42
- Sugiuchi H, Uji Y, Shirahase Y, Okabe H
A novel automated assay for malate dehydrogenase isoenzymes.
Journal of clinical laboratory analysis 1996;10(2):78-84
- Lo AS, Liew CT, Law PT, Garcia-Barcelo M, Tsui SK, Fung KP, Lee CY, Waye MM
Radiation hybrid mapping of human cytosolic malate dehydrogenase (hcMDH) to the short arm of chromosome 2.
Somatic cell and molecular genetics 1999 Mar;25(2):109-13
- Modaressi S, Brechtel K, Christ B, Jungermann K
Human mitochondrial phosphoenolpyruvate carboxykinase 2 gene. Structure, chromosomal localization and tissue-specific expression.
The Biochemical journal 1998 Jul 15;333 ( Pt 2):359-66
- Suzuki M, Yamasaki T, Shinohata R, Hata M, Nakajima H, Kono N
Cloning and reporter analysis of human mitochondrial phosphoenolpyruvate carboxykinase gene promoter.
Gene 2004 Sep 1;338(2):157-62
- Ting CN, Burgess DL, Chamberlain JS, Keith TP, Falls K, Meisler MH
Phosphoenolpyruvate carboxykinase (GTP): characterization of the human PCK1 gene and localization distal to MODY on chromosome 20.
Genomics 1993 Jun;16(3):698-706
- O'Brien RM, Printz RL, Halmi N, Tiesinga JJ, Granner DK
Structural and functional analysis of the human phosphoenolpyruvate carboxykinase gene promoter.
Biochimica et biophysica acta 1995 Dec 27;1264(3):284-8