Glycolysis and gluconeogenesis (short map)
Glycolysis and gluconeogenesis (short map)
D-Glucose is the major energy source for mammalian cells as well as animportant substrate for protein and lipid synthesis. Mammalian cells take upD-Glucose from extracellular fluid into the cell through two families ofstructurally related glucose transporters. Solute carrier family 2 (facilitated glucosetransporter), member 4 ( GLUT4 ) is one such transporters. It mediatesbidirectional and energy-independent process of glucose transport in most tissues andcells [1], [2].
The first step of D-Glucose conversion is its immediate phosphorylation toalpha - D-Glucose-6-phosphate by the family of hexokinases: Hexokinase 1 (HXK1) [3], [4], Hexokinase 2(HXK2) [5], [6], Hexokinase 3 ( HXK3) [7], [6], and Glucokinase (hexokinase 4) HXK4 [8],[6]. The reverse reaction takes place in gluconeogenesis and plays a crucialrole 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 endoplasmicreticulum [9], [10] where Glucose-6-phosphatase, catalyticsubunit ( G6PT ) hydrolyses the alpha - D-Glucose-6-phosphate intoD-Glucose and phosphate [11], [10].
Alpha - D-Glucose-6-phosphate is further converted to Beta-D-Fructose6-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-phosphateresulting in formation of Beta-D-Fructose 1,6-bisphosphate [15], [16], [17]. Beta-D-Fructose 1,6-bisphosphate is furtherhydrolyzed by important gluconeogenic enzymes Fructose-1,6-bisphosphatase 1 (F16P) and Fructose-1,6-bisphosphatase 2 ( F16Q ) to Beta-D-Fructose6-phosphate and phosphate [18], [19].
Vertebrate aldolases exist as three isozymes with different tissue distributions andkinetics: 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). Theseare ubiquitous enzymes that catalyze the reversible aldol cleavage of Beta-D-Fructose1,6-bisphosphate (and also D-Fructose-1-phosphate ) to Dihydroxyacetonephosphate and either (D)-Glyceraldehyde 3-phosphate or Glyceraldehyde,respectively [20], [21], [22]. Dihydroxyacetonephosphate is further reversibly isomerized to (D)-Glyceraldehyde 3-phosphateby Triosephosphate isomerase 1 ( TPI1 ) [23], [24].
(D)-Glyceraldehyde 3-phosphate is metabolized to 3-Phospho-(D)-glyceroylphosphate by glyceraldehyde-3-phosphate dehydrogenases ( G3P1, G3P2, G3PT )[25], [26], [27]. Enzymes Phosphoglycerate kinase 1 (PGK1 ), Phosphoglycerate kinase 2 ( PGK2 ) catalyze the reversible transferof a phosphoryl group from 3-Phospho-(D)-glyceroyl phosphate to ADP whichresults in formation of D-Glycerate 3-phosphate [28], [29],[30]. D-Glycerate 3-phosphate is enzymatically converted into2-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 multifunctionalenzyme 2,3-Bisphosphoglycerate mutase ( PMGE ) [31], [32],[33], [34], [35]. After releasing water, catalyzed byEnolase 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 Pyruvatekinase, liver and RBC ( KPYR ) [39], [40] and Pyruvatekinase, muscle ( PKM2 ) [41], [42].
Pyruvate carboxylase ( PYC ) converts Pyruvic acid to 2-Oxo-succinicacid [43], [44] that is reversibly reduced by Malatedehydrogenase 1, NAD (soluble) ( MDH1 ) and Malate dehydrogenase 2, NAD(mitochondrial) ( MDH2 ) to (S)-Malic acid [45], [46], [47], [48]and is metabolized back toPhosphoenolpyruvate by Phosphoenolpyruvate carboxykinase 2 (mitochondrial) (PPCKM ) [49], [50] and Phosphoenolpyruvate carboxykinase 1(soluble) ( PPCKC ) [51], [52].
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