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 , . The first step of D-Glucose conversion is its immediate phosphorylation toalpha - D-Glucose-6-phosphate by the family of hexokinases: Hexokinase 1 (HXK1) , , Hexokinase 2(HXK2) , , Hexokinase 3 ( HXK3) , , and Glucokinase (hexokinase 4) HXK4 ,. 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 ,  where Glucose-6-phosphatase, catalyticsubunit ( G6PT ) hydrolyses the alpha - D-Glucose-6-phosphate intoD-Glucose and phosphate , . Alpha - D-Glucose-6-phosphate is further converted to Beta-D-Fructose6-phosphate by Glucose phosphate isomerase ( GPI ) , , . 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 , , . 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 , . 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 , , . Dihydroxyacetonephosphate is further reversibly isomerized to (D)-Glyceraldehyde 3-phosphateby Triosephosphate isomerase 1 ( TPI1 ) , . (D)-Glyceraldehyde 3-phosphate is metabolized to 3-Phospho-(D)-glyceroylphosphate by glyceraldehyde-3-phosphate dehydrogenases ( G3P1, G3P2, G3PT ), , . 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 , ,. 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 ) , ,, , . After releasing water, catalyzed byEnolase 1, (alpha), ( ENO1 ), Enolase 3 (beta, muscle) (ENO3), Enolase 2 (gamma,neuronal) ( ENO2 ) Phosphoenolpyruvate is formed , , . Then it is converted to Pyruvic acid by Pyruvatekinase, liver and RBC ( KPYR ) ,  and Pyruvatekinase, muscle ( PKM2 ) , . Pyruvate carboxylase ( PYC ) converts Pyruvic acid to 2-Oxo-succinicacid ,  that is reversibly reduced by Malatedehydrogenase 1, NAD (soluble) ( MDH1 ) and Malate dehydrogenase 2, NAD(mitochondrial) ( MDH2 ) to (S)-Malic acid , , , and is metabolized back toPhosphoenolpyruvate by Phosphoenolpyruvate carboxykinase 2 (mitochondrial) (PPCKM ) ,  and Phosphoenolpyruvate carboxykinase 1(soluble) ( PPCKC ) , .