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 , .
The first step of D-Glucose conversion is its immediate
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 crucial role in maintaining
D-Glucose homeostasis. Solute carrier family 37
(glucose-6-phosphate transporter), member 4 (G6PT1)
from the cytoplasm into the lumen of the endoplasmic reticulum ,  where Glucose-6-phosphatase, catalytic subunit
(G6PT) hydrolyses the
into D-Glucose and phosphate , .
is further converted to Beta-D-Fructose
6-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-phosphate resulting in formation of Beta-D-Fructose
1,6-bisphosphate , , .
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 , .
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
, , . Dihydroxyacetone
phosphate is further reversibly isomerized to
(D)-Glyceraldehyde 3-phosphate by Triosephosphate isomerase
1 (TPI1) , .
(D)-Glyceraldehyde 3-phosphate is metabolized to
3-Phospho-(D)-glyceroyl phosphate by
glyceraldehyde-3-phosphate dehydrogenases (G3P1, G3P2, G3PT)
, , . 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 , , .
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) , , , , . After releasing water, catalyzed by Enolase 1,
(alpha), (ENO1), Enolase 3 (beta, muscle) (ENO3), Enolase 2
(gamma, neuronal) (ENO2)
Phosphoenolpyruvate is formed , , . Then it is converted to Pyruvic
acid by Pyruvate kinase, liver and RBC
(KPYR) ,  and
Pyruvate kinase, muscle (PKM2)
Pyruvate carboxylase (PYC) converts Pyruvic
acid to 2-Oxo-succinic acid ,  that is reversibly reduced by Malate dehydrogenase 1, NAD (soluble)
(MDH1) and Malate dehydrogenase 2, NAD
(mitochondrial) (MDH2) to
(S)-Malic acid , , , and is metabolized back to
Phosphoenolpyruvate by Phosphoenolpyruvate carboxykinase 2
(mitochondrial) (PPCKM) , 
and Phosphoenolpyruvate carboxykinase 1 (soluble) (PPCKC)
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