GLYCOLYSIS & GLUCONEOGENESIS

Glucose is the major energy source for mammalian cells as well as an important substrate for protein and lipid synthesis. It enters from extracellular fluid into the cell through two distinct families of structurally related glucose transporters. Once in the cells, glucose is transformed through the Glycolysis generic pathway.

Glycolysis

The first step of D-glucose conversion concerns its immediate phosphorylation into α-D-glucose-6-phosphate (G6P) through the hexokinases family: hexokinase 1,2,3 (HK1-3) and glucokinase (hexokinase 4, HK4=GCK). Then α-D-glucose-6-phosphate is further converted to β-D-fructose 6-phosphate by glucose phosphate isomerase (GPI). Phosphofructokinases (PFKs, displaying three main isoforms: muscle (PFKM), platelet (PFKP), liver (PFKL)) attach the second phosphate group to β-D-fructose-6-phosphate generating β-D-fructose 1.6-bisphosphate (F16P2).
Vertebrate aldolases (ALDOs)are ubiquitous enzymes that catalyze the reversible aldol cleavage of β-D-fructose 1.6-bisphosphate to Dihydroxyacetone phosphate (DHAP) and either (D)-Glyceraldehyde 3-phosphate (GAP). Three isozymes, aldolases A,B,C, with different tissue distributions and kinetics exist (ALDOA in muscle and red blood cell, ALDOB in liver, kidney, and small intestine and ALDOC in brain and neuronal tissues). DHAP is further reversibly isomerized to GAP by triosephosphate isomerase (TPI).
(D)-Glyceraldehyde 3-phosphate is metabolized to 1,3-bisphospho-D-glycerate (1.3BPG) by glyceraldehyde-3-phosphate dehydrogenases (GAPDH1,2) enzymes. Phosphoglycerate kinases 1 et 2 (PGKs) catalyze the reversible transfer of a phosphoryl group from 1.3BPG to ADP which results in formation of 3-Phospho-(D)-glyceric acid (3PG). 3PG is enzymatically converted into 2-Phospho-(D)-glyceric acid (2PG) by phosphoglycerate mutase (PGAM) that displays several isoforms (PGAM1 in brain, PGAM2,3 in muscle and a multifunctional enzyme 2,3-Bisphosphoglycerate mutase (BPGM) that converts 1.3BPG into 2,3-Bisphospho-D-glycerate (2.3BPG), one of the major regulator of hemoglobin affinity for oxygen. After water release, catalyzed by different enolases (ENOs, ubiquitarious α-ENO=ENO1, muscle β-ENO=ENO3, neuronal ϒ-ENO=ENO2), phosphoenolpyruvate (PEP) is formed. Then PEP is converted to pyruvic acid, the end product of glycolysis, by pyruvate kinase (PKLR in liver and RBC and PKM in muscle).

Pyruvic acid can then be either transformed into lactate through enzymatic action of lactic acid dehydrogenases (LDH, LDHA in muscle, LDHB in heart, LDHC in germ cells) or into acetyl-coA by pyruvate dehydrogenase (PDH) that can be the major substrate of the tricarboxylic acid cycle in mitochondria.

glycolysis-off

Gluconeogenesis

Pyruvic acid can also be the initial substrate of the glycolysis reverse reaction, namely Gluconeogenesis (often associated with Ketosis) that plays a crucial role in maintaining glucose homeostasis. Pyruvate carboxylase (PC) converts pyruvic acid to 2-oxo-succinic (oxaloacetic) acid that is reversibly reduced by malate dehydrogenases (MDHs, cytosolic MDH1 and mitochondrial MDH2) to malic acid and is metabolized back to PEP by phosphoenolpyruvate carboxykinase (PCKs, cytosolic PCK1 and mitochondrial PCK2). The next steps in the reaction are the same as reversed glycolysis. However, two fructose-1,6-bisphosphatases (FBPs, FBP1, FBP2) are able to convert fructose-1,6-bisphosphate to fructose 6-phosphate, requiring one water molecule and releasing one phosphate. This is also the rate-limiting step of gluconeogenesis. G6P is further translocated from the cytoplasm into the lumen of the endoplasmic reticulum where glucose-6-phosphatase (G6PT) hydrolyses G6P into D-Glucose and phosphate.