The overall equation for glycolysis from glucose to lactate is as follows:

Glucose + 2 ADP + 2 P_i → 2 Lactate + 2 ATP + 2 H₂O

All of the enzymes of glycolysis (Figure 1) are cytosolic. The general mechanism for the generation of ATP during glycolysis rearranges a phosphorylated monosaccharide glucose-6-phosphate to phosphorylated compounds with a high potential to transfer their phosphate groups. These triosephosphates transfer their phosphate to ADP to form ATP. This process is called substrate-level phosphorylation, as the phosphate is directly donated to ATP from an intermediate in the pathway. This pathway uses ADP and produces ATP. As ADP is limiting, it is required that the generated ATP be used to perform some metabolic work to regenerate the ADP to sustain glycolysis.

Fig1. The pathway of glycolysis. Ⓟ, —PO₃^2–; P_i , HOPO₃^2–; ⊖, inhibition.) Carbons 1–3 of fructose bisphosphate form dihydroxy acetone phosphate, and carbons 4–6 form glyceraldehyde-3-phosphate. Glucose-6-phosphatase is expressed only in the liver, kidney, and pancreatic islet; it is not expressed in other tissues.

After being transported across the plasma membrane by facilitated glucose transporters glucose enters glycolysis by phosphorylation to glucose-6-phosphate, catalyzed by hexokinase, using ATP as the phosphate donor. Under physiologic conditions, the phosphorylation of glucose to glucose 6-phosphate can be regarded as irreversible. Hexokinase is inhibited allosterically by its product, glucose-6-phosphate.

In muscle and adipose tissue, the transport of glucose is stimulated by insulin. In muscle glucose is used for glycolysis (or glycogen synthesis). In adipose tissue, it is used for lipogenesis . The hexokinase expressed in most tissues has a high affinity (low K_m ) for glucose and is allosterically inhibited by its product glucose 6-phosphate. When transport activity is low, transport acts as a barrier to glucose uptake. Thus transport activity is an important determinant of the overall rate of glycolysis. The combined effect of a low transport activity and the high affinity of hexokinase for glucose keeps the intracellular glucose very low. Thus, the concentration of plasma glucose and the cellular ATP demand are the primary determinants of glycolysis in an aerobic environment. In the presence of insulin transport activity increases, thus lowering the barrier to glucose entry. If, for example, transport activity increased 10-fold glycolysis will not increase 10-fold because the consequent increase in glucose-6-phosphate would serve as a brake on hexokinase to limit the overall rate of glycolysis. This effectively shifts the control of glycolysis to pathways (eg, pyruvate oxidation) downstream of hexokinase. In muscle, hexokinase is found bound to the outer mitochondrial membrane. As hexokinase requires ATP, it creates a coupling between hexokinase activity and mitochondrial ATP generation.

In the liver transport activity is not regulated and a different isozyme of hexokinase is expressed (glucokinase). Glucokinase has a Km higher than the normal plasma concentration of glucose and it is not inhibited by its product glucose-6-phosphate. Because of the relatively high constitutive glucose transport activity and the low affinity of glucokinase for glucose, the intracellular glucose in the liver is very similar to plasma glucose. The liver can be both a consumer and producer of glucose (feasting vs fasting). In contrast to most tissues the liver also expresses glucose 6-phosphatase, which allows the liver in the fasting state to dephosphorylate glucose-6-phosphate generated by the liver and release glucose. In the fed state the function of glucokinase in the liver is to remove glucose from the hepatic portal blood following a meal; this limits the quantity of glucose available to peripheral tissues. Glucokinase in the fasted setting is found inactive in the nucleus bound to a glucokinase regulatory protein. In response to signals during a meal it leaves the nucleus and resides in the cytosol where it is active. Because of the high capacity of glucokinase to phosphorylate glucose and the increase in glucose in the portal vein during a meal, it provides more glucose-6-phosphate than is required for liver glucose oxidation, thus a large fraction is used for glycogen synthesis and a smaller amount is used for lipogenesis.

Glucokinase is also found in pancreatic islet β cells, where it functions to detect changes in concentrations of glucose in the systemic circulation. When glucose is increased more glucose is phosphorylated by glucokinase, increasing glycolysis, and leading to increased formation of ATP. The increase in ATP leads to closure of an ATP sensitive potassium channel, causing membrane depolarization and opening of a voltage gated calcium channel. The resultant influx of calcium ions leads to fusion of the insulin secretory granules with the cell membrane and the release of insulin.

Glucose-6-phosphate is an important compound at the junction of several metabolic pathways: glycolysis, gluconeogenesis, the pentose phosphate pathway, glycogenesis, and glycogenolysis. In glycolysis, it is converted to fructose-6-phosphate by phosphohexose isomerase, which involves an aldose–ketose isomerization. This reaction is followed by another phosphorylation catalyzed by the enzyme phosphofructokinase (phosphofructokinase-1) forming fructose 1,6-bisphosphate. The phosphofructokinase reaction is irreversible under physiologic conditions. Phosphofructokinase is both inducible and subject to allosteric regulation, and has a major role in regulating the rate of glycolysis. Note up to this point in the path way no ATP is generated; ATP is only being consumed. Fructose 1,6-bisphosphate is cleaved byaldolase(fructose 1,6-bisphosphate aldolase) into two triose phosphates, glyceraldehyde-3-phosphate and dihydroxyacetone phosphate, which are interconverted by the enzyme phosphotriose isomerase.

Glycolysis continues with the oxidation of glyceraldehyde 3-phosphate to 1,3-bisphosphoglycerate and the formation of NADH. The enzyme catalyzing this oxidation, glyceraldehyde 3-phosphate dehydrogenase, is NAD dependent. Structurally, it consists of four identical polypeptides (monomers) forming a tetramer. Four —SH groups are present on each polypeptide, derived from cysteine residues within the poly peptide chain. One of the —SH groups is found at the active site of the enzyme (Figure 2). The substrate initially com bines with this —SH group, forming a thiohemiacetal that is oxidized to a thiol ester; the hydrogens removed in this oxidation are transferred to NAD+. The thiol ester then undergoes phosphorolysis; inorganic phosphate (Pi) is added, forming 1,3-bisphosphoglycerate and the free —SH group.

Fig2. Mechanism of oxidation of glyceraldehyde-3-phosphate.(Enz, glyceraldehyde-3-phosphate dehydrogenase.) The enzyme is inhibited by the —SH poison iodoacetate, which is thus able to inhibit glycolysis. The NADH produced on the enzyme is not so firmly bound to the enzyme as is NAD+. Consequently, NADH is easily displaced by another molecule of NAD+.

In the next reaction, catalyzed by phosphoglycerate kinase, phosphate is transferred from 1,3-bisphosphoglycerate onto ADP, forming ATP (substrate-level phosphorylation) and 3-phosphoglycerate. Since two molecules of triose phosphate are formed per molecule of glucose metabolized, 2× ATP are formed in this reaction per molecule of glucose undergoing glycolysis. The toxicity of arsenic is the result of competition of arsenate with inorganic phosphate (Pi ) forming 1-arseno 3-phosphoglycerate, which undergoes spontaneous hydrolysis to 3-phosphoglycerate without forming ATP. 3-Phosphoglycerate is isomerized to 2-phosphoglycerate byphosphoglycerate mutase. It is likely that 2,3-bisphosphoglycerate (diphosphoglycerate, DPG) is an intermediate in this reaction.

Enolase catalyzes the next step. It involves dehydration, forming phosphoenolpyruvate. Enolase is inhibited by fluoride. When blood samples are taken for measurement of glucose, the sample is placed into tubes containing fluoride to inhibit glycolysis and prevent the breakdown of the glucose until the sample is analyzed. Enolase is also dependent on the presence of either Mg²⁺ or Mn²⁺ ions.

The phosphate of phosphoenolpyruvate is transferred to ADP in another substrate-level phosphorylation catalyzed by pyruvate kinase to form 2× ATP per molecule of glucose oxidized. The reaction of pyruvate kinase is essentially irreversible under physiologic conditions, partly because of the large free-energy change involved and partly because the immediate product of the enzyme-catalyzed reaction is enolpyruvate, which undergoes spontaneous isomerization to pyruvate, so that the product of the reaction is not available to undergo the reverse reaction.

The availability of oxygen determines which of the two path ways pyruvate follows. Underanaerobic conditions, the NADH cannot be reoxidized through the respiratory chain, and pyruvate is reduced to lactate catalyzed by lactate dehydrogenase. This permits the oxidization of NADH to form NAD permit ting another molecule of glucose to undergo glycolysis. Under aerobic conditions, pyruvate is transported into the mitochondria and undergoes oxidative decarboxylation to acetyl-CoA then oxidation to CO2 in the citric acid cycle. The reducing equivalents from the NADH formed in glycolysis are taken up into mitochondria for oxidation via either the malate-aspartate shuttle or the glycerophosphate shuttle .

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مواضيع ذات صلة

Cyclic AMP Integrates The Regulation of Glycogenolysis & Glycogenesis

Glycogenolysis is not the Reverse of Glycogenesis, it is A Separate Pathway

Glycogenesis Occurs Mainly in Muscle & Liver

The Oxidation of Pyruvate to Acetyl-COA is The Irreversible Route from Glycolysis to The Citric Acid Cycle

Glycolysis is Regulated at Three Nonequilibrium Reactions

Tissues That Function Under Hypoxic Conditions or have Intrinsically High Rates of Glucose Oxidation Produce Lactate

Glycolysis Can Function Under Anaerobic Conditions

Regulation of the Citric Acid Cycle Depends Primarily on a Supply of Oxidized Cofactors

The Citric Acid Cycle Takes Part in Fatty Acid Synthesis

The Citric Acid Cycle Takes Part in Gluconeogenesis, Transamination, & Deamination

Reactions of The Citric Acid Cycle Generate Reducing Equivalents & CO2

The Citric Acid Cycle Provides Substrates for The Respiratory Chain