# 6.3: Some details of glycolysis (2023)

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## A. Glycolysis, Stage 1

Reaction 1:In the first reaction of glycolysis, the enzymeHexoquinaserapidly phosphorylates glucose entering the cell and formsGlucose-6-phosphat(G-6-P). As shown below is the overall responseexergonic; Öfree energy exchangefor the reaction is -4 Kcal per mole of G-6-P synthesized.

That is acoupled reaction, in whichphosphorylationGlucose is coupled to ATP hydrolysis. Free energy from ATP hydrolysis (an energetically favorable reaction) drives glucose phosphorylation (an energetically favorable reaction).efavorable reaction). The reaction is toobiologically irreversible, as shown by the single vertical arrow. Excess dietary glucose can be stored in most cells (especially liver and kidney cells) as a highly branched polymer of so-called glucose monomersGlycogen. In green algae and plants, the glucose produced by photosynthesis is stored as a starch polymer. When glucose is needed for energy, hydrolysis of glycogen and starch forms glucose-1-phosphate (G-1-P), which is then convertedG-6-P.

Let's consider the energetics (free energy flux) of the reaction catalyzed by hexokinase. This reaction can be viewed as the sum of two reactions shown below.

Remember that ATP hydrolysis is aexergonic reaction, releasing ~7 Kcal/mol (rounded off!) in a closed system under standard conditions. The condensation reaction of glucose phosphorylation occurs with a DGo of +3 Kcal/mol. That is aendergonicoReaction under standard conditions. By summing the free energy changes of the two reactions, we can calculate the total DGo of -4 Kcal/mol for the coupled reaction under standard conditions in a closed system.

The reactions above are written as if they were reversible. However, we have said that the overall coupled response isbiologically irreversible. Where's the contradiction? To explain, we say that an enzyme-catalyzed reaction is biologically irreversible if the products have a relatively low affinity for the enzyme's active site, making the catalysis (acceleration) of the reverse reaction very inefficient. Enzymes that catalyze biologically irreversible reactions must not be based on reactants but are often allosterically regulated. Such is the case with hexokinase. Imagine a cell reducing its G-6-P consumption because its energy needs are being met. What happens when the levels of G-6-P in the cells increase? You can expect the hexokinase reaction to slow down so the cell isn't wasting a valuable nutritious energy source. OAllosterische Regulationof hexokinase is shown below.

When the G-6-P concentration in the cell increases,excessG-6-P binds to an allosteric site on hexokinase. The enzyme's conformational change is then transferred to the active site, thereby inhibiting the reaction.

152 Glycolysis Stage 1, Reaction 1

Reaction 2:In this slightly endergonic and reversible reactionIsomerasecatalyzes the isomerization ofG-6-PforFructose-6-P(F-6-P), as shown below.

Reaction 3:In this biologically irreversible reaction6-Phosphofructokinase(6-P-Fructokinase) catalyzes the phosphorylation of F-6-P to makeFructose-1,6-diphosphat(F1,6 diP). This is also acoupled reaction, where ATP supplies the second phosphate. The total reaction is written as the sum of two reactions as shown below.

Like the hexokinase reaction, the6-P-FrutoquinaseThe reaction is a coupled, exergonic and allosterically regulated reaction. Severalallosteric effectors, including ATP, ADP and AMP, and long-chain fatty acids regulate this enzyme.

Reactions 4 and 5:These are the final reactions of the first stage of glycolysis. InReaction 4, F1,6 diP (a 6-C sugar) is reversibly cleavedDihydroxyacetonphosphat(DHAP) EGlycerinaldehyd-3-phosphat(G-3-P). EmReaction 5(also reversible) the DHAP is converted into another G-3-P. Here are the reactions:

The net result is the formation of two molecules G-3-P in the final reactions ofstage 1of glycolysis. the enzymesF-diP-AldolaseeTriose-P-Isomeraseboth catalyze freely reversible reactions. Furthermore, both reactions occur with, and therefore are, a positive free energy changeendergonico. The sum of the free energy changes for the splitting of F1.6 diP into two G-3-Ps is a whopping +7.5 Kcal per mole, an energetically very unfavorable process.

In short, in the endstage 1from glycolysis we consume two molecules of ATP and split a 6-C carbohydrate into two 3-C carbohydrates. We also saw two biologically irreversible and allosterically regulated enzymes.

153 glycolysis level 1; reactions 2-5

## B. Glycolysis, Stage 2

We will only follow one of the two G-3-P molecules that are generated at the end of thestage 1of glycolysis, but remember that both will go throughLevel 2of glycolysis.

Reaction 6:This is a redox reaction. G-3-P becomes too oxidized1,3, diphosphoglyceric acid(1.3, in PG) and NAD+ is reduced to NADH. The by gLyceraldehyd-3-phosphatDehydrogenaseis shown below.

Darinfreely reversible endergonicreaction, a hydrogen molecule (H2) is removed from the G-3-P leaving the phosphoglyceric acid. This short-lived oxidation intermediate is phosphorylated to produce1,3-diphosphoglyceric acid(1,3diPG). At the same time, the hydrogen molecule is converted into a hydride ion (H-) and a proton (H+). Reduce H ionsSHE+to NADH, leaving the protons in solution. Remember that this is all happening at the active site of the same enzyme!

Although it catalyzes a reversible reaction,G-3-P-Desidrogenaseis allosterically regulated. In contrast to the regulation of hexokinase, however, that of G-3-P dehydrogenase is more complicated! The regulator is NAD+ and the mechanism of allosteric regulation ofG-3-P-Desidrogenasecalled by NAD+negative willingness to cooperate. It turns out that the higher the [NAD+] in the cell, the lower the enzyme's affinity for more NAD+ and the faster the reaction in the cell! The mechanism is explained at the link below.

154 glycolysis level 2; reaction 6

Reaction 7:The reaction shown below is catalyzed byPhosphoglyceratkinase. It is freely reversible andexergonic, production of ATP and3-phosphoglyceric acid(3PG).

Catalysis is the transfer of phosphate groups between molecules by kinasesPhosphorylation at the substrate level, usually the phosphorylation of ADP to produce ATP. In thiscoupled reactionthe free energy released by the hydrolysis of a 1,3-DiPG phosphate is used to produce ATP. Remember that this reaction occurs twice per starting glucose. Up to this point, two ATPs have been synthesized in glycolysis. We call 1.3 diPGvery high-energy phosphate compound.

Reaction 8:This freely reversible endergonic reaction moves phosphate from carbon number 3 of 3PG to carbon number 2 as shown below.

I had movedifPhosphoglycerato-Mutasecatalyze the transfer of functional groups within a molecule.

Reaction 9:In this reaction (shown below)Enolasecatalyzes the conversion of 2PG toPhosphoenolpyruvat(PEP).

Reaction 10:This reaction leads to the formation ofpyruvic acid(Pyruvate), as shown below. remember again,Two pyruvates are produced per starting glucose molecule.

the enzymePyruvatkinasecouples orbiologically irreversible,exergonic hydrolysis of a phosphate from PEP and transfer of the phosphate to ADP in acoupled reaction. The product of the reaction, PEP, is anothervery high energyphosphate compound.

155 glycolysis level 2; reactions 7-10

Pyruvate kinase is allosterically regulated by ATP, citric acid, long chain fatty acids, F1,6 diP and one of its own substrates, PEP.

Emincomplete glycolysis (aerobic), pyruvate is oxidized in the mitochondria during respiration (cfAlternative targets for pyruvateabove).fermentationsyour name iscomplete glycolysisbecause pyruvate is reduced to one end product or another. Remember that muscle fatigue occurs when skeletal muscles use anaerobic digestion for energy during intense exercise. If pyruvate is too reducedlactic acid(lactate), the accumulation of lactic acid leads to muscle fatigue. the enzymeLactate dehydrogenase(LDH) that catalyzes this reaction is regulated but not allosterically. Instead, different muscle tissues regulate LDH by producing different versions of the enzyme! Click on the link below for an explanation.

156 Fermentation: regulation of pyruvate reduction IS NOT allosteric!

## C. A chemical and energy balance for glycolysis

Compare the balances of complete glycolysis (fermentation) with lactic acid andincompleteGlycolysis (aerobic) showing chemical products and energy transfers.

There are two reactionsLevel 2glycolysis, each producing one molecule of ATP. Since each of these reactions occurs twice per starting molecule of glucose, Stage 2 of glycolysis produces four molecules of ATP. Sincestage 1For example, if two ATPs are consumed, the net yield of chemical energy as ATP at the end of glycolysis is two ATPs, whether complete for lactate or incomplete for pyruvate! Because they can't use oxygen, anaerobes have to make do with the meager 15 Kcal of ATP they make from fermentation. Since there are potentially 687 kcal available to fully burn one mole of glucose, there is much more free energy to capture during the rest of the breath.

157 Equilibrium of Glycolysis

Also remember that the only redox reaction in aerobic glycolysis occurs in stage 2. This is the oxidation of G-3-P, a 3C glycolysis intermediate. Now look at the redox reaction and a fermentation pathway. When pyruvate, also a 3C intermediate, was reduced, there wasno net glucose oxidation(i.e. glycolytic intermediates) in complete glycolysis.

You will have recognized by now that glycolysis is an energetically favorable network (Downhill,spontaneous) reaction pathway in a closed system with globally negative ΔGo. Glycolysis is also normally spontaneous in most of our cells, driven by a constant need for energy to perform cellular work. Thus, the actual free energy of glycolysis, or ΔG', is also negative. In fact, glycolysis occurs in actively breathing cells releasing more free energy than in a closed system. In other words, the ΔG' of glycolysis in active cells is more negative than the ΔGo of glycolysis!

Now let's look at gluconeogenesis, the Atkins diet, and some not-so-normal circumstances for a moment when glycolysis is essentially reversed, at least in some cell types. Under these conditions, glycolysis is energetically unfavorable and it is these reverse reactions that are associated with a ΔG'! Negative!

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