Glycolysis

Source: Wikipedia, the free encyclopedia.


A summary pathway diagram of glycolysis, showing the multi-step conversion of glucose to pyruvate. Each step in the pathway is catalysed by a unique enzyme.
G6P
F6P
1,3BPG
3PG
2PG
PEP
Pyruvate
HK
PGI
PFK
TPI
GAPDH
PGK
PGM
ENO
PK
Glycolysis
The image above contains clickable links
The
pyruvate via a series of intermediate metabolites.    Each chemical modification is performed by a different enzyme.    Steps 1 and 3 consume ATP
and    steps 7 and 10 produce ATP. Since steps 6–10 occur twice per glucose molecule, this leads to a net production of ATP.
Summary of aerobic respiration

Glycolysis is the

reduced nicotinamide adenine dinucleotide (NADH).[1] Glycolysis is a sequence of ten reactions catalyzed by enzymes
.

Summary of the 10 reactions of the glycolysis pathway

The wide occurrence of glycolysis in other species indicates that it is an ancient metabolic pathway.

oxygen-free conditions of the Archean oceans, also in the absence of enzymes, catalyzed by metal ions, meaning this is a plausible prebiotic pathway for abiogenesis.[3]

The most common type of glycolysis is the Embden–Meyerhof–Parnas (EMP) pathway, which was discovered by

Otto Meyerhof, and Jakub Karol Parnas. Glycolysis also refers to other pathways, such as the Entner–Doudoroff pathway and various heterofermentative and homofermentative pathways. However, the discussion here will be limited to the Embden–Meyerhof–Parnas pathway.[4]

The glycolysis pathway can be separated into two phases:[5]

  1. Investment phase – wherein ATP is consumed
  2. Yield phase – wherein more ATP is produced than originally consumed

Overview

The overall reaction of glycolysis is:

 

+ 2 [NAD]+
+ 2 [ADP]
+ 2 [P]i

 

Rightward reaction arrow

2 ×

Pyruvate

2 × 

 

+ 2 [NADH]
+ 2 H+
+ 2 [ATP]
+ 2 H2O
Glycolysis pathway overview.

The use of symbols in this equation makes it appear unbalanced with respect to oxygen atoms, hydrogen atoms, and charges. Atom balance is maintained by the two phosphate (Pi) groups:[6]

  • Each exists in the form of a hydrogen phosphate anion ([HPO4]2−), dissociating to contribute 2H+ overall
  • Each liberates an oxygen atom when it binds to an adenosine diphosphate (ADP) molecule, contributing 2 O overall

Charges are balanced by the difference between ADP and ATP. In the cellular environment, all three hydroxyl groups of ADP dissociate into −O and H+, giving ADP3−, and this ion tends to exist in an ionic bond with Mg2+, giving ADPMg. ATP behaves identically except that it has four hydroxyl groups, giving ATPMg2−. When these differences along with the true charges on the two phosphate groups are considered together, the net charges of −4 on each side are balanced.

For simple

fermentations, the metabolism of one molecule of glucose to two molecules of pyruvate has a net yield of two molecules of ATP. Most cells will then carry out further reactions to "repay" the used NAD+ and produce a final product of ethanol or lactic acid
. Many bacteria use inorganic compounds as hydrogen acceptors to regenerate the NAD+.

Cells performing

pyruvate, and NADH + H+ from glycolysis. Eukaryotic aerobic respiration produces approximately 34 additional molecules of ATP for each glucose molecule, however most of these are produced by a mechanism vastly different from the substrate-level phosphorylation
in glycolysis.

The lower-energy production, per glucose, of anaerobic respiration relative to aerobic respiration, results in greater flux through the pathway under hypoxic (low-oxygen) conditions, unless alternative sources of anaerobically oxidizable substrates, such as fatty acids, are found.

History

The pathway of glycolysis as it is known today took almost 100 years to fully elucidate.[7] The combined results of many smaller experiments were required in order to understand the intricacies of the entire pathway.

The first steps in understanding glycolysis began in the nineteenth century with the wine industry. For economic reasons, the French wine industry sought to investigate why wine sometimes turned distasteful, instead of fermenting into alcohol. French scientist Louis Pasteur researched this issue during the 1850s, and the results of his experiments began the long road to elucidating the pathway of glycolysis.[8] His experiments showed that fermentation occurs by the action of living microorganisms, yeasts, and that yeast's glucose consumption decreased under aerobic conditions of fermentation, in comparison to anaerobic conditions (the Pasteur effect).[9]

Eduard Buchner. Discovered cell-free fermentation.

Insight into the component steps of glycolysis were provided by the non-cellular fermentation experiments of Eduard Buchner during the 1890s.[10][11] Buchner demonstrated that the conversion of glucose to ethanol was possible using a non-living extract of yeast, due to the action of enzymes in the extract.[12]: 135–148  This experiment not only revolutionized biochemistry, but also allowed later scientists to analyze this pathway in a more controlled laboratory setting. In a series of experiments (1905-1911), scientists Arthur Harden and William Young discovered more pieces of glycolysis.[13] They discovered the regulatory effects of ATP on glucose consumption during alcohol fermentation. They also shed light on the role of one compound as a glycolysis intermediate: fructose 1,6-bisphosphate.[12]: 151–158 

The elucidation of fructose 1,6-bisphosphate was accomplished by measuring CO2 levels when yeast juice was incubated with glucose. CO2 production increased rapidly then slowed down. Harden and Young noted that this process would restart if an inorganic phosphate (Pi) was added to the mixture. Harden and Young deduced that this process produced organic phosphate esters, and further experiments allowed them to extract fructose diphosphate (F-1,6-DP).

Arthur Harden and William Young along with Nick Sheppard determined, in a second experiment, that a heat-sensitive high-molecular-weight subcellular fraction (the enzymes) and a heat-insensitive low-molecular-weight cytoplasm fraction (ADP, ATP and NAD+ and other cofactors) are required together for fermentation to proceed. This experiment begun by observing that dialyzed (purified) yeast juice could not ferment or even create a sugar phosphate. This mixture was rescued with the addition of undialyzed yeast extract that had been boiled. Boiling the yeast extract renders all proteins inactive (as it denatures them). The ability of boiled extract plus dialyzed juice to complete fermentation suggests that the cofactors were non-protein in character.[13]

Otto Meyerhof. One of the main scientists involved in completing the puzzle of glycolysis

In the 1920s

muscle tissue, and combine them to artificially create the pathway from glycogen to lactic acid.[14][15]

In one paper, Meyerhof and scientist Renate Junowicz-Kockolaty investigated the reaction that splits fructose 1,6-diphosphate into the two triose phosphates. Previous work proposed that the split occurred via 1,3-diphosphoglyceraldehyde plus an oxidizing enzyme and cozymase. Meyerhoff and Junowicz found that the equilibrium constant for the isomerase and aldoses reaction were not affected by inorganic phosphates or any other cozymase or oxidizing enzymes. They further removed diphosphoglyceraldehyde as a possible intermediate in glycolysis.[15]

With all of these pieces available by the 1930s, Gustav Embden proposed a detailed, step-by-step outline of that pathway we now know as glycolysis.[16] The biggest difficulties in determining the intricacies of the pathway were due to the very short lifetime and low steady-state concentrations of the intermediates of the fast glycolytic reactions. By the 1940s, Meyerhof, Embden and many other biochemists had finally completed the puzzle of glycolysis.[15] The understanding of the isolated pathway has been expanded in the subsequent decades, to include further details of its regulation and integration with other metabolic pathways.

Sequence of reactions

Summary of reactions

ATP
ADP
Rightward reaction arrow with minor substrate(s) from top left and minor product(s) to top right

Phosphofructokinase-1

ATP
ADP
Rightward reaction arrow with minor substrate(s) from top left and minor product(s) to top right

+

+

Glyceraldehyde-3-phosphate
dehydrogenase

NAD++ Pi
NADH + H+
Reversible left-right reaction arrow with minor forward substrate(s) from top left, minor forward product(s) to top right, minor reverse substrate(s) from bottom right and minor reverse product(s) to bottom left
NAD++ Pi
NADH + H+

2 ×

1,3-Bisphosphoglycerate

2 × 
ADP
ATP
Reversible left-right reaction arrow with minor forward substrate(s) from top left, minor forward product(s) to top right, minor reverse substrate(s) from bottom right and minor reverse product(s) to bottom left
ADP
ATP
2 × 
2 × 

Phosphopyruvate
hydratase (enolase
)

Reversible left-right reaction arrow with minor forward product(s) to top right and minor reverse substrate(s) from bottom right
 
H2O

2 ×

Phosphoenolpyruvate

2 × 
ADP
ATP
Rightward reaction arrow with minor substrate(s) from top left and minor product(s) to top right

2 × Pyruvate

2 × 


Preparatory phase

The first five steps of Glycolysis are regarded as the preparatory (or investment) phase, since they consume energy to convert the glucose into two three-carbon sugar phosphates[5] (G3P).

d-Glucose (Glc) Hexokinase glucokinase (HK)
a transferase
α-d-
Glucose-6-phosphate
(G6P)
 
ATP H+ + ADP
 
 

Once glucose enters the cell, the first step is phosphorylation of glucose by a family of enzymes called hexokinases to form glucose 6-phosphate (G6P). This reaction consumes ATP, but it acts to keep the glucose concentration inside the cell low, promoting continuous transport of blood glucose into the cell through the plasma membrane transporters. In addition, phosphorylation blocks the glucose from leaking out – the cell lacks transporters for G6P, and free diffusion out of the cell is prevented due to the charged nature of G6P. Glucose may alternatively be formed from the phosphorolysis or hydrolysis of intracellular starch or glycogen.

In animals, an isozyme of hexokinase called glucokinase is also used in the liver, which has a much lower affinity for glucose (Km in the vicinity of normal glycemia), and differs in regulatory properties. The different substrate affinity and alternate regulation of this enzyme are a reflection of the role of the liver in maintaining blood sugar levels.

Cofactors: Mg2+


α-d-Glucose 6-phosphate (G6P)
Phosphoglucoisomerase (PGI)
an isomerase
β-d-Fructose 6-phosphate (F6P)
 
 
 

G6P is then rearranged into

glucose phosphate isomerase. Fructose
can also enter the glycolytic pathway by phosphorylation at this point.

The change in structure is an isomerization, in which the G6P has been converted to F6P. The reaction requires an enzyme, phosphoglucose isomerase, to proceed. This reaction is freely reversible under normal cell conditions. However, it is often driven forward because of a low concentration of F6P, which is constantly consumed during the next step of glycolysis. Under conditions of high F6P concentration, this reaction readily runs in reverse. This phenomenon can be explained through

Le Chatelier's Principle
. Isomerization to a keto sugar is necessary for carbanion stabilization in the fourth reaction step (below).


β-d-Fructose 6-phosphate (F6P) Phosphofructokinase (PFK-1)
a transferase
β-d-Fructose 1,6-bisphosphate (F1,6BP)
 
ATP H+ + ADP
 
 

The energy expenditure of another ATP in this step is justified in 2 ways: The glycolytic process (up to this step) becomes irreversible, and the energy supplied destabilizes the molecule. Because the reaction catalyzed by phosphofructokinase 1 (PFK-1) is coupled to the hydrolysis of ATP (an energetically favorable step) it is, in essence, irreversible, and a different pathway must be used to do the reverse conversion during gluconeogenesis. This makes the reaction a key regulatory point (see below).

Furthermore, the second phosphorylation event is necessary to allow the formation of two charged groups (rather than only one) in the subsequent step of glycolysis, ensuring the prevention of free diffusion of substrates out of the cell.

The same reaction can also be catalyzed by pyrophosphate-dependent phosphofructokinase (PFP or PPi-PFK), which is found in most plants, some bacteria, archea, and protists, but not in animals. This enzyme uses pyrophosphate (PPi) as a phosphate donor instead of ATP. It is a reversible reaction, increasing the flexibility of glycolytic metabolism.[17] A rarer ADP-dependent PFK enzyme variant has been identified in archaean species.[18]

Cofactors: Mg2+


Destabilizing the molecule in the previous reaction allows the hexose ring to be split by aldolase into two triose sugars: dihydroxyacetone phosphate (a ketose), and glyceraldehyde 3-phosphate (an aldose). There are two classes of aldolases: class I aldolases, present in animals and plants, and class II aldolases, present in fungi and bacteria; the two classes use different mechanisms in cleaving the ketose ring.

Electrons delocalized in the carbon-carbon bond cleavage associate with the alcohol group. The resulting carbanion is stabilized by the structure of the carbanion itself via resonance charge distribution and by the presence of a charged ion prosthetic group.


Triosephosphate isomerase rapidly interconverts dihydroxyacetone phosphate with glyceraldehyde 3-phosphate (GADP) that proceeds further into glycolysis. This is advantageous, as it directs dihydroxyacetone phosphate down the same pathway as glyceraldehyde 3-phosphate, simplifying regulation.

Pay-off phase

The second half of glycolysis is known as the pay-off phase, characterised by a net gain of the energy-rich molecules ATP and NADH.[5] Since glucose leads to two triose sugars in the preparatory phase, each reaction in the pay-off phase occurs twice per glucose molecule. This yields 2 NADH molecules and 4 ATP molecules, leading to a net gain of 2 NADH molecules and 2 ATP molecules from the glycolytic pathway per glucose.

Glyceraldehyde 3-phosphate (GADP)
Glyceraldehyde phosphate dehydrogenase (GAPDH)
an oxidoreductase
d-
1,3-Bisphosphoglycerate
(1,3BPG)
 
NAD+ + Pi NADH + H+
   
 
 

The aldehyde groups of the triose sugars are

1,3-bisphosphoglycerate
.

The hydrogen is used to reduce two molecules of

NAD+
, a hydrogen carrier, to give NADH + H+ for each triose.

Hydrogen atom balance and charge balance are both maintained because the phosphate (Pi) group actually exists in the form of a hydrogen phosphate anion (HPO2−4),[6] which dissociates to contribute the extra H+ ion and gives a net charge of -3 on both sides.

Here,

1-3 bisphosphoglycerate in the next reaction will not be made, even though the reaction proceeds. As a result, arsenate is an uncoupler of glycolysis.[19]


1,3-Bisphosphoglycerate
(1,3BPG)
Phosphoglycerate kinase (PGK)
a transferase
3-Phosphoglycerate
(3PG)
 
ADP ATP
   
 
  Phosphoglycerate kinase (PGK)

This step is the enzymatic transfer of a phosphate group from

3-phosphoglycerate. At this step, glycolysis has reached the break-even point: 2 molecules of ATP were consumed, and 2 new molecules have now been synthesized. This step, one of the two substrate-level phosphorylation
steps, requires ADP; thus, when the cell has plenty of ATP (and little ADP), this reaction does not occur. Because ATP decays relatively quickly when it is not metabolized, this is an important regulatory point in the glycolytic pathway.

ADP actually exists as ADPMg, and ATP as ATPMg2−, balancing the charges at −5 both sides.

Cofactors: Mg2+


3-Phosphoglycerate
(3PG)
Phosphoglycerate mutase (PGM)
a mutase
2-Phosphoglycerate
(2PG)
 
 
 

2-phosphoglycerate
.


2-Phosphoglycerate
(2PG)
Enolase (ENO)
a lyase
Phosphoenolpyruvate
(PEP)
 
H2O
 
 
  Enolase (ENO)

phosphoenolpyruvate. This reaction is an elimination reaction involving an E1cB
mechanism.

Cofactors: 2 Mg2+, one "conformational" ion to coordinate with the carboxylate group of the substrate, and one "catalytic" ion that participates in the dehydration.


Phosphoenolpyruvate
(PEP)
Pyruvate kinase (PK)
a transferase
Pyruvate
(Pyr)
 
ADP + H+ ATP
 
 

A final

pyruvate and a molecule of ATP by means of the enzyme pyruvate kinase
. This serves as an additional regulatory step, similar to the phosphoglycerate kinase step.

Cofactors: Mg2+

Biochemical logic

The existence of more than one point of regulation indicates that intermediates between those points enter and leave the glycolysis pathway by other processes. For example, in the first regulated step, hexokinase converts glucose into glucose-6-phosphate. Instead of continuing through the glycolysis pathway, this intermediate can be converted into glucose storage molecules, such as glycogen or starch. The reverse reaction, breaking down, e.g., glycogen, produces mainly glucose-6-phosphate; very little free glucose is formed in the reaction. The glucose-6-phosphate so produced can enter glycolysis after the first control point.

In the second regulated step (the third step of glycolysis), phosphofructokinase converts fructose-6-phosphate into fructose-1,6-bisphosphate, which then is converted into glyceraldehyde-3-phosphate and dihydroxyacetone phosphate. The dihydroxyacetone phosphate can be removed from glycolysis by conversion into glycerol-3-phosphate, which can be used to form triglycerides.[20] Conversely, triglycerides can be broken down into fatty acids and glycerol; the latter, in turn, can be converted into dihydroxyacetone phosphate, which can enter glycolysis after the second control point.

Free energy changes

Concentrations of metabolites in erythrocytes[21]: 584 
Compound Concentration / mM
Glucose 5.0
Glucose-6-phosphate 0.083
Fructose-6-phosphate 0.014
Fructose-1,6-bisphosphate 0.031
Dihydroxyacetone phosphate 0.14
Glyceraldehyde-3-phosphate 0.019
1,3-Bisphosphoglycerate 0.001
2,3-Bisphosphoglycerate 4.0
3-Phosphoglycerate 0.12
2-Phosphoglycerate 0.03
Phosphoenolpyruvate 0.023
Pyruvate 0.051
ATP 1.85
ADP 0.14
Pi 1.0

The change in free energy, ΔG, for each step in the glycolysis pathway can be calculated using ΔG = ΔG°′ + RTln Q, where Q is the

NAD+ to NADH
in the cytoplasm is approximately 1000, which makes the oxidation of glyceraldehyde-3-phosphate (step 6) more favourable.

Using the measured concentrations of each step, and the standard free energy changes, the actual free energy change can be calculated. (Neglecting this is very common - the delta G of ATP hydrolysis in cells is not the standard free energy change of ATP hydrolysis quoted in textbooks).

Change in free energy for each step of glycolysis[21]: 582–583 
Step Reaction ΔG°′
(kJ/mol)
ΔG
(kJ/mol)
1 Glucose + ATP4− → Glucose-6-phosphate2− + ADP3− + H+ −16.7 −34
2 Glucose-6-phosphate2− → Fructose-6-phosphate2− 1.67 −2.9
3 Fructose-6-phosphate2− + ATP4− → Fructose-1,6-bisphosphate4− + ADP3− + H+ −14.2 −19
4 Fructose-1,6-bisphosphate4− → Dihydroxyacetone phosphate2− + Glyceraldehyde-3-phosphate2− 23.9 −0.23
5 Dihydroxyacetone phosphate2− → Glyceraldehyde-3-phosphate2− 7.56 2.4
6 Glyceraldehyde-3-phosphate2− + Pi2− + NAD+ → 1,3-Bisphosphoglycerate4− + NADH + H+ 6.30 −1.29
7 1,3-Bisphosphoglycerate4− + ADP3− → 3-Phosphoglycerate3− + ATP4− −18.9 0.09
8 3-Phosphoglycerate3− → 2-Phosphoglycerate3− 4.4 0.83
9 2-Phosphoglycerate3− → Phosphoenolpyruvate3− + H2O 1.8 1.1
10 Phosphoenolpyruvate3− + ADP3− + H+ → Pyruvate + ATP4− −31.7 −23.0

From measuring the physiological concentrations of metabolites in an erythrocyte it seems that about seven of the steps in glycolysis are in equilibrium for that cell type. Three of the steps — the ones with large negative free energy changes — are not in equilibrium and are referred to as irreversible; such steps are often subject to regulation.

Step 5 in the figure is shown behind the other steps, because that step is a side-reaction that can decrease or increase the concentration of the intermediate glyceraldehyde-3-phosphate. That compound is converted to dihydroxyacetone phosphate by the enzyme triose phosphate isomerase, which is a

catalytically perfect
enzyme; its rate is so fast that the reaction can be assumed to be in equilibrium. The fact that ΔG is not zero indicates that the actual concentrations in the erythrocyte are not accurately known.

Regulation

The enzymes that catalyse glycolysis are regulated via a range of biological mechanisms in order to control overall

metabolic adaptation to a changing environment or need.[22] The details of regulation for some enzymes are highly conserved between species, whereas others vary widely.[23][24]

  1. Gene Expression: Firstly, the cellular concentrations of glycolytic enzymes are modulated via
    transcription factors,[25] with several glycolysis enzymes themselves acting as regulatory protein kinases in the nucleus.[26]
  2. end-product inhibition of regulated enzymes by metabolites such as ATP serves as negative feedback regulation of the pathway.[23][27]
  3. Allosteric inhibition and activation by Protein-protein interactions (PPI).[28] Indeed, some proteins interact with and regulate multiple glycolytic enzymes.[29]
  4. Post-translational modification (PTM).[30] In particular, phosphorylation and dephosphorylation is a key mechanism of regulation of pyruvate kinase in the liver.
  5. Localization[27]

Regulation by insulin in animals

In animals, regulation of blood glucose levels by the pancreas in conjunction with the liver is a vital part of

adrenal glands into the blood. This has the same action as glucagon on glucose metabolism, but its effect is more pronounced.[31] In the liver glucagon and epinephrine cause the phosphorylation of the key, regulated enzymes of glycolysis, fatty acid synthesis, cholesterol synthesis, gluconeogenesis, and glycogenolysis. Insulin has the opposite effect on these enzymes.[32] The phosphorylation and dephosphorylation of these enzymes (ultimately in response to the glucose level in the blood) is the dominant manner by which these pathways are controlled in the liver, fat, and muscle cells. Thus the phosphorylation of phosphofructokinase inhibits glycolysis, whereas its dephosphorylation through the action of insulin stimulates glycolysis.[32]

Regulated Enzymes in Glycolysis

The three

flux through the glycolytic pathway is adjusted in response to conditions both inside and outside the cell. The internal factors that regulate glycolysis do so primarily to provide ATP in adequate quantities for the cell's needs. The external factors act primarily on the liver, fat tissue, and muscles, which can remove large quantities of glucose from the blood after meals (thus preventing hyperglycemia by storing the excess glucose as fat or glycogen, depending on the tissue type). The liver is also capable of releasing glucose into the blood between meals, during fasting, and exercise thus preventing hypoglycemia by means of glycogenolysis and gluconeogenesis
. These latter reactions coincide with the halting of glycolysis in the liver.

In addition hexokinase and

glucose-6-phosphate (G6P) level in the cell, or, in the case of glucokinase, to the blood sugar level in the blood to impart entirely intracellular controls of the glycolytic pathway in different tissues (see below).[32]

When glucose has been converted into G6P by hexokinase or glucokinase, it can either be converted to

exercise or hypoglycemia, glucagon and epinephrine are released into the blood. This causes liver glycogen to be converted back to G6P, and then converted to glucose by the liver-specific enzyme glucose 6-phosphatase and released into the blood. Glucagon and epinephrine also stimulate gluconeogenesis, which converts non-carbohydrate substrates into G6P, which joins the G6P derived from glycogen, or substitutes for it when the liver glycogen store have been depleted. This is critical for brain function, since the brain utilizes glucose as an energy source under most conditions.[33] The simultaneously phosphorylation of, particularly, phosphofructokinase
, but also, to a certain extent pyruvate kinase, prevents glycolysis occurring at the same time as gluconeogenesis and glycogenolysis.

Hexokinase and glucokinase

Yeast hexokinase B (PDB: 1IG8​)

All cells contain the enzyme

glucose-6-phosphate (G6P). Since the cell membrane is impervious to G6P, hexokinase essentially acts to transport glucose into the cells from which it can then no longer escape. Hexokinase is inhibited by high levels of G6P in the cell. Thus the rate of entry of glucose into cells partially depends on how fast G6P can be disposed of by glycolysis, and by glycogen synthesis (in the cells which store glycogen, namely liver and muscles).[32][34]

glucose-6-phosphate (G6P), when the glucose in the blood is abundant. This being the first step in the glycolytic pathway in the liver, it therefore imparts an additional layer of control of the glycolytic pathway in this organ.[32]

Phosphofructokinase

​)

Phosphofructokinase is an important control point in the glycolytic pathway, since it is one of the irreversible steps and has key allosteric effectors, AMP and fructose 2,6-bisphosphate (F2,6BP).

epinephrine cause high levels of cAMP in the liver. The result of lower levels of liver fructose-2,6-bisphosphate is a decrease in activity of phosphofructokinase and an increase in activity of fructose 1,6-bisphosphatase
, so that gluconeogenesis (in essence, "glycolysis in reverse") is favored. This is consistent with the role of the liver in such situations, since the response of the liver to these hormones is to release glucose to the blood.

ATP competes with AMP for the allosteric effector site on the PFK enzyme. ATP concentrations in cells are much higher than those of AMP, typically 100-fold higher,[35] but the concentration of ATP does not change more than about 10% under physiological conditions, whereas a 10% drop in ATP results in a 6-fold increase in AMP.[36] Thus, the relevance of ATP as an allosteric effector is questionable. An increase in AMP is a consequence of a decrease in energy charge in the cell.

Citrate inhibits phosphofructokinase when tested in vitro by enhancing the inhibitory effect of ATP. However, it is doubtful that this is a meaningful effect in vivo, because citrate in the cytosol is utilized mainly for conversion to acetyl-CoA for fatty acid and cholesterol
synthesis.

TIGAR, a p53 induced enzyme, is responsible for the regulation of phosphofructokinase and acts to protect against oxidative stress.[37] TIGAR is a single enzyme with dual function that regulates F2,6BP. It can behave as a phosphatase (fructuose-2,6-bisphosphatase) which cleaves the phosphate at carbon-2 producing F6P. It can also behave as a kinase (PFK2) adding a phosphate onto carbon-2 of F6P which produces F2,6BP. In humans, the TIGAR protein is encoded by C12orf5 gene. The TIGAR enzyme will hinder the forward progression of glycolysis, by creating a build up of fructose-6-phosphate (F6P) which is isomerized into glucose-6-phosphate (G6P). The accumulation of G6P will shunt carbons into the pentose phosphate pathway.[38][39]

Pyruvate kinase

Yeast pyruvate kinase (PDB: 1A3W​)

The final step of glycolysis is catalysed by pyruvate kinase to form pyruvate and another ATP. It is regulated by a range of different transcriptional, covalent and non-covalent regulation mechanisms, which can vary widely in different tissues.[40][41][42] For example, in the liver, pyruvate kinase is regulated based on glucose availability. During fasting (no glucose available), glucagon activates protein kinase A which phosphorylates pyruvate kinase to inhibit it.[43] An increase in blood sugar leads to secretion of insulin, which activates protein phosphatase 1, leading to dephosphorylation and re-activation of pyruvate kinase.[43] These controls prevent pyruvate kinase from being active at the same time as the enzymes that catalyze the reverse reaction (pyruvate carboxylase and phosphoenolpyruvate carboxykinase), preventing a futile cycle.[43] Conversely, the isoform of pyruvate kinasein found in muscle is not affected by protein kinase A (which is activated by adrenaline in that tissue), so that glycolysis remains active in muscles even during fasting.[43]

Post-glycolysis processes

The overall process of glycolysis is:

Glucose + 2 NAD+ + 2 ADP + 2 Pi → 2 Pyruvate + 2 NADH + 2 H+ + 2 ATP + 2 H2O

If glycolysis were to continue indefinitely, all of the NAD+ would be used up, and glycolysis would stop. To allow glycolysis to continue, organisms must be able to oxidize NADH back to NAD+. How this is performed depends on which external electron acceptor is available.

Anoxic regeneration of NAD+

One method of doing this is to simply have the pyruvate do the oxidation; in this process, pyruvate is converted to

conjugate base of lactic acid) in a process called lactic acid fermentation
:

Pyruvate + NADH + H+ → Lactate + NAD+

This process occurs in the

bacteria involved in making yogurt
(the lactic acid causes the milk to curdle). This process also occurs in animals under hypoxic (or partially anaerobic) conditions, found, for example, in overworked muscles that are starved of oxygen. In many tissues, this is a cellular last resort for energy; most animal tissue cannot tolerate anaerobic conditions for an extended period of time.

Some organisms, such as yeast, convert NADH back to NAD+ in a process called ethanol fermentation. In this process, the pyruvate is converted first to acetaldehyde and carbon dioxide, and then to ethanol.

Lactic acid fermentation and ethanol fermentation can occur in the absence of oxygen. This anaerobic fermentation allows many single-cell organisms to use glycolysis as their only energy source.

Anoxic regeneration of NAD+ is only an effective means of energy production during short, intense exercise in vertebrates, for a period ranging from 10 seconds to 2 minutes during a maximal effort in humans. (At lower exercise intensities it can sustain muscle activity in

diving animals
, such as seals, whales and other aquatic vertebrates, for very much longer periods of time.) Under these conditions NAD+ is replenished by NADH donating its electrons to pyruvate to form lactate. This produces 2 ATP molecules per glucose molecule, or about 5% of glucose's energy potential (38 ATP molecules in bacteria). But the speed at which ATP is produced in this manner is about 100 times that of oxidative phosphorylation. The pH in the cytoplasm quickly drops when hydrogen ions accumulate in the muscle, eventually inhibiting the enzymes involved in glycolysis.

The burning sensation in muscles during hard exercise can be attributed to the release of hydrogen ions during the shift to glucose fermentation from glucose oxidation to carbon dioxide and water, when aerobic metabolism can no longer keep pace with the energy demands of the muscles. These hydrogen ions form a part of lactic acid. The body falls back on this less efficient but faster method of producing ATP under low oxygen conditions. This is thought to have been the primary means of energy production in earlier organisms before oxygen reached high concentrations in the atmosphere between 2000 and 2500 million years ago, and thus would represent a more ancient form of energy production than the aerobic replenishment of NAD+ in cells.

The liver in mammals gets rid of this excess lactate by transforming it back into pyruvate under aerobic conditions; see Cori cycle.

Fermentation of pyruvate to lactate is sometimes also called "anaerobic glycolysis", however, glycolysis ends with the production of pyruvate regardless of the presence or absence of oxygen.

In the above two examples of fermentation, NADH is oxidized by transferring two electrons to pyruvate. However, anaerobic bacteria use a wide variety of compounds as the terminal electron acceptors in cellular respiration: nitrogenous compounds, such as nitrates and nitrites; sulfur compounds, such as sulfates, sulfites, sulfur dioxide, and elemental sulfur; carbon dioxide; iron compounds; manganese compounds; cobalt compounds; and uranium compounds.

Aerobic regeneration of NAD+ and further catabolism of pyruvate

In

prokaryotes, which lack mitochondria, use a variety of simpler mechanisms
.

Conversion of carbohydrates into fatty acids and cholesterol

The pyruvate produced by glycolysis is an important intermediary in the conversion of carbohydrates into

bile salts, and vitamin D.[34][45][46]

Conversion of pyruvate into oxaloacetate for the citric acid cycle

Pyruvate molecules produced by glycolysis are

skeletal muscle) are suddenly increased by activity.[47]
In the citric acid cycle all the intermediates (e.g. citrate, iso-citrate, alpha-ketoglutarate, succinate, fumarate, malate and oxaloacetate) are regenerated during each turn of the cycle. Adding more of any of these intermediates to the mitochondrion therefore means that that additional amount is retained within the cycle, increasing all the other intermediates as one is converted into the other. Hence the addition of oxaloacetate greatly increases the amounts of all the citric acid intermediates, thereby increasing the cycle's capacity to metabolize acetyl CoA, converting its acetate component into CO2 and water, with the release of enough energy to form 11 ATP and 1 GTP molecule for each additional molecule of acetyl CoA that combines with oxaloacetate in the cycle.[47]

To cataplerotically remove oxaloacetate from the citric cycle,

malate can be transported from the mitochondrion into the cytoplasm, decreasing the amount of oxaloacetate that can be regenerated.[47] Furthermore, citric acid intermediates are constantly used to form a variety of substances such as the purines, pyrimidines and porphyrins.[47]

Intermediates for other pathways

This article concentrates on the

anabolic pathways, and, as a consequence, flux through the pathway is critical to maintain a supply of carbon skeletons for biosynthesis.[48]

The following metabolic pathways are all strongly reliant on glycolysis as a source of metabolites: and many more.

Although gluconeogenesis and glycolysis share many intermediates the one is not functionally a branch or tributary of the other. There are two regulatory steps in both pathways which, when active in the one pathway, are automatically inactive in the other. The two processes can therefore not be simultaneously active.[49] Indeed, if both sets of reactions were highly active at the same time the net result would be the hydrolysis of four high energy phosphate bonds (two ATP and two GTP) per reaction cycle.[49]

nucleic acids, or it can be catabolized to pyruvate.[49]

Glycolysis in disease

Diabetes

Cellular uptake of glucose occurs in response to insulin signals, and glucose is subsequently broken down through glycolysis, lowering blood sugar levels. However, the low insulin levels seen in diabetes result in hyperglycemia, where glucose levels in the blood rise and glucose is not properly taken up by cells. Hepatocytes further contribute to this hyperglycemia through gluconeogenesis. Glycolysis in hepatocytes controls hepatic glucose production, and when glucose is overproduced by the liver without having a means of being broken down by the body, hyperglycemia results.[50]

Genetic diseases

Glycolytic mutations are generally rare due to importance of the metabolic pathway; the majority of occurring mutations result in an inability of the cell to respire, and therefore cause the death of the cell at an early stage. However, some mutations (glycogen storage diseases and other inborn errors of carbohydrate metabolism) are seen with one notable example being pyruvate kinase deficiency, leading to chronic hemolytic anemia.[citation needed]

Cancer

Malignant tumor cells perform glycolysis at a rate that is ten times faster than their noncancerous tissue counterparts.[51] During their genesis, limited capillary support often results in hypoxia (decreased O2 supply) within the tumor cells. Thus, these cells rely on anaerobic metabolic processes such as glycolysis for ATP (adenosine triphosphate). Some tumor cells overexpress specific glycolytic enzymes which result in higher rates of glycolysis.[52] Often these enzymes are Isoenzymes, of traditional glycolysis enzymes, that vary in their susceptibility to traditional feedback inhibition. The increase in glycolytic activity ultimately counteracts the effects of hypoxia by generating sufficient ATP from this anaerobic pathway.[53] This phenomenon was first described in 1930 by Otto Warburg and is referred to as the Warburg effect. The Warburg hypothesis claims that cancer is primarily caused by dysfunctionality in mitochondrial metabolism, rather than because of the uncontrolled growth of cells. A number of theories have been advanced to explain the Warburg effect. One such theory suggests that the increased glycolysis is a normal protective process of the body and that malignant change could be primarily caused by energy metabolism.[54]

This high glycolysis rate has important medical applications, as high

There is ongoing research to affect mitochondrial metabolism and treat cancer by reducing glycolysis and thus starving cancerous cells in various new ways, including a ketogenic diet.[57][58][59]

Interactive pathway map

The diagram below shows human protein names. Names in other organisms may be different and the number of isozymes (such as HK1, HK2, ...) is likely to be different too.

Click on genes, proteins and metabolites below to link to respective articles.[§ 1]

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GlycolysisGluconeogenesis_WP534go to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to WikiPathwaysgo to articlego to Entrezgo to article
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GlycolysisGluconeogenesis_WP534go to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to articlego to WikiPathwaysgo to articlego to Entrezgo to article
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  1. ^ The interactive pathway map can be edited at WikiPathways: "GlycolysisGluconeogenesis_WP534".

Alternative nomenclature

Some of the metabolites in glycolysis have alternative names and nomenclature. In part, this is because some of them are common to other pathways, such as the Calvin cycle.

This article Alternative
1 Glucose Glc Dextrose
2
Glucose-6-phosphate
G6P
3
Fructose-6-phosphate
F6P
4
Fructose-1,6-bisphosphate
F1,6BP Fructose 1,6-diphosphate FBP; FDP; F1,6DP
5 Dihydroxyacetone phosphate DHAP Glycerone phosphate
6
Glyceraldehyde-3-phosphate
GADP 3-Phosphoglyceraldehyde PGAL; G3P; GALP; GAP; TP
7
1,3-Bisphosphoglycerate
1,3BPG Glycerate-1,3-bisphosphate,
glycerate-1,3-diphosphate,
1,3-diphosphoglycerate
PGAP; BPG; DPG
8
3-Phosphoglycerate
3PG Glycerate-3-phosphate PGA; GP
9
2-Phosphoglycerate
2PG Glycerate-2-phosphate
10
Phosphoenolpyruvate
PEP
11
Pyruvate
Pyr Pyruvic acid conjugate base

Structure of glycolysis components in Fischer projections and polygonal model

The intermediates of glycolysis depicted in Fischer projections show the chemical changing step by step. Such image can be compared to polygonal model representation.[60] Another comparation of Fischer projections and Poligonal Model in glycolysis is shown in a video.[61] Video animations in the same channel in YouTube can be seen for another metabolic pathway (Krebs Cycle) and the representation and applying of Polygonal Model in Organic Chemistry [62]

Glycolysis - Structure of anaerobic glycolysis components showed using Fischer projections, left, and polygonal model, right. The compounds correspond to glucose (GLU), glucose 6-phosphate (G6P), fructose 6-phosphate (F6P), fructose 1,6-bisphosphate ( F16BP), dihydroxyacetone phosphate (DHAP), glyceraldehyde 3-phosphate(GA3P), 1,3-bisphosphoglycerate (13BPG), 3-phosphoglycerate (3PG), 2-phosphoglycerate (2PG), phosphoenolpyruvate (PEP), pyruvate (PIR), and lactate (LAC). The enzymes which participate of this pathway are indicated by underlined numbers, and correspond to hexokinase (1), glucose-6-phosphate isomerase (2), phosphofructokinase-1 (3), fructose-bisphosphate aldolase (4), triosephosphate isomerase (5), glyceraldehyde-3-phosphate dehydrogenase (5), phosphoglycerate kinase (7), phosphoglycerate mutase (8), phosphopyruvate hydratase (enolase) (9), pyruvate kinase (10), and lactate dehydrogenase (11). The participant coenzymes (NAD+, NADH + H+, ATP and ADP), inorganic phosphate, H2O and CO2 were omitted in these representations. The phosphorylation reactions from ATP, as well the ADP phosphorylation reactions in later steps of glycolysis are shown as ~P respectively entering or going out the pathway. The oxireduction reactions using NAD+ or NADH are observed as hydrogens “2H” going out or entering the pathway.

See also

References

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External links