![Aerobic respiration summary](https://upload.wikimedia.org/wikipedia/commons/e/e2/Aerobic_respiration_summary.jpg)
Glycolysis is the
metabolic pathway
In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical reac ...
that converts
glucose
Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...
() into
pyruvate
Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell.
Pyruvic aci ...
(). The
free energy released in this process is used to form the high-energy molecules
adenosine triphosphate
Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms of ...
(ATP) and
reduced nicotinamide adenine dinucleotide (NADH). Glycolysis is a sequence of ten reactions catalyzed by
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
s.
![Glycolysis Summary](https://upload.wikimedia.org/wikipedia/commons/8/88/Glycolysis_Summary.svg)
Glycolysis is a metabolic pathway that does not require oxygen (In anaerobic conditions pyruvate is converted to lactic acid). The wide occurrence of glycolysis in other species indicates that it is an ancient metabolic pathway. Indeed, the reactions that make up glycolysis and its parallel pathway, the
pentose phosphate pathway
The pentose phosphate pathway (also called the phosphogluconate pathway and the hexose monophosphate shunt and the HMP Shunt) is a metabolic pathway parallel to glycolysis. It generates NADPH and pentoses (5-carbon sugars) as well as ribose 5-pho ...
, occur in the
oxygen-free conditions of the
Archean
The Archean Eon ( , also spelled Archaean or Archæan) is the second of four geologic eons of Earth's history, representing the time from . The Archean was preceded by the Hadean Eon and followed by the Proterozoic.
The Earth
Earth ...
oceans, also in the absence of enzymes, catalyzed by metal.
In most organisms, glycolysis occurs in the liquid part of cells, the
cytosol
The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells (intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...
. The most common type of glycolysis is the ''Embden–Meyerhof–Parnas (EMP) pathway'', which was discovered by
Gustav Embden
Gustav Georg Embden (10 November 1874 – 25 July 1933) was a German physiological chemist.
Background
Gustav Embden was a son of the Hamburg lawyer and politician George Heinrich Embden. His grandmother Charlotte Heine was a well-known salonn ...
,
Otto Meyerhof
Otto Fritz Meyerhof (; April 12, 1884 – October 6, 1951) was a German physician and biochemist who won the 1922 Nobel Prize in Physiology and Medicine.
Biography
Otto Fritz Meyerhof was born in Hannover, at Theaterplatz 16A (now:Rathenaustrasse ...
, and
Jakub Karol Parnas
Jakub Karol Parnas, also known as Yakov Oskarovich Parnas (russian: Яков Оскарович Парнас) (January 16, 1884 – January 29, 1949) was a prominent Polish–Soviet biochemist who contributed to the discovery of the Embden ...
. Glycolysis also refers to other pathways, such as the ''
Entner–Doudoroff pathway
The Entner–Doudoroff pathway (ED Pathway) is a metabolic pathway that is most notable in Gram-negative bacteria, certain Gram-positive bacteria and archaea. Glucose is the substrate in the ED pathway and through a series of enzyme assisted chem ...
'' and various heterofermentative and homofermentative pathways. However, the discussion here will be limited to the Embden–Meyerhof–Parnas pathway.
The glycolysis pathway can be separated into two phases:
# Investment phase – wherein ATP is consumed
# Yield phase – wherein more ATP is produced than originally consumed
Overview
The overall reaction of glycolysis is:
![Glycolysis](https://upload.wikimedia.org/wikipedia/commons/a/a0/Glycolysis.svg)
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 (P
i) groups:
* Each exists in the form of a
hydrogen phosphate anion (), dissociating to contribute overall
* Each liberates an oxygen atom when it binds to an
adenosine diphosphate
Adenosine diphosphate (ADP), also known as adenosine pyrophosphate (APP), is an important organic compound in metabolism and is essential to the flow of energy in living cells. ADP consists of three important structural components: a sugar backbon ...
(ADP) molecule, contributing 2O 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 ADP
3−, and this ion tends to exist in an ionic bond with Mg
2+, giving ADPMg
−. ATP behaves identically except that it has four hydroxyl groups, giving ATPMg
2−. 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
Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an Alcohol (chemistry), alcohol with the chemical formula . Its formula can be also written as or (an ethyl ...
or
lactic acid
Lactic acid is an organic acid. It has a molecular formula . It is white in the solid state and it is miscible with water. When in the dissolved state, it forms a colorless solution. Production includes both artificial synthesis as well as natu ...
. Many bacteria use inorganic compounds as hydrogen acceptors to regenerate the NAD
+.
Cells performing
aerobic respiration
Cellular respiration is the process by which biological fuels are oxidised in the presence of an inorganic electron acceptor such as oxygen to produce large amounts of energy, to drive the bulk production of ATP. Cellular respiration may be des ...
synthesize much more ATP, but not as part of glycolysis. These further aerobic reactions use
pyruvate
Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell.
Pyruvic aci ...
, 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
Substrate-level phosphorylation is a metabolism reaction that results in the production of ATP or GTP by the transfer of a phosphate group from a substrate directly to ADP or GDP. Transferring from a higher energy (whether phosphate group atta ...
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.
The combined results of many smaller experiments were required in order to understand the pathway as a whole.
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
Louis Pasteur (, ; 27 December 1822 – 28 September 1895) was a French chemist and microbiologist renowned for his discoveries of the principles of vaccination, microbial fermentation and pasteurization, the latter of which was named afte ...
researched this issue during the 1850s, and the results of his experiments began the long road to elucidating the pathway of glycolysis. His experiments showed that fermentation occurs by the action of living
microorganism
A microorganism, or microbe,, ''mikros'', "small") and ''organism'' from the el, ὀργανισμός, ''organismós'', "organism"). It is usually written as a single word but is sometimes hyphenated (''micro-organism''), especially in olde ...
s, yeasts, and that yeast's glucose consumption decreased under aerobic conditions of fermentation, in comparison to anaerobic conditions (the
Pasteur effect
The Pasteur effect describes how available oxygen inhibits ethanol fermentation, driving yeast to switch toward aerobic respiration for increased generation of the energy carrier adenosine triphosphate (ATP).
Discovery
The effect was described b ...
).
![Eduardbuchner](https://upload.wikimedia.org/wikipedia/commons/b/b2/Eduardbuchner.jpg)
Insight into the component steps of glycolysis were provided by the non-cellular fermentation experiments of
Eduard Buchner
Eduard Buchner (; 20 May 1860 – 13 August 1917) was a German chemist and zymologist, awarded the 1907 Nobel Prize in Chemistry for his work on fermentation.
Biography
Early years
Buchner was born in Munich to a physician and Doctor Extraor ...
during the 1890s. Buchner demonstrated that the conversion of glucose to ethanol was possible using a non-living extract of yeast, due to the action of
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
s in the extract.
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
Sir Arthur Harden, FRS (12 October 1865 – 17 June 1940) was a British biochemist. He shared the Nobel Prize in Chemistry in 1929 with Hans Karl August Simon von Euler-Chelpin for their investigations into the fermentation of sugar and ferment ...
and
William Young William, Will, Bill or Billy Young may refer to:
Arts and entertainment
* William Young (composer) (died 1662), English composer and viola da gambist
* William Young (architect) (1843–1900), Scottish architect, designer of Glasgow City Chambers ...
discovered more pieces of glycolysis.
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.
The elucidation of fructose 1,6-bisphosphate was accomplished by measuring levels when yeast juice was incubated with glucose. 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
Sir Arthur Harden, FRS (12 October 1865 – 17 June 1940) was a British biochemist. He shared the Nobel Prize in Chemistry in 1929 with Hans Karl August Simon von Euler-Chelpin for their investigations into the fermentation of sugar and ferment ...
and
William Young William, Will, Bill or Billy Young may refer to:
Arts and entertainment
* William Young (composer) (died 1662), English composer and viola da gambist
* William Young (architect) (1843–1900), Scottish architect, designer of Glasgow City Chambers ...
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
Cofactor may also refer to:
* Cofactor (biochemistry), a substance that needs to be present in addition to an enzyme for a certain reaction to be catalysed
* A domain parameter in elliptic curve cryptography, defined as the ratio between the order ...
) 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.
![Otto Fritz Meyerhof](https://upload.wikimedia.org/wikipedia/commons/0/05/Otto_Fritz_Meyerhof.jpg)
In the 1920s
Otto Meyerhof
Otto Fritz Meyerhof (; April 12, 1884 – October 6, 1951) was a German physician and biochemist who won the 1922 Nobel Prize in Physiology and Medicine.
Biography
Otto Fritz Meyerhof was born in Hannover, at Theaterplatz 16A (now:Rathenaustrasse ...
was able to link together some of the many individual pieces of glycolysis discovered by Buchner, Harden, and Young. Meyerhof and his team were able to extract different glycolytic enzymes from
muscle tissue
Muscle tissue (or muscular tissue) is soft tissue that makes up the different types of muscles in most animals, and give the ability of muscles to contract. Muscle tissue is formed during embryonic development, in a process known as myogenesis. Mu ...
, and combine them to artificially create the pathway from glycogen to lactic acid.
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.
With all of these pieces available by the 1930s,
Gustav Embden
Gustav Georg Embden (10 November 1874 – 25 July 1933) was a German physiological chemist.
Background
Gustav Embden was a son of the Hamburg lawyer and politician George Heinrich Embden. His grandmother Charlotte Heine was a well-known salonn ...
proposed a detailed, step-by-step outline of that pathway we now know as glycolysis. 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.
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
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
(
G3P).
The first step is phosphorylation of glucose by a family of enzymes called
hexokinase
A hexokinase is an enzyme that phosphorylates hexoses (six-carbon sugars), forming hexose phosphate. In most organisms, glucose is the most important substrate for hexokinases, and glucose-6-phosphate is the most important product. Hexokina ...
s to form glucose 6-phosphate (G6P). This reaction consumes ATP, but it acts to keep the glucose concentration low, promoting continuous transport of glucose into the cell through the plasma membrane transporters. In addition, it 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 Phosphorolysis is the cleavage of a compound in which inorganic phosphate is the attacking group. It is analogous to hydrolysis.Stryer, L. (1988) Biochemistry, 3rd ed., Freeman (p. 451)
An example of this is glycogen breakdown by glycogen phospho ...
or
hydrolysis
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...
of intracellular starch or glycogen.
In
animal
Animals are multicellular, eukaryotic organisms in the Kingdom (biology), biological kingdom Animalia. With few exceptions, animals Heterotroph, consume organic material, Cellular respiration#Aerobic respiration, breathe oxygen, are Motilit ...
s, an
isozyme In biochemistry, isozymes (also known as isoenzymes or more generally as multiple forms of enzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Isozymes usually have different kinetic parameters (e.g. dif ...
of hexokinase called
glucokinase
Glucokinase () is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an important role in ...
is also used in the liver, which has a much lower affinity for glucose (K
m 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:'' Mg
2+
G6P is then rearranged into
fructose 6-phosphate
Fructose 6-phosphate (sometimes called the Neuberg ester) is a derivative of fructose, which has been phosphorylated at the 6-hydroxy group. It is one of several possible fructosephosphates. The β-D-form of this compound is very common in cells ...
(F6P) by
glucose phosphate isomerase.
Fructose
Fructose, or fruit sugar, is a Ketose, ketonic monosaccharide, simple sugar found in many plants, where it is often bonded to glucose to form the disaccharide sucrose. It is one of the three dietary monosaccharides, along with glucose and galacto ...
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
Le Chatelier's principle (pronounced or ), also called Chatelier's principle (or the Equilibrium Law), is a principle of chemistry used to predict the effect of a change in conditions on chemical equilibria. The principle is named after French c ...
. Isomerization to a keto sugar is necessary for carbanion stabilization in the fourth reaction step (below).
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
Phosphofructokinase-1 (PFK-1) is one of the most important regulatory enzymes () of glycolysis. It is an allosteric enzyme made of 4 subunits and controlled by many activators and inhibitors. PFK-1 catalyzes the important "committed" step of g ...
(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
Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrat ...
. 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. A rarer ADP-dependent PFK enzyme variant has been identified in archaean species.
''Cofactors:'' Mg
2+
Destabilizing the molecule in the previous reaction allows the hexose ring to be split by
aldolase
Fructose-bisphosphate aldolase (), often just aldolase, is an enzyme catalyzing a reversible reaction that splits the aldol, fructose 1,6-bisphosphate, into the triose phosphates dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phosphate ( ...
into two triose sugars:
dihydroxyacetone phosphate
Dihydroxyacetone phosphate (DHAP, also glycerone phosphate in older texts) is the anion with the formula HOCH2C(O)CH2OPO32-. This anion is involved in many metabolic pathways, including the Calvin cycle in plants and glycolysis.Nelson, D. L.; ...
(a ketose), and
glyceraldehyde 3-phosphate
Glyceraldehyde 3-phosphate, also known as triose phosphate or 3-phosphoglyceraldehyde and abbreviated as G3P, GA3P, GADP, GAP, TP, GALP or PGAL, is a metabolite that occurs as an intermediate in several central pathways of all organisms.Nelson, D ...
(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
Triose-phosphate isomerase (TPI or TIM) is an enzyme () that catalyzes the reversible interconversion of the triose phosphate isomers dihydroxyacetone phosphate and D-glyceraldehyde 3-phosphate.
TPI plays an important role in glycolysis and ...
rapidly interconverts dihydroxyacetone phosphate with
glyceraldehyde 3-phosphate
Glyceraldehyde 3-phosphate, also known as triose phosphate or 3-phosphoglyceraldehyde and abbreviated as G3P, GA3P, GADP, GAP, TP, GALP or PGAL, is a metabolite that occurs as an intermediate in several central pathways of all organisms.Nelson, D ...
(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.
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.
The aldehyde groups of the triose sugars are
oxidised
Redox (reduction–oxidation, , ) is a type of chemical reaction in which the oxidation states of substrate change. Oxidation is the loss of electrons or an increase in the oxidation state, while reduction is the gain of electrons or a d ...
, and
inorganic phosphate
In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid .
The phosphate or orthophosphate ion is derived from phosphor ...
is added to them, forming
1,3-bisphosphoglycerate
1,3-Bisphosphoglyceric acid (1,3-Bisphosphoglycerate or 1,3BPG) is a 3-carbon organic molecule present in most, if not all, living organisms. It primarily exists as a metabolic intermediate in both glycolysis during respiration and the Calvin cycl ...
.
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 (P
i) group actually exists in the form of a
hydrogen phosphate anion (),
which dissociates to contribute the extra H
+ ion and gives a net charge of -3 on both sides.
Here,
arsenate
The arsenate ion is .
An arsenate (compound) is any compound that contains this ion. Arsenates are salts or esters of arsenic acid.
The arsenic atom in arsenate has a valency of 5 and is also known as pentavalent arsenic or As(V).
Arsenate resem ...
(), an anion akin to inorganic phosphate may replace phosphate as a substrate to form 1-arseno-3-phosphoglycerate. This, however, is unstable and readily hydrolyzes to form
3-phosphoglycerate
3-Phosphoglyceric acid (3PG, 3-PGA, or PGA) is the conjugate acid of 3-phosphoglycerate or glycerate 3-phosphate (GP or G3P). This glycerate is a biochemically significant metabolic intermediate in both glycolysis and the Calvin-Benson cycle. Th ...
, the intermediate in the next step of the pathway. As a consequence of bypassing this step, the molecule of ATP generated from
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.
This step is the enzymatic transfer of a phosphate group from
1,3-bisphosphoglycerate
1,3-Bisphosphoglyceric acid (1,3-Bisphosphoglycerate or 1,3BPG) is a 3-carbon organic molecule present in most, if not all, living organisms. It primarily exists as a metabolic intermediate in both glycolysis during respiration and the Calvin cycl ...
to ADP by
phosphoglycerate kinase
Phosphoglycerate kinase () (PGK 1) is an enzyme that catalyzes the reversible transfer of a phosphate group from 1,3-bisphosphoglycerate (1,3-BPG) to ADP producing 3-phosphoglycerate (3-PG) and ATP :
:1,3-bisphosphoglycerate + ADP glycera ...
, forming ATP and
3-phosphoglycerate
3-Phosphoglyceric acid (3PG, 3-PGA, or PGA) is the conjugate acid of 3-phosphoglycerate or glycerate 3-phosphate (GP or G3P). This glycerate is a biochemically significant metabolic intermediate in both glycolysis and the Calvin-Benson cycle. Th ...
. 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
Substrate-level phosphorylation is a metabolism reaction that results in the production of ATP or GTP by the transfer of a phosphate group from a substrate directly to ADP or GDP. Transferring from a higher energy (whether phosphate group atta ...
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 ATPMg
2−, balancing the charges at −5 both sides.
''Cofactors:'' Mg
2+
Phosphoglycerate mutase
:''This enzyme is not to be confused with Bisphosphoglycerate mutase which catalyzes the conversion of 1,3-bisphosphoglycerate to 2,3-bisphosphoglycerate.''
Phosphoglycerate mutase (PGM) is any enzyme that catalyzes step 8 of glycolysis ...
isomerises
3-phosphoglycerate
3-Phosphoglyceric acid (3PG, 3-PGA, or PGA) is the conjugate acid of 3-phosphoglycerate or glycerate 3-phosphate (GP or G3P). This glycerate is a biochemically significant metabolic intermediate in both glycolysis and the Calvin-Benson cycle. Th ...
into
2-phosphoglycerate.
Enolase
Phosphopyruvate hydratase, usually known as enolase, is a metalloenzyme () that catalyses the conversion of 2-phosphoglycerate (2-PG) to phosphoenolpyruvate (PEP), the ninth and penultimate step of glycolysis. The chemical reaction is:
:2-p ...
next converts
2-phosphoglycerate to
phosphoenolpyruvate
Phosphoenolpyruvate (2-phosphoenolpyruvate, PEP) is the ester derived from the enol of pyruvate and phosphate. It exists as an anion. PEP is an important intermediate in biochemistry. It has the highest-energy phosphate bond found (−61.9 kJ/ ...
. This reaction is an elimination reaction involving an
E1cB
The E1cB elimination reaction is a type of elimination reaction which occurs under basic conditions, where the hydrogen to be removed is relatively acidic, while the leaving group (such as -OH or -OR) is a relatively poor one. Usually a moderate t ...
mechanism.
''Cofactors:'' 2 Mg
2+, one "conformational" ion to coordinate with the carboxylate group of the substrate, and one "catalytic" ion that participates in the dehydration.
A final
substrate-level phosphorylation
Substrate-level phosphorylation is a metabolism reaction that results in the production of ATP or GTP by the transfer of a phosphate group from a substrate directly to ADP or GDP. Transferring from a higher energy (whether phosphate group atta ...
now forms a molecule of
pyruvate
Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell.
Pyruvic aci ...
and a molecule of ATP by means of the enzyme
pyruvate kinase
Pyruvate kinase is the enzyme involved in the last step of glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP), yielding one molecule of pyruvate and one molecule of ATP. Pyru ...
. This serves as an additional regulatory step, similar to the phosphoglycerate kinase step.
''Cofactors:'' Mg
2+
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
A hexokinase is an enzyme that phosphorylates hexoses (six-carbon sugars), forming hexose phosphate. In most organisms, glucose is the most important substrate for hexokinases, and glucose-6-phosphate is the most important product. Hexokina ...
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
Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. The polysaccharide structure represents the main storage form of glucose in the body.
Glycogen functions as one o ...
or
starch
Starch or amylum is a polymeric carbohydrate consisting of numerous glucose units joined by glycosidic bonds. This polysaccharide is produced by most green plants for energy storage. Worldwide, it is the most common carbohydrate in human diets ...
. 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
Phosphofructokinase (PFK) is a kinase enzyme that phosphorylates fructose 6-phosphate in glycolysis.
Function
The enzyme-catalysed transfer of a phosphoryl group from ATP is an important reaction in a wide variety of biological processes. Ph ...
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. Conversely,
triglyceride
A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''tri-'' and ''glyceride'').
Triglycerides are the main constituents of body fat in humans and other vertebrates, as w ...
s 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
The change in free energy, Δ''G'', for each step in the glycolysis pathway can be calculated using Δ''G'' = Δ''G''°' + ''RT''ln ''Q'', where ''Q'' is the
reaction quotient In chemical thermodynamics, the reaction quotient (''Q''r or just ''Q'') is a dimensionless quantity that provides a measurement of the relative amounts of products and reactants present in a reaction mixture for a reaction with well-defined overall ...
. This requires knowing the concentrations of the
metabolites
In biochemistry, a metabolite is an intermediate or end product of metabolism.
The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
. All of these values are available for
erythrocytes
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "holl ...
, with the exception of the concentrations of NAD
+ and NADH. The ratio of
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).
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 Δ''G'' 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
flux
Flux describes any effect that appears to pass or travel (whether it actually moves or not) through a surface or substance. Flux is a concept in applied mathematics and vector calculus which has many applications to physics. For transport ph ...
though the pathway. This is vital for both
homeostatsis in a static environment, and
metabolic adaptation to a changing environment or need. The details of regulation for some enzymes are highly conserved between species, whereas others vary widely.
# Gene Expression: Firstly, the cellular concentrations of glycolytic enzymes are modulated via
regulation of gene expression
Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products (protein or RNA). Sophisticated programs of gene expression are wide ...
via
transcription factors
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The func ...
, with several glycolysis enzymes themselves acting as
regulatory protein kinases in the nucleus.
#
Allosteric inhibition
In biochemistry, allosteric regulation (or allosteric control) is the regulation of an enzyme by binding an effector molecule at a site other than the enzyme's active site.
The site to which the effector binds is termed the ''allosteric site ...
and activation by metabolites: In particular
end-product inhibition
An enzyme inhibitor is a molecule that binds to an enzyme and blocks its activity. Enzymes are proteins that speed up chemical reactions necessary for life, in which substrate molecules are converted into products. An enzyme facilitates a sp ...
of regulated enzymes by metabolites such as ATP serves as negative feedback regulation of the pathway.
# Allosteric inhibition and activation by
Protein-protein interactions (PPI). Indeed, some proteins interact with and regulate multiple glycolytic enzymes.
#
Post-translational modification (PTM). In particular, phosphorylation and dephosphorylation is a key mechanism of regulation of pyruvate kinase in the liver.
#
Localization
Localization or localisation may refer to:
Biology
* Localization of function, locating psychological functions in the brain or nervous system; see Linguistic intelligence
* Localization of sensation, ability to tell what part of the body is a ...
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
homeostasis
In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...
. The
beta cells
Beta cells (β-cells) are a type of cell found in pancreatic islets that synthesize and secrete insulin and amylin. Beta cells make up 50–70% of the cells in human islets. In patients with Type 1 diabetes, beta-cell mass and function are dimini ...
in the
pancreatic islets
The pancreatic islets or islets of Langerhans are the regions of the pancreas that contain its endocrine (hormone-producing) cells, discovered in 1869 by German pathological anatomist Paul Langerhans. The pancreatic islets constitute 1–2% of ...
are sensitive to the blood glucose concentration.
A rise in the blood glucose concentration causes them to release
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...
into the blood, which has an effect particularly on the liver, but also on
fat
In nutrition science, nutrition, biology, and chemistry, fat usually means any ester of fatty acids, or a mixture of such chemical compound, compounds, most commonly those that occur in living beings or in food.
The term often refers spec ...
and
muscle
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
cells, causing these tissues to remove glucose from the blood. When the blood sugar falls the pancreatic beta cells cease insulin production, but, instead, stimulate the neighboring pancreatic
alpha cells
Alpha cells (α cells) are endocrine cells that are found in the Islets of Langerhans in the pancreas. Alpha cells secrete the peptide hormone glucagon in order to increase glucose levels in the blood stream.
Discovery
Islets of Langerhans were ...
to release
glucagon
Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises concentration of glucose and fatty acids in the bloodstream, and is considered to be the main catabolic hormone of the body. It is also used as a Glucagon (medicati ...
into the blood.
This, in turn, causes the liver to release glucose into the blood by breaking down stored
glycogen
Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. The polysaccharide structure represents the main storage form of glucose in the body.
Glycogen functions as one o ...
, and by means of gluconeogenesis. If the fall in the blood glucose level is particularly rapid or severe, other glucose sensors cause the release of
epinephrine
Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...
from the
adrenal glands
The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex which ...
into the blood. This has the same action as glucagon on glucose metabolism, but its effect is more pronounced.
In the liver glucagon and epinephrine cause the
phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
of the key, regulated enzymes of glycolysis,
fatty acid synthesis
In biochemistry, fatty acid synthesis is the creation of fatty acids from acetyl-CoA and NADPH through the action of enzymes called fatty acid synthases. This process takes place in the cytoplasm of the cell. Most of the acetyl-CoA which is conve ...
,
cholesterol synthesis
The mevalonate pathway, also known as the isoprenoid pathway or HMG-CoA reductase pathway is an essential metabolic pathway present in eukaryotes, archaea, and some bacteria. The pathway produces two five-carbon building blocks called isopenten ...
, gluconeogenesis, and glycogenolysis. Insulin has the opposite effect on these enzymes.
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
Phosphofructokinase (PFK) is a kinase enzyme that phosphorylates fructose 6-phosphate in glycolysis.
Function
The enzyme-catalysed transfer of a phosphoryl group from ATP is an important reaction in a wide variety of biological processes. Ph ...
inhibits glycolysis, whereas its dephosphorylation through the action of insulin stimulates glycolysis.
Regulated Enzymes in Glycolysis
The three
regulatory enzymes are
hexokinase
A hexokinase is an enzyme that phosphorylates hexoses (six-carbon sugars), forming hexose phosphate. In most organisms, glucose is the most important substrate for hexokinases, and glucose-6-phosphate is the most important product. Hexokina ...
(or
glucokinase
Glucokinase () is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an important role in ...
in the liver),
phosphofructokinase
Phosphofructokinase (PFK) is a kinase enzyme that phosphorylates fructose 6-phosphate in glycolysis.
Function
The enzyme-catalysed transfer of a phosphoryl group from ATP is an important reaction in a wide variety of biological processes. Ph ...
, and
pyruvate kinase
Pyruvate kinase is the enzyme involved in the last step of glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP), yielding one molecule of pyruvate and one molecule of ATP. Pyru ...
. The
flux
Flux describes any effect that appears to pass or travel (whether it actually moves or not) through a surface or substance. Flux is a concept in applied mathematics and vector calculus which has many applications to physics. For transport ph ...
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
The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...
,
fat tissue
Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular en ...
, and
muscle
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
s, which can remove large quantities of glucose from the blood after meals (thus preventing
hyperglycemia
Hyperglycemia is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a blood sugar level higher than 11.1 mmol/L (200 mg/dL), but symptoms may not start to become noticeable until even ...
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
Hypoglycemia, also called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's triad is used to properly identify hypoglycemic episodes. It is defined as blood glucose belo ...
by means of
glycogenolysis
Glycogenolysis is the breakdown of glycogen (n) to glucose-1-phosphate and glycogen (n-1). Glycogen branches are catabolized by the sequential removal of glucose monomers via phosphorolysis, by the enzyme glycogen phosphorylase.
Mechanism
The ...
and
gluconeogenesis
Gluconeogenesis (GNG) is a metabolic pathway that results in the generation of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrat ...
. These latter reactions coincide with the halting of glycolysis in the liver.
In addition hexokinase and
glucokinase
Glucokinase () is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an important role in ...
act independently of the hormonal effects as controls at the entry points of glucose into the cells of different tissues. Hexokinase responds to the
glucose-6-phosphate
Glucose 6-phosphate (G6P, sometimes called the Robison ester) is a glucose sugar phosphorylated at the hydroxy group on carbon 6. This dianion is very common in cells as the majority of glucose entering a cell will become phosphorylated in this wa ...
(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
Below may refer to:
*Earth
*Ground (disambiguation)
*Soil
*Floor
*Bottom (disambiguation)
Bottom may refer to:
Anatomy and sex
* Bottom (BDSM), the partner in a BDSM who takes the passive, receiving, or obedient role, to that of the top or ...
).
When glucose has been converted into G6P by hexokinase or glucokinase, it can either be converted to
glucose-1-phosphate
Glucose 1-phosphate (also called cori ester) is a glucose molecule with a phosphate group on the 1'-carbon. It can exist in either the α- or β-anomeric form.
Reactions of α-glucose 1-phosphate Catabolic
In glycogenolysis, it is the direct pro ...
(G1P) for conversion to
glycogen
Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. The polysaccharide structure represents the main storage form of glucose in the body.
Glycogen functions as one o ...
, or it is alternatively converted by glycolysis to
pyruvate
Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell.
Pyruvic aci ...
, which enters the
mitochondrion
A mitochondrion (; ) is an organelle found in the cells of most Eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is used ...
where it is converted into
acetyl-CoA
Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized for ...
and then into
citrate
Citric acid is an organic compound with the chemical formula HOC(CO2H)(CH2CO2H)2. It is a colorless weak organic acid. It occurs naturally in citrus fruits. In biochemistry, it is an intermediate in the citric acid cycle, which occurs in t ...
. Excess
citrate
Citric acid is an organic compound with the chemical formula HOC(CO2H)(CH2CO2H)2. It is a colorless weak organic acid. It occurs naturally in citrus fruits. In biochemistry, it is an intermediate in the citric acid cycle, which occurs in t ...
is exported from the mitochondrion back into the cytosol, where
ATP citrate lyase
ATP citrate synthase (also ATP citrate lyase (ACLY)) is an enzyme that in animals represents an important step in fatty acid biosynthesis. By converting citrate to acetyl-CoA, the enzyme links carbohydrate metabolism, which yields citrate as an ...
regenerates
acetyl-CoA
Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism. Its main function is to deliver the acetyl group to the citric acid cycle (Krebs cycle) to be oxidized for ...
and
oxaloacetate
Oxaloacetic acid (also known as oxalacetic acid or OAA) is a crystalline organic compound with the chemical formula HO2CC(O)CH2CO2H. Oxaloacetic acid, in the form of its conjugate base oxaloacetate, is a metabolic intermediate in many processes ...
(OAA). The acetyl-CoA is then used for
fatty acid synthesis
In biochemistry, fatty acid synthesis is the creation of fatty acids from acetyl-CoA and NADPH through the action of enzymes called fatty acid synthases. This process takes place in the cytoplasm of the cell. Most of the acetyl-CoA which is conve ...
and
cholesterol synthesis
The mevalonate pathway, also known as the isoprenoid pathway or HMG-CoA reductase pathway is an essential metabolic pathway present in eukaryotes, archaea, and some bacteria. The pathway produces two five-carbon building blocks called isopenten ...
, two important ways of utilizing excess glucose when its concentration is high in blood. The regulated enzymes catalyzing these reactions perform these functions when they have been dephosphorylated through the action of insulin on the liver cells. Between meals, during
fasting
Fasting is the abstention from eating and sometimes drinking. From a purely physiological context, "fasting" may refer to the metabolic status of a person who has not eaten overnight (see " Breakfast"), or to the metabolic state achieved after ...
,
exercise
Exercise is a body activity that enhances or maintains physical fitness and overall health and wellness.
It is performed for various reasons, to aid growth and improve strength, develop muscles and the cardiovascular system, hone athletic ...
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
The enzyme glucose 6-phosphatase (EC 3.1.3.9, G6Pase; systematic name D-glucose-6-phosphate phosphohydrolase) catalyzes the hydrolysis of glucose 6-phosphate, resulting in the creation of a phosphate group and free glucose:
: D-glucose 6-phos ...
and released into the blood. Glucagon and epinephrine also stimulate gluconeogenesis, which coverts 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.
The simultaneously phosphorylation of, particularly,
phosphofructokinase
Phosphofructokinase (PFK) is a kinase enzyme that phosphorylates fructose 6-phosphate in glycolysis.
Function
The enzyme-catalysed transfer of a phosphoryl group from ATP is an important reaction in a wide variety of biological processes. Ph ...
, but also, to a certain extent pyruvate kinase, prevents glycolysis occurring at the same time as gluconeogenesis and glycogenolysis.
Hexokinase and glucokinase
![Hexokinase B 1IG8 wpmp](https://upload.wikimedia.org/wikipedia/commons/b/bb/Hexokinase_B_1IG8_wpmp.png)
All cells contain the enzyme
hexokinase
A hexokinase is an enzyme that phosphorylates hexoses (six-carbon sugars), forming hexose phosphate. In most organisms, glucose is the most important substrate for hexokinases, and glucose-6-phosphate is the most important product. Hexokina ...
, which catalyzes the conversion of glucose that has entered the cell into
glucose-6-phosphate
Glucose 6-phosphate (G6P, sometimes called the Robison ester) is a glucose sugar phosphorylated at the hydroxy group on carbon 6. This dianion is very common in cells as the majority of glucose entering a cell will become phosphorylated in this wa ...
(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
Glycogenesis is the process of glycogen synthesis, in which glucose molecules are added to chains of glycogen for storage. This process is activated during rest periods following the Cori cycle, in the liver, and also activated by insulin in resp ...
(in the cells which store glycogen, namely liver and muscles).
Glucokinase
Glucokinase () is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an important role in ...
, unlike
hexokinase
A hexokinase is an enzyme that phosphorylates hexoses (six-carbon sugars), forming hexose phosphate. In most organisms, glucose is the most important substrate for hexokinases, and glucose-6-phosphate is the most important product. Hexokina ...
, is not inhibited by G6P. It occurs in liver cells, and will only phosphorylate the glucose entering the cell to form
glucose-6-phosphate
Glucose 6-phosphate (G6P, sometimes called the Robison ester) is a glucose sugar phosphorylated at the hydroxy group on carbon 6. This dianion is very common in cells as the majority of glucose entering a cell will become phosphorylated in this wa ...
(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.
Phosphofructokinase
Phosphofructokinase
Phosphofructokinase (PFK) is a kinase enzyme that phosphorylates fructose 6-phosphate in glycolysis.
Function
The enzyme-catalysed transfer of a phosphoryl group from ATP is an important reaction in a wide variety of biological processes. Ph ...
is an important control point in the glycolytic pathway, since it is one of the irreversible steps and has key allosteric effectors,
AMP #REDIRECT Amp #REDIRECT Amp
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(F2,6BP) is a very potent activator of phosphofructokinase (PFK-1) that is synthesized when F6P is phosphorylated by a second phosphofructokinase (
). In the liver, when blood sugar is low and
. The phosphorylation inactivates
, which converts F2,6BP back to F6P. Both
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
, 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.
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