gluconeogenesis
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Gluconeogenesis (GNG) is a
metabolic pathway In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell (biology), cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence ...
that results in the generation of
glucose Glucose is a simple sugar with the Chemical formula#Molecular formula, molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis f ...
from certain non-
carbohydrate In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may or may ...
carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrates, gluconeogenesis occurs mainly in 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 ...
and, to a lesser extent, in the cortex of the
kidney The kidneys are two reddish-brown bean-shaped organ (anatomy), organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal ...
s. It is one of two primary mechanisms – the other being degradation of
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 of ...
(
glycogenolysis Glycogenolysis is the breakdown of glycogen, glycogen (n) to glucose-1-phosphate and glycogen (n-1). Glycogen branches are catabolism, catabolized by the sequential removal of glucose monomers via phosphorolysis, by the enzyme glycogen phosphory ...
) – used by humans and many other animals to maintain
blood sugar level Glycaemia, also known as blood sugar level, blood sugar concentration, or blood glucose level is the measure of glucose concentrated in the blood of humans or other animals. Approximately 4 grams of glucose, a simple sugar, is present in the blo ...
s, avoiding low levels (
hypoglycemia Hypoglycemia, also called low blood sugar, is a fall in blood sugar Glycaemia, also known as blood sugar level, blood sugar concentration, or blood glucose level is the measure of glucose concentrated in the blood of humans or other animals ...
). In
ruminant Ruminants ( suborder Ruminantia) are hoofed herbivorous grazing or browsing mammals that are able to acquire nutrients from plant-based food by fermenting it in a specialized stomach prior to digestion, principally through microbial actions. ...
s, because dietary carbohydrates tend to be metabolized by
rumen The rumen, also known as a paunch, is the largest stomach compartment in ruminant Ruminants ( suborder Ruminantia) are hoofed herbivorous grazing or browsing mammals that are able to acquire nutrients from plant-based food by fermenting it ...
organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc. In many other animals, the process occurs during periods of
fasting Fasting is the abstention from eating and sometimes drinking. From a purely physiology, physiological context, "fasting" may refer to the metabolism, metabolic status of a person who has not eaten overnight (see "Breakfast"), or to the metabolic ...
,
starvation Starvation is a severe deficiency in caloric food energy, energy intake, below the level needed to maintain an organism's life. It is the most extreme form of malnutrition. In humans, prolonged starvation can cause permanent organ (anatomy), org ...
,
low-carbohydrate diet Low-carbohydrate diets restrict carbohydrate consumption relative to the average diet. Foods high in carbohydrates (e.g., sugar, bread, pasta) are limited, and replaced with foods containing a higher percentage of fat and protein (nutrient), pr ...
s, or intense
exercise Exercise is a Human body, 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 ...
. In humans, substrates for gluconeogenesis may come from any non-carbohydrate sources that can be converted to
pyruvate Pyruvic acid (CH3COCOOH) is the simplest of the keto acids, alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate acid, conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throug ...
or intermediates of
glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvic acid, pyruvate (). The Thermodynamic free energy, free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and NADH, red ...
(see figure). For the breakdown of
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metabo ...
s, these substrates include glucogenic amino acids (although not ketogenic amino acids); from breakdown of
lipid Lipids are a broad group of naturally-occurring molecules which includes fats, waxes, sterols, fat-soluble vitamins (such as vitamins Vitamin A, A, Vitamin D, D, Vitamin E, E and Vitamin K, K), monoglycerides, diglycerides, phospholipids, and o ...
s (such as
triglyceride A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''wikt:tri-#Prefix, tri-'' and ''glyceride''). Triglycerides are the main constituents of body fat in humans and other ...
s), they include
glycerol Glycerol (), also called glycerine in British English and glycerin in American English, is a simple triol compound. It is a colorless, odorless, viscous liquid that is sweet-tasting and non-toxic. The glycerol backbone is found in lipids known ...
, odd-chain fatty acids (although not even-chain fatty acids, see below); and from other parts of
metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...
they include lactate from the Cori cycle. Under conditions of prolonged fasting, acetone derived from
ketone bodies Ketone bodies are water-soluble molecules that contain the ketone, ketone groups produced from fatty acids by the liver (ketogenesis). Ketone bodies are readily transported into tissues outside the liver, where they are converted into acetyl-CoA ( ...
can also serve as a substrate, providing a pathway from fatty acids to glucose. Although most gluconeogenesis occurs in the liver, the relative contribution of gluconeogenesis by the kidney is increased in diabetes and prolonged fasting. The gluconeogenesis pathway is highly endergonic until it is coupled to the hydrolysis of ATP or GTP, effectively making the process exergonic. For example, the pathway leading from
pyruvate Pyruvic acid (CH3COCOOH) is the simplest of the keto acids, alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate acid, conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throug ...
to glucose-6-phosphate requires 4 molecules of ATP and 2 molecules of GTP to proceed spontaneously. These ATPs are supplied from fatty acid catabolism via
beta oxidation In biochemistry and metabolism, beta-oxidation is the catabolism, catabolic process by which fatty acid molecules are broken down in the cytosol in prokaryotes and in the mitochondria in eukaryotes to generate acetyl-CoA, which enters the citric ...
.


Precursors

In humans the main gluconeogenic precursors are lactate,
glycerol Glycerol (), also called glycerine in British English and glycerin in American English, is a simple triol compound. It is a colorless, odorless, viscous liquid that is sweet-tasting and non-toxic. The glycerol backbone is found in lipids known ...
(which is a part of the
triglyceride A triglyceride (TG, triacylglycerol, TAG, or triacylglyceride) is an ester derived from glycerol and three fatty acids (from ''wikt:tri-#Prefix, tri-'' and ''glyceride''). Triglycerides are the main constituents of body fat in humans and other ...
molecule),
alanine Alanine (symbol Ala or A), or α-alanine, is an α-amino acid that is used in the biosynthesis of proteins. It contains an amine, amine group and a carboxylic acid, carboxylic acid group, both attached to the central carbon atom which also carrie ...
and
glutamine Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins ...
. Altogether, they account for over 90% of the overall gluconeogenesis. Other glucogenic amino acids and all
citric acid cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the Redox, oxidation of acetyl-CoA derived from carbohydrates, fats, and p ...
intermediates (through conversion to
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 ...
) can also function as substrates for gluconeogenesis. Generally, human consumption of gluconeogenic substrates in food does not result in increased gluconeogenesis. In
ruminant Ruminants ( suborder Ruminantia) are hoofed herbivorous grazing or browsing mammals that are able to acquire nutrients from plant-based food by fermenting it in a specialized stomach prior to digestion, principally through microbial actions. ...
s, propionate is the principal gluconeogenic substrate. In nonruminants, including human beings, propionate arises from the β-oxidation of odd-chain and branched-chain fatty acids is a (relatively minor) substrate for gluconeogenesis. Lactate is transported back to the liver where it is converted into
pyruvate Pyruvic acid (CH3COCOOH) is the simplest of the keto acids, alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate acid, conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throug ...
by the Cori cycle using the enzyme
lactate dehydrogenase Lactate dehydrogenase (LDH or LD) is an enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enz ...
. Pyruvate, the first designated substrate of the gluconeogenic pathway, can then be used to generate glucose.
Transamination Transamination is a chemical reaction that transfers an amino group to a ketoacid to form new amino acids. This pathway is responsible for the deamination of most amino acids. This is one of the major degradation pathways which convert essential a ...
or
deamination Deamination is the removal of an amino group from a molecule. Enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), su ...
of amino acids facilitates entering of their carbon skeleton into the cycle directly (as pyruvate or oxaloacetate), or indirectly via the citric acid cycle. The contribution of Cori cycle lactate to overall glucose production increases with
fasting Fasting is the abstention from eating and sometimes drinking. From a purely physiology, physiological context, "fasting" may refer to the metabolism, metabolic status of a person who has not eaten overnight (see "Breakfast"), or to the metabolic ...
duration. Specifically, after 12, 20, and 40 hours of fasting by human volunteers, the contribution of Cori cycle lactate to gluconeogenesis was 41%, 71%, and 92%, respectively. Whether even-chain
fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated and unsaturated compounds#Organic chemistry, saturated or unsaturated. Most naturally occurring fatty acids have an B ...
s can be converted into glucose in animals has been a longstanding question in biochemistry. Odd-chain fatty acids can be oxidized to yield
acetyl-CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining che ...
and propionyl-CoA, the latter serving as a precursor to succinyl-CoA, which can be converted to pyruvate and enter into gluconeogenesis. In contrast, even-chain fatty acids are oxidized to yield only acetyl-CoA, whose entry into gluconeogenesis requires the presence of a glyoxylate cycle (also known as glyoxylate shunt) to produce four-carbon dicarboxylic acid precursors. The glyoxylate shunt comprises two enzymes, malate synthase and isocitrate lyase, and is present in fungi, plants, and bacteria. Despite some reports of glyoxylate shunt enzymatic activities detected in animal tissues, genes encoding both enzymatic functions have only been found in
nematode The nematodes ( or grc-gre, Νηματώδη; la, Nematoda) or roundworms constitute the phylum Nematoda (also called Nemathelminthes), with plant-Parasitism, parasitic nematodes also known as eelworms. They are a diverse animal phylum inhab ...
s, in which they exist as a single bi-functional enzyme. Genes coding for malate synthase alone (but not isocitrate lyase) have been identified in other
animal Animals are multicellular, eukaryotic organisms in the biological kingdom Animalia. With few exceptions, animals consume organic material, breathe oxygen, are able to move, can reproduce sexually, and go through an ontogenetic stage i ...
s including
arthropod Arthropods (, (gen. ποδός)) are invertebrate animals with an exoskeleton, a Segmentation (biology), segmented body, and paired jointed appendages. Arthropods form the phylum Arthropoda. They are distinguished by their jointed limbs and Arth ...
s,
echinoderm An echinoderm () is any member of the phylum Echinodermata (). The adults are recognisable by their (usually five-point) radial symmetry, and include starfish, brittle stars, sea urchins, sand dollars, and sea cucumbers, as well as the Crinoi ...
s, and even some
vertebrate Vertebrates () comprise all animal Animals are multicellular, eukaryotic organisms in the biological kingdom Animalia. With few exceptions, animals consume organic material, breathe oxygen, are able to move, can reproduce sexually ...
s. Mammals found to possess the malate synthase gene include
monotreme Monotremes () are prototherian mammals of the order Monotremata. They are one of the three groups of living mammals, along with placentals (Eutheria), and marsupials (Metatheria). Monotremes are typified by structural differences in their brains, ...
s (
platypus The platypus (''Ornithorhynchus anatinus''), sometimes referred to as the duck-billed platypus, is a semiaquatic, egg-laying mammal Endemic (ecology), endemic to Eastern states of Australia, eastern Australia, including Tasmania. The platypu ...
) and
marsupial Marsupials are any members of the mammalian infraclass Marsupialia. All extant marsupials are endemic to Australasia, Wallacea and the Americas. A distinctive characteristic common to most of these species is that the young are carried in a pou ...
s (
opossum Opossums () are members of the marsupial Order (biology), order Didelphimorphia () Endemism, endemic to the Americas. The largest order of marsupials in the Western Hemisphere, it comprises 93 species in 18 Genus, genera. Opossums originated in ...
), but not
placental mammal Placental mammals (infraclass Placentalia ) are one of the three extant subdivisions of the class Mammalia, the other two being Monotremata and Marsupialia. Placentalia contains the vast majority of extant mammals, which are partly distinguished ...
s. The existence of the glyoxylate cycle in humans has not been established, and it is widely held that fatty acids cannot be converted to glucose in humans directly.
Carbon-14 Carbon-14, C-14, or radiocarbon, is a radioactive isotope of carbon with an atomic nucleus containing 6 protons and 8 neutrons. Its presence in organic materials is the basis of the radiocarbon dating method pioneered by Willard Libby and colle ...
has been shown to end up in glucose when it is supplied in fatty acids, but this can be expected from the incorporation of labelled atoms derived from acetyl-CoA into
citric acid cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the Redox, oxidation of acetyl-CoA derived from carbohydrates, fats, and p ...
intermediates which are interchangeable with those derived from other physiological sources, such as glucogenic amino acids. In the absence of other glucogenic sources, the 2-carbon
acetyl-CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining che ...
derived from the oxidation of fatty acids cannot produce a net yield of glucose via the
citric acid cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the Redox, oxidation of acetyl-CoA derived from carbohydrates, fats, and p ...
, since an equivalent two carbon atoms are released as carbon dioxide during the cycle. During
ketosis Ketosis is a metabolic state characterized by elevated levels of ketone bodies in the blood or urine. Physiological ketosis is a normal response to low glucose availability, such as low-carbohydrate diets or fasting, that provides an additional ...
, however, acetyl-CoA from fatty acids yields
ketone bodies Ketone bodies are water-soluble molecules that contain the ketone, ketone groups produced from fatty acids by the liver (ketogenesis). Ketone bodies are readily transported into tissues outside the liver, where they are converted into acetyl-CoA ( ...
, including
acetone Acetone (2-propanone or dimethyl ketone), is an organic compound with the chemical formula, formula . It is the simplest and smallest ketone (). It is a colorless, highly Volatile organic compound, volatile and flammable liquid with a character ...
, and up to ~60% of acetone may be oxidized in the liver to the pyruvate precursors acetol and methylglyoxal. Thus ketone bodies derived from fatty acids could account for up to 11% of gluconeogenesis during starvation. Catabolism of fatty acids also produces energy in the form of ATP that is necessary for the gluconeogenesis pathway.


Location

In mammals, gluconeogenesis has been believed to be restricted to the liver, the kidney, the intestine, and muscle, but recent evidence indicates gluconeogenesis occurring in
astrocyte Astrocytes (from Ancient Greek Ancient Greek includes the forms of the Greek language used in ancient Greece and the classical antiquity, ancient world from around 1500 BC to 300 BC. It is often roughly divided into the following perio ...
s of the brain. These organs use somewhat different gluconeogenic precursors. The liver preferentially uses lactate, glycerol, and glucogenic amino acids (especially
alanine Alanine (symbol Ala or A), or α-alanine, is an α-amino acid that is used in the biosynthesis of proteins. It contains an amine, amine group and a carboxylic acid, carboxylic acid group, both attached to the central carbon atom which also carrie ...
) while the kidney preferentially uses lactate,
glutamine Glutamine (symbol Gln or Q) is an α-amino acid that is used in the biosynthesis of protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins ...
and glycerol. Lactate from the Cori cycle is quantitatively the largest source of substrate for gluconeogenesis, especially for the kidney. The liver uses both
glycogenolysis Glycogenolysis is the breakdown of glycogen, glycogen (n) to glucose-1-phosphate and glycogen (n-1). Glycogen branches are catabolism, catabolized by the sequential removal of glucose monomers via phosphorolysis, by the enzyme glycogen phosphory ...
and gluconeogenesis to produce glucose, whereas the kidney only uses gluconeogenesis. After a meal, the liver shifts to glycogen synthesis, whereas the kidney increases gluconeogenesis. The intestine uses mostly glutamine and glycerol. Propionate is the principal substrate for gluconeogenesis in the ruminant liver, and the ruminant liver may make increased use of gluconeogenic amino acids (e.g., alanine) when glucose demand is increased. The capacity of liver cells to use lactate for gluconeogenesis declines from the preruminant stage to the ruminant stage in calves and lambs. In sheep kidney tissue, very high rates of gluconeogenesis from propionate have been observed. In all species, the formation of
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 ...
from
pyruvate Pyruvic acid (CH3COCOOH) is the simplest of the keto acids, alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate acid, conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throug ...
and TCA cycle intermediates is restricted to the mitochondrion, and the enzymes that convert Phosphoenolpyruvic acid (PEP) to glucose-6-phosphate are found in the cytosol. The location of the enzyme that links these two parts of gluconeogenesis by converting
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 ...
to PEP – PEP carboxykinase (PEPCK) – is variable by species: it can be found entirely within the
mitochondria 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 i ...
, entirely within the
cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cell (biology), cells (Fluid compartments#Intracellular compartment, intracellular fluid (ICF)). It is separated into compartments by membranes. For ...
, or dispersed evenly between the two, as it is in humans. Transport of PEP across the mitochondrial membrane is accomplished by dedicated transport proteins; however no such proteins exist for
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 ...
. Therefore, in species that lack intra-mitochondrial PEPCK,
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 ...
must be converted into
malate Malic acid is an organic compound with the molecular formula . It is a dicarboxylic acid that is made by all living organisms, contributes to the sour taste of fruits, and is used as a food additive. Malic acid has two stereoisomeric forms (L ...
or
aspartate Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...
, exported from the
mitochondrion A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
, and converted back into
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 ...
in order to allow gluconeogenesis to continue.


Pathway

Gluconeogenesis is a pathway consisting of a series of eleven enzyme-catalyzed reactions. The pathway will begin in either the liver or kidney, in the mitochondria or cytoplasm of those cells, this being dependent on the substrate being used. Many of the reactions are the reverse of steps found in
glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvic acid, pyruvate (). The Thermodynamic free energy, free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and NADH, red ...
. * Gluconeogenesis begins in the mitochondria with the formation of oxaloacetate by the carboxylation of pyruvate. This reaction also requires one molecule of ATP, and is catalyzed by pyruvate carboxylase. This enzyme is stimulated by high levels of
acetyl-CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining che ...
(produced in β-oxidation in the liver) and inhibited by high levels of ADP and glucose. * Oxaloacetate is reduced to
malate Malic acid is an organic compound with the molecular formula . It is a dicarboxylic acid that is made by all living organisms, contributes to the sour taste of fruits, and is used as a food additive. Malic acid has two stereoisomeric forms (L ...
using
NADH Nicotinamide adenine dinucleotide (NAD) is a Cofactor (biochemistry), coenzyme central to metabolism. Found in all living cell (biology), cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphat ...
, a step required for its transportation out of the mitochondria. * Malate is oxidized to oxaloacetate using NAD+ in the cytosol, where the remaining steps of gluconeogenesis take place. * Oxaloacetate is decarboxylated and then phosphorylated to form
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 high-energy phosphate, highest-energy phosphate bo ...
using the enzyme PEPCK. A molecule of GTP is hydrolyzed to
GDP Gross domestic product (GDP) is a money, monetary Measurement in economics, measure of the market value of all the final goods and services produced and sold (not resold) in a specific time period by countries. Due to its complex and subjec ...
during this reaction. * The next steps in the reaction are the same as reversed
glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvic acid, pyruvate (). The Thermodynamic free energy, free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and NADH, red ...
. However, fructose 1,6-bisphosphatase converts
fructose 1,6-bisphosphate Fructose 1,6-bisphosphate, also known as Harden-Young ester, is fructose sugar phosphorylated on carbons 1 and 6 (i.e., is a fructosephosphate). The β-D-form of this compound is common in cell (biology), cells. Upon entering the cell, most glucos ...
to
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 cell (b ...
, using one water molecule and releasing one phosphate (in glycolysis,
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 Enzyme activator, activators and Enzyme inhibitor, inhibitors. PFK-1 catalyzes t ...
converts F6P and ATP to F1,6BP and
ADP Adp or ADP may refer to: Aviation * Aéroports de Paris, airport authority for the Parisian region in France * Aeropuertos del Perú, airport operator for airports in northern Peru * SLAF Anuradhapura, an airport in Sri Lanka * Ampara Airpor ...
). This is also the rate-limiting step of gluconeogenesis. * Glucose-6-phosphate is formed from
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 cell (b ...
by phosphoglucoisomerase (the reverse of step 2 in glycolysis). Glucose-6-phosphate can be used in other metabolic pathways or dephosphorylated to free glucose. Whereas free glucose can easily diffuse in and out of the cell, the phosphorylated form (glucose-6-phosphate) is locked in the cell, a mechanism by which intracellular glucose levels are controlled by cells. * The final gluconeogenesis, the formation of glucose, occurs in the lumen of the
endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ...
, where glucose-6-phosphate is hydrolyzed by glucose-6-phosphatase to produce glucose and release an inorganic phosphate. Like two steps prior, this step is not a simple reversal of glycolysis, in which
hexokinase A hexokinase is an enzyme that phosphorylation, phosphorylates hexoses (six-carbon sugars), forming hexose phosphate. In most organisms, glucose is the most important substrate (biochemistry), substrate for hexokinases, and glucose-6-phospha ...
catalyzes the conversion of glucose and ATP into G6P and ADP. Glucose is shuttled into the cytoplasm by
glucose transporter Glucose transporters are a wide group of membrane protein Membrane proteins are common proteins that are part of, or interact with, biological membranes. Membrane proteins fall into several broad categories depending on their location. Integ ...
s located in the endoplasmic reticulum's membrane.


Regulation

While most steps in gluconeogenesis are the reverse of those found in
glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvic acid, pyruvate (). The Thermodynamic free energy, free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and NADH, red ...
, three regulated and strongly endergonic reactions are replaced with more kinetically favorable reactions.
Hexokinase A hexokinase is an enzyme that phosphorylation, phosphorylates hexoses (six-carbon sugars), forming hexose phosphate. In most organisms, glucose is the most important substrate (biochemistry), substrate for hexokinases, and glucose-6-phospha ...
/
glucokinase Glucokinase () is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cell (biology), cells in the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an imp ...
,
phosphofructokinase Phosphofructokinase (PFK) is a kinase enzyme that phosphorylation, phosphorylates fructose 6-phosphate in glycolysis. Function The enzyme-catalysed transfer of a phosphoryl group from Adenosine triphosphate, ATP is an important reaction in a ...
, and
pyruvate kinase Pyruvate kinase is the enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the s ...
enzymes of glycolysis are replaced with glucose-6-phosphatase, fructose-1,6-bisphosphatase, and PEP carboxykinase/pyruvate carboxylase. These enzymes are typically regulated by similar molecules, but with opposite results. For example,
acetyl CoA Acetyl-CoA (acetyl coenzyme A) is a molecule that participates in many biochemical reactions in protein, carbohydrate and lipid metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining che ...
and
citrate Citric acid is an organic compound with the chemical formula HOC(CO2H)(CH2CO2H)2. It is a Transparency and translucency, colorless Weak acid, weak organic acid. It occurs naturally in Citrus, citrus fruits. In biochemistry, it is an intermedi ...
activate gluconeogenesis enzymes (pyruvate carboxylase and fructose-1,6-bisphosphatase, respectively), while at the same time inhibiting the glycolytic enzyme
pyruvate kinase Pyruvate kinase is the enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the s ...
. This system of reciprocal control allow glycolysis and gluconeogenesis to inhibit each other and prevents a futile cycle of synthesizing glucose to only break it down. Pyruvate kinase can be also bypassed by 86 pathways not related to gluconeogenesis, for the purpose of forming pyruvate and subsequently lactate; some of these pathways use carbon atoms originated from glucose. The majority of the
enzymes Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
responsible for gluconeogenesis are found in the
cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cell (biology), cells (Fluid compartments#Intracellular compartment, intracellular fluid (ICF)). It is separated into compartments by membranes. For ...
; the exceptions are mitochondrial pyruvate carboxylase and, in animals, phosphoenolpyruvate carboxykinase. The latter exists as an isozyme located in both the
mitochondrion A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
and the
cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cell (biology), cells (Fluid compartments#Intracellular compartment, intracellular fluid (ICF)). It is separated into compartments by membranes. For ...
. The rate of gluconeogenesis is ultimately controlled by the action of a key enzyme, fructose-1,6-bisphosphatase, which is also regulated through signal transduction by cAMP and its phosphorylation. Global control of gluconeogenesis is mediated by
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 ...
(''released when blood glucose is low''); it triggers phosphorylation of enzymes and regulatory proteins by
Protein Kinase A In cell biology, protein kinase A (PKA) is a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, including regulatio ...
(a cyclic AMP regulated kinase) resulting in inhibition of glycolysis and stimulation of gluconeogenesis.
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 Anabolism, anabolic hormone of the body. It regulates the m ...
counteracts glucagon by inhibiting gluconeogenesis. Type 2 diabetes is marked by excess glucagon and
insulin resistance Insulin resistance (IR) is a pathological condition in which cell (biology), cells fail to respond normally to the hormone insulin. Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood gluco ...
from the body. Insulin can no longer inhibit the gene expression of enzymes such as PEPCK which leads to increased levels of hyperglycemia in the body. The anti-diabetic drug
metformin Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type 2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome ...
reduces blood glucose primarily through inhibition of gluconeogenesis, overcoming the failure of insulin to inhibit gluconeogenesis due to insulin resistance. Studies have shown that the absence of hepatic glucose production has no major effect on the control of fasting plasma glucose concentration. Compensatory induction of gluconeogenesis occurs in the kidneys and intestine, driven by
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 ...
, glucocorticoids, and acidosis.


Insulin resistance

In the liver, the FOX protein FOXO6 normally promotes gluconeogenesis in the fasted state, but
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 Anabolism, anabolic hormone of the body. It regulates the m ...
blocks FOXO6 upon feeding. In a condition of
insulin resistance Insulin resistance (IR) is a pathological condition in which cell (biology), cells fail to respond normally to the hormone insulin. Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood gluco ...
, insulin fails to block FOXO6 resulting in continued gluconeogenesis even upon feeding, resulting in high blood glucose (
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 Blood sugar#Units, mmol/L (200 Blood sugar#Units, mg/dL), but symptoms may not s ...
). Insulin resistance is a common feature of
metabolic syndrome Metabolic syndrome is a clustering of at least three of the following five medical conditions: abdominal obesity, hypertension, high blood pressure, hyperglycemia, high blood sugar, Hypertriglyceridemia, high serum triglycerides, and low serum hi ...
and
type 2 diabetes Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by hyperglycemia, high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include polydipsia, increased th ...
. For this reason gluconeogenesis is a target of therapy for type 2 diabetes, such as the antidiabetic drug
metformin Metformin, sold under the brand name Glucophage, among others, is the main first-line medication for the treatment of type 2 diabetes, particularly in people who are overweight. It is also used in the treatment of polycystic ovary syndrome ...
, which inhibits gluconeogenic glucose formation, and stimulates glucose uptake by cells.  


See also

*
Bioenergetics Bioenergetics is a field in biochemistry and cell biology that concerns energy flow through living systems. This is an active area of Biology, biological research that includes the study of the transformation of energy in living organisms and the ...


References


External links


Overview at indstate.edu





''metpath'': Interactive representation of gluconeogenesis
{{MetabolismMap Metabolism Biochemistry Metabolic pathways Carbohydrates Glycobiology Exercise physiology Hepatology Diabetes