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The Cori cycle (also known as the lactic acid cycle), named after its discoverers,
Carl Ferdinand Cori and
Gerty Cori
Gerty Theresa Cori (; August 15, 1896 – October 26, 1957) was an Austro-Hungarian and American biochemist who in 1947 was the third woman to win a Nobel Prize in science, and the first woman to be awarded the Nobel Prize in Physiology or Me ...
,
is a metabolic pathway in which
lactate, produced by anaerobic
glycolysis
Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...
in muscles, is transported to the liver and converted to glucose, which then returns to the muscles and is cyclically metabolized back to lactate.
Process
Muscular activity requires
ATP, which is provided by the breakdown 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 o ...
in the
skeletal muscles
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 muscle ...
. The breakdown of glycogen, known as
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 ...
, releases
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 ...
in the form of
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 ...
(G1P). The G1P is converted to
G6P
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 way ...
by
phosphoglucomutase
Phosphoglucomutase () is an enzyme that transfers a phosphate group on an α-D-glucose monomer from the 1 to the 6 position in the forward direction or the 6 to the 1 position in the reverse direction.
More precisely, it facilitates the interconve ...
. G6P is readily fed into
glycolysis
Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...
, (or can go into 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 ...
if G6P concentration is high) a process that provides ATP to the
muscle cells
A muscle cell is also known as a myocyte when referring to either a cardiac muscle cell (cardiomyocyte), or a smooth muscle cell as these are both small cells. A skeletal muscle cell is long and threadlike with many nuclei and is called a mus ...
as an energy source. During muscular activity, the store of ATP needs to be constantly replenished. When the supply of
oxygen
Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as wel ...
is sufficient, this energy comes from feeding
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 ...
, one product of glycolysis, into 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 oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins ...
, which ultimately generates ATP through oxygen-dependent
oxidative phosphorylation
Oxidative phosphorylation (UK , US ) or electron transport-linked phosphorylation or terminal oxidation is the metabolic pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in order to produce adenosine tri ...
.
When oxygen supply is insufficient, typically during intense muscular activity, energy must be released through
anaerobic metabolism
Anaerobic respiration is respiration using electron acceptors other than molecular oxygen (O2). Although oxygen is not the final electron acceptor, the process still uses a respiratory electron transport chain.
In aerobic organisms undergoing re ...
.
Lactic acid fermentation
Lactic acid fermentation is a metabolic process by which glucose or other six-carbon sugars (also, disaccharides of six-carbon sugars, e.g. sucrose or lactose) are converted into cellular energy and the metabolite lactate, which is lactic acid ...
converts pyruvate to
lactate by
lactate dehydrogenase
Lactate dehydrogenase (LDH or LD) is an enzyme found in nearly all living cells. LDH catalyzes the conversion of lactate to pyruvate and back, as it converts NAD+ to NADH and back. A dehydrogenase is an enzyme that transfers a hydride from on ...
. Most importantly, fermentation regenerates
NAD+, maintaining its concentration so additional glycolysis reactions can occur. The fermentation step oxidizes the
NADH
Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an aden ...
produced by glycolysis back to NAD
+, transferring two electrons from
NADH
Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an aden ...
to reduce pyruvate into lactate. (Refer to the main articles on
glycolysis
Glycolysis is the metabolic pathway that converts glucose () into pyruvate (). The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH ...
and
fermentation
Fermentation is a metabolic process that produces chemical changes in organic substrates through the action of enzymes. In biochemistry, it is narrowly defined as the extraction of energy from carbohydrates in the absence of oxygen. In food ...
for the details.)
Instead of accumulating inside the muscle cells, lactate produced by anaerobic fermentation is taken up by 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 ...
. This initiates the other half of the Cori cycle. In the liver,
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 ...
occurs. From an intuitive perspective, gluconeogenesis reverses both glycolysis and fermentation by converting lactate first into pyruvate, and finally back to glucose. The glucose is then supplied to the muscles through the
bloodstream
The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
; it is ready to be fed into further glycolysis reactions. If muscle activity has stopped, the glucose is used to replenish the supplies of glycogen through
glycogenesis
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 re ...
.
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Overall, the glycolysis steps of the cycle produce 2 ATP molecules at a cost of 6 ATP molecules consumed in the gluconeogenesis steps. Each iteration of the cycle must be maintained by a net consumption of 4 ATP molecules. As a result, the cycle cannot be sustained indefinitely. The intensive consumption of ATP molecules in the Cori cycle shifts the
metabolic
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 ...
burden from the muscles to the liver.
Significance
The cycle's importance is based on preventing
lactic acidosis
Lactic acidosis is a medical condition characterized by a build-up of lactate (especially -lactate) in the body, with formation of an excessively low pH in the bloodstream. It is a form of metabolic acidosis, in which excessive acid accumulates ...
during anaerobic conditions in the muscle. However, normally, before this happens, the lactic acid is moved out of the muscles and into the liver.
Additionally, this cycle is important in ATP production, an energy source, during muscle exertion. The end of muscle exertion allows the Cori cycle to function more effectively. This repays the oxygen debt so both the electron transport chain and citric acid cycle can produce energy at optimum effectiveness.
The Cori cycle is a much more important source of substrate for
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 ...
than food.
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 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 ...
duration before plateauing.
Specifically, after 12, 20, and 40 hours of fasting by human volunteers, gluconeogenesis accounts for 41%, 71%, and 92% of glucose production, but the contribution of Cori cycle lactate to gluconeogenesis is 18%, 35%, and 36%, respectively.
The remaining glucose production comes from protein breakdown,
muscle glycogen,
and
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 ...
from
lipolysis
Lipolysis is the metabolic pathway through which lipid triglycerides are hydrolyzed into a glycerol and free fatty acids. It is used to mobilize stored energy during fasting or exercise, and usually occurs in fat adipocytes. The most important ...
.
The 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. ...
can cause lactic acidosis in patients with
kidney failure
Kidney failure, also known as end-stage kidney disease, is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney failure is classified as eit ...
because metformin inhibits the hepatic gluconeogenesis of the Cori cycle, particularly the mitochondrial respiratory chain complex 1.
The buildup of lactate and its substrates for lactate production, pyruvate and alanine, lead to excess lactate.
Normally, the excess acid that is the result of the inhibition of the mitochondrial chain complex would be cleared by the kidneys, but in patients with kidney failure, the kidneys cannot handle the excess acid.
A common misconception posits that lactate is the agent responsible for the acidosis, but lactate is a
conjugate base
A conjugate acid, within the Brønsted–Lowry acid–base theory, is a chemical compound formed when an acid donates a proton () to a base—in other words, it is a base with a hydrogen ion added to it, as in the reverse reaction it loses a ...
, being mostly ionised at physiologic pH, and serves as a marker of associated acid production rather than being its cause.
See also
*
Alanine cycle
The Cahill cycle, also known as the alanine cycle or glucose-alanine cycle, is the series of reactions in which amino groups and carbons from muscle are transported to the liver. It is quite similar to the Cori cycle in the cycling of nutrients b ...
*
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 oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins ...
References
Further reading
*
{{DEFAULTSORT:Cori Cycle
Metabolic pathways
Exercise physiology
1929 in science