The monocarboxylate transporters, or MCTs, are a family of

proton A proton is a stable subatomic particle, symbol , Hydron (chemistry), H+, or 1H+ with a positive electric charge of +1 ''e'' (elementary charge). Its mass is slightly less than the mass of a neutron and approximately times the mass of an e ...

-linked plasma membrane transporters that carry molecules having one

carboxylate In organic chemistry, a carboxylate is the conjugate base of a carboxylic acid, (or ). It is an anion, an ion with negative charge. Carboxylate salts are salts that have the general formula , where M is a metal and ''n'' is 1, 2,... ...

group (monocarboxylates), such as lactate,

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 ...

, and

ketone In organic chemistry, a ketone is an organic compound with the structure , where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group (a carbon-oxygen double bond C=O). The simplest ketone is acetone ( ...

s across biological membranes.

Acetate An acetate is a salt formed by the combination of acetic acid with a base (e.g. alkaline, earthy, metallic, nonmetallic, or radical base). "Acetate" also describes the conjugate base or ion (specifically, the negatively charged ion called ...

is actively transported to intestinal enteroendocrine cells via MCT, termed Targ (short for Tarag in Mongolian). MCTs are expressed in nearly every kind of cell. There are 14 MCTs corresponding to 14 solute carrier 16A transporters, although the cardinal numbers do not match (for example MCT3 is SLC16A8). MCTs 1-4 have been more carefully investigated than MCTs 5-14. MCTs can be upregulated by PPAR-α, HIF-1α,

Nrf2 Nuclear factor erythroid 2-related factor 2 (NRF2), also known as nuclear factor erythroid-derived 2-like 2, is a transcription factor that in humans is encoded by the ''NFE2L2'' gene. NRF2 is a basic leucine zipper (bZIP) protein that may regu ...

, and AMPK.

Lactate and the Cori cycle

Lactate has long been considered a byproduct resulting from glucose breakdown through

glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvic acid, pyruvate and, in most organisms, occurs in the liquid part of cells (the cytosol). The Thermodynamic free energy, free energy released in this process is used to form ...

during anaerobic metabolism. Glycolysis requires the coenzyme NAD⁺, and reduces it to NADH. As a means of regenerating NAD⁺ to allow glycolysis to continue,

lactate dehydrogenase Lactate dehydrogenase (LDH or LD) is an enzyme found in nearly all living cells. LDH catalyzes the conversion of pyruvic acid, pyruvate to lactic acid, lactate and back, as it converts NAD+ to NADH and back. A dehydrogenase is an enzyme that t ...

catalyzes the conversion of

to lactate in the cytosol, oxidizing NADH to NAD⁺. Lactate is then transported from the peripheral tissues to the liver. There it is reformed into pyruvate and ultimately to glucose, which can travel back to the peripheral tissues, completing the

Cori cycle The Cori cycle (also known as the lactic acid cycle), named after its discoverers, Carl Ferdinand Cori and Gerty Cori, is a metabolic pathway in which lactic acid, lactate, produced by anaerobic glycolysis in muscles, is transported to the liver ...

. Thus, lactate has traditionally been considered a toxic metabolic byproduct that could give rise to fatigue and muscle pain during anaerobic respiration. Lactate can be thought of essentially as payment for " oxygen debt", defined by Hill and Lupton as the "total amount of oxygen used, after cessation of exercise in recovery there from".

Clinical significance

Highly malignant tumors rely heavily on aerobic glycolysis (metabolism of glucose to lactic acid even under presence of oxygen; Warburg effect) and thus need to efflux lactic acid via MCTs to the tumor micro-environment to maintain a robust glycolytic flux and to prevent the tumor from being "pickled to death". The MCTs have been successfully targeted in pre-clinical studies using RNAi and a small-molecule inhibitor alpha-cyano-4-hydroxycinnamic acid (ACCA; CHC) to show that inhibiting lactic acid efflux is a very effective therapeutic strategy against highly glycolytic malignant tumors.Colen, CB, PhD Thesis (2005) http://elibrary.wayne.edu/record=b3043899~S47

References

{{Reflist Transmembrane transporters

Lactate and the Cori cycle

Clinical significance

See also

References