The monocarboxylate transporters, or MCTs, are a family of
proton-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 ion with negative charge.
Carboxylate salts are salts that have the general formula , where M is a metal and ''n'' is 1, 2,...; ''carboxylat ...
group (monocarboxylates), such as
lactate,
pyruvate, and
ketones across
biological membranes
A biological membrane, biomembrane or cell membrane is a selectively permeable membrane that separates the interior of a cell from the external environment or creates intracellular compartments by serving as a boundary between one part of the c ...
.
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
In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary pro ...
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 reg ...
, and
AMPK AMPK may refer to:
* AMP-activated protein kinase
5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme (EC 2.7.11.31) that plays a role in cellular energy homeostasis, largely to activate gl ...
.
Lactate and the Cori cycle
Lactate has long been considered a byproduct resulting from glucose breakdown through
glycolysis 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 lactate to pyruvate and back, as it converts NAD+ to NADH and back. A dehydrogenase is an enzyme that transfers a hydride from one ...
catalyzes the conversion of
pyruvate 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 lactate, produced by anaerobic glycolysis in muscles, is transported to the liver and convert ...
.
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 anaerobic 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]
See also
Monocarboxylate transporters:
References
{{Reflist
Transmembrane transporters