Monocarboxylate transporter 1 explained

Monocarboxylate transporter 1 is a ubiquitous protein that in humans is encoded by the SLC16A1 gene (also known as MCT1).^{[1] [2] [3]} It is a proton coupled monocarboxylate transporter.

Biochemistry

Detailed kinetic analysis of monocarboxylate transport in erythrocytes revealed that MCT1 operates through an ordered mechanism. MCT1 has a substrate binding site open to the extracellular matrix which binds a proton first followed by the lactate anion. The protein then undergoes a conformational change to a new ‘closed’’ conformation that exposes both the proton and lactate to the opposite surface of the membrane where they are released, lactate first and then the proton. For net transport of lactic acid, the rate-limiting step is the return of MCT1 without bound substrate to the open conformation. For this reason, exchange of one monocarboxylate inside the cell with another outside is considerably faster than net transport of a monocarboxylate across the membrane.

MCT1 can be upregulated by PPAR-α, Nrf2, and AMPK.^[4]

Animal studies

Overexpression of MCT1 has been shown to increase the efficacy of an anti-cancer drug currently undergoing clinical trials called 3-bromopyruvate in breast cancer cells.^[5]

Clinical significance

Most cases of alveolar soft part sarcoma show PAS(+), diastase-resistant (PAS-D (+)) intracytoplasmic crystals which contain CD147 and monocarboxylate transporter 1 (MCT1).^[6] Overexpression of MCT1 in pancreatic beta cells leads to hyperinsulinism during exercise.^[7]

Hyperinsulinemic hypoglycemia, familial, 7 (HHF7) is an autosomal dominant disease on the SLC16A1/MCT gene on chromosome 1p13.2. It causes hyperinsulinemic hypoglycemia, where hyperinsulinism is exercise-induced.^[8]

Monocarboxylate transporter 1 deficiency (MCTD1) is an autosomal dominant and recessive disease on the SLC16A1/MCT1 gene on chromosome 1p13.2. It causes poor feeding and vomiting, intellectual disability, ketotic hypoglycemia, ketoacidosis, ketonuria, with episodes brought on by fasting or infection.^[9]

Erythrocyte lactate transporter defect (formerly, myopathy due to lactate transport defect) is an autosomal dominant disease on the SLC16A1/MCT gene on chromosome 1p.13.2. It causes exercise-induced muscle cramping, stiffness, and fatigue (exercise intolerance); symptoms may also be induced by heat. Although symptoms present in the muscles, muscle biopsy and EMG are normal. Decreased erythrocyte (red blood cell) lactate clearance, decreased lactate clearance from muscle after exercise, and elevated serum creatine kinase.^[10]

Further reading

• Bonen A . The expression of lactate transporters (MCT1 and MCT4) in heart and muscle . European Journal of Applied Physiology . 86 . 1 . 6–11 . Nov 2001 . 11820324 . 10.1007/s004210100516 . 12166288 .
• Halestrap AP, Meredith D . The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond . Pflügers Archiv: European Journal of Physiology . 447 . 5 . 619–28 . Feb 2004 . 12739169 . 10.1007/s00424-003-1067-2 . 15498611 .
• Kim CM, Goldstein JL, Brown MS . cDNA cloning of MEV, a mutant protein that facilitates cellular uptake of mevalonate, and identification of the point mutation responsible for its gain of function . The Journal of Biological Chemistry . 267 . 32 . 23113–21 . Nov 1992 . 10.1016/S0021-9258(18)50064-8 . 1429658 . free .
• Bonaldo MF, Lennon G, Soares MB . Normalization and subtraction: two approaches to facilitate gene discovery . Genome Research . 6 . 9 . 791–806 . Sep 1996 . 8889548 . 10.1101/gr.6.9.791 . free .
• Ritzhaupt A, Wood IS, Ellis A, Hosie KB, Shirazi-Beechey SP . Identification and characterization of a monocarboxylate transporter (MCT1) in pig and human colon: its potential to transport L-lactate as well as butyrate . The Journal of Physiology . 513 . Pt 3 . 719–32 . Dec 1998 . 9824713 . 2231331 . 10.1111/j.1469-7793.1998.719ba.x.
• Rahman B, Schneider HP, Bröer A, Deitmer JW, Bröer S . Helix 8 and helix 10 are involved in substrate recognition in the rat monocarboxylate transporter MCT1 . Biochemistry . 38 . 35 . 11577–84 . Aug 1999 . 10471310 . 10.1021/bi990973f .
• Brooks GA, Brown MA, Butz CE, Sicurello JP, Dubouchaud H . Cardiac and skeletal muscle mitochondria have a monocarboxylate transporter MCT1 . Journal of Applied Physiology . 87 . 5 . 1713–8 . Nov 1999 . 10562613 . 10.1152/jappl.1999.87.5.1713. 1484319 .
• Merezhinskaya N, Fishbein WN, Davis JI, Foellmer JW . Mutations in MCT1 cDNA in patients with symptomatic deficiency in lactate transport . Muscle & Nerve . 23 . 1 . 90–7 . Jan 2000 . 10590411 . 10.1002/(SICI)1097-4598(200001)23:1<90::AID-MUS12>3.0.CO;2-M . 36707820 . free .
• Kirk P, Wilson MC, Heddle C, Brown MH, Barclay AN, Halestrap AP . CD147 is tightly associated with lactate transporters MCT1 and MCT4 and facilitates their cell surface expression . The EMBO Journal . 19 . 15 . 3896–904 . Aug 2000 . 10921872 . 306613 . 10.1093/emboj/19.15.3896 .
• Cuff MA, Lambert DW, Shirazi-Beechey SP . Substrate-induced regulation of the human colonic monocarboxylate transporter, MCT1 . The Journal of Physiology . 539 . Pt 2 . 361–71 . Mar 2002 . 11882670 . 2290148 . 10.1113/jphysiol.2001.014241 .
• Cuff MA, Shirazi-Beechey SP . The human monocarboxylate transporter, MCT1: genomic organization and promoter analysis . Biochemical and Biophysical Research Communications . 292 . 4 . 1048–56 . Apr 2002 . 11944921 . 10.1006/bbrc.2002.6763 .
• Lambert DW, Wood IS, Ellis A, Shirazi-Beechey SP . Molecular changes in the expression of human colonic nutrient transporters during the transition from normality to malignancy . British Journal of Cancer . 86 . 8 . 1262–9 . Apr 2002 . 11953883 . 2375337 . 10.1038/sj.bjc.6600264 .
• Zhang GZ, Huang GJ, Li WL, Wu GM, Qian GS . [Effect of co-inhibition of MCT1 gene and NHE1 gene on proliferation and growth of human lung adenocarcinoma cells] . AI Zheng = Aizheng = Chinese Journal of Cancer . 21 . 7 . 719–23 . Jul 2002 . 12479094 .
• Philp NJ, Wang D, Yoon H, Hjelmeland LM . Polarized expression of monocarboxylate transporters in human retinal pigment epithelium and ARPE-19 cells . Investigative Ophthalmology & Visual Science . 44 . 4 . 1716–21 . Apr 2003 . 12657613 . 10.1167/iovs.02-0287 . free .
• Asada K, Miyamoto K, Fukutomi T, Tsuda H, Yagi Y, Wakazono K, Oishi S, Fukui H, Sugimura T, Ushijima T . Reduced expression of GNA11 and silencing of MCT1 in human breast cancers . Oncology . 64 . 4 . 380–8 . 2003 . 12759536 . 10.1159/000070297 . 9041712 .

Notes and References

1. Garcia CK, Goldstein JL, Pathak RK, Anderson RG, Brown MS . Molecular characterization of a membrane transporter for lactate, pyruvate, and other monocarboxylates: implications for the Cori cycle . Cell . 76 . 5 . 865–73 . Mar 1994 . 8124722 . 10.1016/0092-8674(94)90361-1 . 22137883 .
2. Garcia CK, Li X, Luna J, Francke U . cDNA cloning of the human monocarboxylate transporter 1 and chromosomal localization of the SLC16A1 locus to 1p13.2-p12 . Genomics . 23 . 2 . 500–3 . Sep 1994 . 7835905 . 10.1006/geno.1994.1532 . free .
3. Web site: Entrez Gene: SLC16A1 solute carrier family 16, member 1 (monocarboxylic acid transporter 1).
4. Felmlee MA, Jones RS, Morris ME . Monocarboxylate Transporters (SLC16): Function, Regulation, and Role in Health and Disease . . 72 . 2 . 466–485 . 2020 . 10.1124/pr.119.018762 . 7062045 . 32144120.
5. Liu Z, Sun Y, Hong H, Zhao S, Zou X, Ma R, Jiang C, Wang Z, Li H, Liu H . 3-bromopyruvate enhanced daunorubicin-induced cytotoxicity involved in monocarboxylate transporter 1 in breast cancer cells . American Journal of Cancer Research . 5 . 9 . 2673–85 . 2015-08-15 . 10.1158/1538-7445.AM2015-2673 . 26609475 . 4633897 .
6. Ladanyi M, Antonescu CR, Drobnjak M, Baren A, Lui MY, Golde DW, Cordon-Cardo C . The precrystalline cytoplasmic granules of alveolar soft part sarcoma contain monocarboxylate transporter 1 and CD147 . The American Journal of Pathology . 160 . 4 . 1215–21 . Apr 2002 . 11943706 . 10.1016/S0002-9440(10)62548-5 . 1867200.
7. Pullen TJ, Sylow L, Sun G, Halestrap AP, Richter EA, Rutter GA . Overexpression of monocarboxylate transporter-1 (SLC16A1) in mouse pancreatic β-cells leads to relative hyperinsulinism during exercise . Diabetes . 61 . 7 . 1719–25 . Jul 2012 . 22522610 . 3379650 . 10.2337/db11-1531 .
8. Web site: HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 7; HHF7 . 2023-08-21 . omim.org . en-us.
9. Web site: MONOCARBOXYLATE TRANSPORTER 1 DEFICIENCY; MCT1D . 2023-08-21 . omim.org . en-us.
10. Web site: ERYTHROCYTE LACTATE TRANSPORTER DEFECT . 2023-08-21 . omim.org . en-us.