Biology:Monocarboxylate transporter 1

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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]

References

  1. ↑ "Molecular characterization of a membrane transporter for lactate, pyruvate, and other monocarboxylates: implications for the Cori cycle". Cell 76 (5): 865–73. Mar 1994. doi:10.1016/0092-8674(94)90361-1. PMID 8124722. 
  2. ↑ "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. doi:10.1006/geno.1994.1532. PMID 7835905. 
  3. ↑ "Entrez Gene: SLC16A1 solute carrier family 16, member 1 (monocarboxylic acid transporter 1)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6566. 
  4. ↑ "Monocarboxylate Transporters (SLC16): Function, Regulation, and Role in Health and Disease". Pharmacological Reviews 72 (2): 466–485. 2020. doi:10.1124/pr.119.018762. PMID 32144120. 
  5. ↑ "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. doi:10.1158/1538-7445.AM2015-2673. PMID 26609475. 
  6. ↑ "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. doi:10.1016/S0002-9440(10)62548-5. PMID 11943706. 
  7. ↑ "Overexpression of monocarboxylate transporter-1 (SLC16A1) in mouse pancreatic β-cells leads to relative hyperinsulinism during exercise". Diabetes 61 (7): 1719–25. Jul 2012. doi:10.2337/db11-1531. PMID 22522610. 
  8. ↑ "HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 7; HHF7" (in en-us). https://omim.org/entry/610021. 
  9. ↑ "MONOCARBOXYLATE TRANSPORTER 1 DEFICIENCY; MCT1D" (in en-us). https://omim.org/entry/616095. 
  10. ↑ "ERYTHROCYTE LACTATE TRANSPORTER DEFECT" (in en-us). https://omim.org/entry/245340. 

Further reading




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