Article Figures & Data
Figures
- Fig. 1.
The proposed topology of the MCT family members. CD147, the ancillary protein that associates with MCT1 and MCT4, is also shown. The N and C termini and the large loop between transmembrane domains 6 and 7 show the greatest variation between family members, whereas the TMDs themselves are highly conserved. Adapted from Halestrap and Meredith (2004) and Halestrap (2013a).
- Fig. 2.
The phylogenetic tree of human MCT isoforms. Sequence alignments were performed using Clustal Omega, and phylogeny trees were made using interactive Tree Of Life (iTOL). The bar indicates the number of per amino acid residue, with one corresponding to a distance of one substitution per 10 amino acid residues. Adapted from Halestrap (2012).
- Fig. 3.
Tissue protein expression of MCT isoforms in humans, based on data compiled by Morris and Felmlee (2008).
- Fig. 4.
The proton antenna effect of CAs in the regulation of MCT1/4. CAII/IX, carbonic anhydrase II/IX; GLUT, glucose transporter; H+, proton; LDH, lactate dehydrogenase. Adapted from Noor et al., 2018. Created with BioRender.com.
- Fig. 5.
A representation of the Warburg Effect by which glycolytic and oxidative cancer cells participate in lactate shuttling. GLUT, glucose transporter; H+, proton; LDHA/B, lactate dehydrogenase A/B; TCA, tricarboxylic acid cycle. Created with BioRender.com.
Tables
- TABLE 1
A summary of the percent amino acid identity of the human MCT isoforms (matrix was generated using Clustal Omega)
MCT1 MCT2 MCT3 MCT4 MCT5 MCT6 MCT7 MCT8 MCT9 MCT10 MCT11 MCT12 MCT13 MCT14 MCT1 100 59.21 39.43 44.57 24.11 29.07 29.05 22.84 23.03 24.23 28.8 29.37 30.81 24.94 MCT2 59.21 100 42.77 46.74 26.39 32.16 31.61 24.22 26.88 24.38 32.05 29.83 31.83 27.23 MCT3 39.43 42.77 100 56.93 24.71 37.5 28.12 26.34 26.46 26.61 36.05 33.47 34.44 23.98 MCT4 44.57 46.74 56.93 100 25.43 36.81 31.82 26.68 28.68 26.33 32.64 34.85 30.56 27.95 MCT5 24.11 26.39 24.71 25.43 100 24.23 27.48 22.43 25.91 24.16 26.59 29.91 29.8 25.58 MCT6 29.07 32.16 37.5 36.81 24.23 100 28.57 24.19 23.94 23.81 30.32 30.18 28.43 24.71 MCT7 29.05 31.61 28.12 31.82 27.48 28.57 100 21.22 26.62 20.5 25.78 25.48 34.36 22.74 MCT8 22.84 24.22 26.34 26.68 22.43 24.19 21.22 100 25.94 52.17 26.01 22.43 23.13 23.68 MCT9 23.03 26.88 26.46 28.68 25.91 23.94 26.62 25.94 100 27.23 27.47 25.68 29.24 32.16 MCT10 24.23 24.38 26.61 26.33 24.16 23.81 20.5 52.17 27.23 100 25.84 23.64 24.28 26.44 MCT11 28.8 32.05 36.05 32.64 26.59 30.32 25.78 26.01 27.47 25.84 100 30.23 46.93 27.51 MCT12 29.37 29.83 33.47 34.85 29.91 30.18 25.48 22.43 25.68 23.64 30.23 100 33.01 28.57 MCT13 30.81 31.83 34.44 30.56 29.8 28.43 34.36 23.13 29.24 24.28 46.93 33.01 100 26.93 MCT14 24.94 27.23 23.98 27.95 25.58 24.71 22.74 23.68 32.16 26.44 27.51 28.57 26.93 100 Transporter Unigene Name Tissue Distribution Subcellular Localization Expression Species References MCT1 SLC16A1 Ubiquitous Apical and basolateral membrane Human Halestrap and Meredith, 2004; Gill et al., 2005 MCT2 SLC16A7 Liver Basolateral membrane Protein Human Garcia et al., 1994; Lin et al., 1998; Halestrap and Meredith, 2004; Wilson et al., 2005; Becker et al., 2010b Kidney Basolateral membrane Protein Human Apical Mouse Skeletal muscle Protein Human Heart Protein Human Brain Protein Human Spleen Protein Human Testis Basolateral membrane Protein Human Pancreas Protein Human MCT3 SLC16A8 Retinal pigment epithelium Basolateral membrane Halestrap and Meredith, 2004 MCT4 SLC16A3 Kidney Basolateral membrane Protein Human Dimmer et al., 2000; Halestrap and Meredith, 2004; Settle et al., 2004; Gill et al., 2005; Wang et al., 2006b Skeletal muscle Protein Human Intestine Basolateral membrane Protein Human Heart Protein Human Lung Protein Human MCT5 SLC16A4 Liver mRNA Rat Felmlee Kidney mRNA Rat MCT6 SLC16A5 Kidney mRNA Rat Felmee Intestine Basolateral membrane Protein Human Gill et al., 2005 MCT7 SLC16A6 Kidney mRNA Rat Felmlee MCT8 SLC16A2 Liver Sinusoidal membrane mRNA Human, Rat Bonen et al., 2006; Nishimura and Naito, 2008; Roberts et al., 2008 Kidney Basolateral membrane (proximal tubule) mRNA Human, Rat Felmlee Adrenal gland mRNA Human Brain (neurons, blood brain barrier) mRNA Human Choroid plexus Apical membrane Protein Human Mouse Ovary mRNA Human Thyroid gland mRNA Human Uterus mRNA Human Placenta mRNA Human Heart mRNA Human Protein Rat Lung mRNA Rat MCT10 SLC16A10 Liver mRNA Rat Felmlee Kidney mRNA Rat Intestine mRNA Rat Lung mRNA Rat MCT11 SLC16A11 Liver mRNA Rat Felmlee Kidney mRNA Rat Lung mRNA Rat MCT12 SLC16A12 Liver mRNA Rat Felmlee Kidney mRNA Rat Lung mRNA Rat MCT13 SLC16A13 Liver mRNA Rat Felmlee Kidney mRNA Rat Intestine mRNA Rat Lung mRNA Rat MCT14 SLC16A14 Peripheral blood mononuclear cells mRNA Human Banerjee et al., 2017 Kidney mRNA Rat Felmlee - TABLE 3
Substrates and inhibitors of monocarboxylate transporters
Km, Ki, and IC50 values were obtained from the listed references and Morris and Felmlee (2008).
Isoform Species Expression System Substrate Km (mM) Inhibitor Ki or IC50 (µM) References MCT1 Human Caco-2 Hesperetin NA Shen et al., 2015 Xenopus oocytes Lactate 3.5–6 Phloretin 28a Bröer et al., 1998; Lin et al., 1998; Juel and Halestrap, 1999; Cuff et al., 2002; Cundy et al., 2004; Nancolas et al., 2016; Curtis et al., 2017 Pyruvate 1.8–2.5 Quercetin NA α-Ketoisovalerate 1.3 CHC 425a α-Oxoisohexanoate 0.67 pCMBS NA α-Oxoisovalerate 1.25 XP13512 0.62b Butyrate 9 Lonidamine 36.8a XP13512 0.22 Jurkat membranes AZD3965 0.0016a Rat MDA-MB231 GHB 4.6 Phloretin 28b Bröer et al., 1998, 1999; Wang et al., 2006a Xenopus oocytes Lactate 3.5 Quercetin 14b GHB 4.6 Benzobromaron 22b CHC 425b MCT2 Human Xenopus oocytes Pyruvate 0.025 CHC NA Lin et al., 1998; Nancolas et al., 2016 L-Lactate NA GHB NA Lonidamine 36.4a Rat Xenopus oocytes Lactate 0.74 Phloretin 14b Broer et al., 1999; Curtis et al., 2017 Pyruvate NA Quercetin 5b Benzobromaron 9b CHC 24b Recombinant MCT2-expressing yeast membranes AZD3965 0.020a MCT3 Human ARPE-19 cells Lactate NA Philp et al., 2003 MCT4 Human Xenopus oocytes L-lactate 28 pCMBS 21a Manning Fox et al., 2000; Kobayashi et al., 2006; Nancolas et al., 2016 D-lactate 519 CHC 991a Pyruvate 153 Phloretin 41a D-β-hydroxybutyrate 130 NPPB 240a Acetoacetate 216 Fluvastatin 32b α-Ketobutyrate 57 Atorvastatin 32b α-Ketoisocaproate 95 Lovastatin 44b α-Ketoisovalerate 113 Simvastatin 79b Lonidamine 40.4a Rat Xenopus oocytes L-lactate 34 CHC 350b Dimmer et al., 2000 Pyruvate 36 pCMBS NA 2-Oxoisohexanoate 13 Acetoacetate 31 β-Hydroxybutyrate 65 MCT5 Unknown MCT6 Human Xenopus oocytes Bumetanide 0.084 Furosemide 46b Murakami et al., 2005; Kohyama et al., 2013 Nateglinide 0.046 Azosemide 21b Prostaglandin F2α NA Piretanide 163b Probenecid NA Torasemide 13b Thiazides NA Probenecid NA Glibenclamide NA Nateglinide 5.4a Quercetin 25b Jones et al., 2017 Luteolin NA Phloretin 23a, 17b Morin 33b MCT7 Human Ketone bodies (β-hydroxybutyrate) NA Hugo et al., 2012 Zebrafish NA MCT8 Human COS1 and JEG3 cells T3 NA Friesema et al., 2006 T4 NA Rat Xenopus oocytes T3 NA N-bromoacetyl-T3 NA Friesema et al., 2003 T4 NA Bromosulfophthalein NA MCT9 Carnitine NA Jones and Morris, 2016 MCT10 Rat Xenopus oocytes L-Trytophan 3.8 Kim et al., 2001 L-Tyrosine 2.6 L-Phenylalanine 7.0 L-DOPA 6.4 MCT11 Unknown Jones and Morris, 2016 MCT12 Human Xenopus oocytes Creatinine 0.57 Abplanalp et al., 2013 Rat Creatinine NA Abplanalp et al., 2013 MCT13 Unknown Jones and Morris, 2016 MCT14 Unknown Jones and Morris, 2016 Health/Disease Relation Reference MCT1, 2, 4 High expression in many cancer types, including breast, bone, colon, bladder, prostate, and renal cancers Park et al., 2018 MCT1 Mutations in promoter region lead to exercise-induced hyperinsulinemia Otonkoski et al., 2007 The missense mutation (1470T > A) results in an amino acid substitution leading to less efficient lactate transport Onali et al., 2018 Deficiency has also been associated with recurrent ketoacidosis in children Fisel et al., 2018 Acute exercise-induced upregulation in skeletal muscle Bickham et al., 2006 MCT2 SNPs (rs10506398 and rs10506399) were associated with increased infertility in Korean men Jones and Morris, 2016 Implicated as a potential biomarker and treatment of prostate cancer Pertega-Gomes et al., 2013 MCT4 Increased expression in obesity, followed by a decreased expression with weight loss Fisel et al., 2018 Upregulation via hypoxia through a HIF-1α–dependent pathway Ullah et al., 2006 MCT3 and 4 Wounded RPE results in a decrease in expression of MCT3, and an increase in the expression of MCT4 Gallagher-Colombo et al., 2010 MCT5 Gene expression was significantly upregulated in colorectal adenocarcinoma Liu et al., 2018 SNP (rs17025736) results in an intron variant of the human MCT5 gene, which is associated with adolescent idiopathic scoliosis Buniello et al., 2019 Enhancement of West Nile virus infection was demonstrated when MCT5 was silenced Krishnan et al., 2008; Fisel et al., 2018 MCT6 Plays a role in the intestinal absorption of nateglinide, bumetanide’s brain penetration Kohyama et al., 2013; Romermann et al., 2017 Hypomethylation of MCT6, along with hypermethylation of a ZFN206, results in significantly prolonged event-free survival in neuroblastomas Sugito et al., 2013 May play a role as a biomarker in Alzheimer’s disease risk Boada et al., 2014; Wei et al., 2019 Significant variant (rs4788863) resulted in a significant decrease in cisplatin-induced ototoxicity severity in testicular cancer patients Drögemöller et al., 2017 MCT7 Suggested to play a role in liver disease primarily from evidence gathered in preclinical models Hugo et al., 2012; Kim et al., 2016; Karanth and Schlegel, 2019 MCT8 Various mutations results in AHDS, which results in increased serum thyroid hormone: T3, due to the decrease in the cellular uptake Friesema et al., 2003; Dumitrescu et al., 2004, 2006; Schwartz et al., 2005; Trajkovic et al., 2007; Wirth et al., 2009 MCT10 A SNP in the gene was found to result in lower free plasma T3 concentrations van der Deure et al., 2007 Importance in maintaining circulating and liver aromatic amino acid concentrations in vivo Mariotta et al., 2012 Functional role in aromatic amino acid transport and its relation to NASH due to the significant downregulation of gene expression Lake et al., 2015 MCT11 Mutations in the gene encoding for MCT11 have been implicated in the risk of T2D Williams et al., 2014; Rusu et al., 2017; Kimura et al., 2018 SNP (rs13342232) was found to be significantly associated with the occurrence of T2D in adults and children Miranda-Lora et al., 2017 MCT12 Mutation in the gene encoding for MCT12 was identified in a Swiss family with autosomal dominant juvenile cataracts, microcornea, as well as renal glucosuria Kloeckener-Gruissem et al., 2008 A SNP was identified in the 5′UTR of MCT12, which provided evidence for its role in regulation of translational efficiency that could potentially be associated with age-related cataracts Zuercher et al., 2010 Mutation in MCT12’s coding region of exon 6 yielded evidence that suggested that the variant most likely impacts correct protein folding and trafficking with basigin Castorino et al., 2011b In vitro and in vivo evidence for MCT12’s role in creatinine transporter, which supported a plausible mechanism by which MCT12 mutations lead to perturbations in the eye Abplanalp et al., 2013 Impacts the renal handling of creatinine transport and systemic concentrations of its precursor, guanidinoacetate Dhayat et al., 2016 MCT13 May also play a functional role in T2D risk Rusu et al., 2017 MCT14 Gene expression was shown to increase 2.1-fold following treatment with ethanol for 48 hours vs. no treatment in immortalized lymphoblastoid cells originally isolated from subjects enrolled in the Collaborative Study on the Genetics of Alcoholism McClintick et al., 2019
In this issue
Jump to section
- Article
- Abstract
- I. Introduction
- II. Structure and Function
- III. Expression and Localization
- IV. Substrates and Inhibitors
- V. Regulation and Development
- VI. Monocarboxylate Transporters in Health and Disease
- VII. Findings from the Use of Genetically-Modified Mct Rodent Models
- VIII. Conclusions and Future Studies
- Authorship Contributions
- Footnotes
- Abbreviations
- References
- Figures & Data
- Info & Metrics
- eLetters
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