6lz0

Structural highlights

Disease

MOT1_HUMAN Metabolic myopathy due to lactate transporter defect;Ketoacidosis due to monocarboxylate transporter-1 deficiency;Exercise-induced hyperinsulinism. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry. The disease is caused by variants affecting the gene represented in this entry.

Function

MOT1_HUMAN Bidirectional proton-coupled monocarboxylate transporter (PubMed:12946269, PubMed:33333023, PubMed:32946811). Catalyzes the rapid transport across the plasma membrane of many monocarboxylates such as lactate, pyruvate, acetate and the ketone bodies acetoacetate and beta-hydroxybutyrate, and thus contributes to the maintenance of intracellular pH (PubMed:12946269, PubMed:33333023). The transport direction is determined by the proton motive force and the concentration gradient of the substrate monocarboxylate. MCT1 is a major lactate exporter (By similarity). Plays a role in cellular responses to a high-fat diet by modulating the cellular levels of lactate and pyruvate that contribute to the regulation of central metabolic pathways and insulin secretion, with concomitant effects on plasma insulin levels and blood glucose homeostasis (By similarity). Facilitates the protonated monocarboxylate form of succinate export, that its transient protonation upon muscle cell acidification in exercising muscle and ischemic heart (PubMed:32946811). Functions via alternate outward- and inward-open conformation states. Protonation and deprotonation of 309-Asp is essential for the conformational transition (PubMed:33333023).[UniProtKB:P53986][UniProtKB:P53987]^{[1] [2] [3]}

References

1. ↑ Galić S, Schneider HP, Bröer A, Deitmer JW, Bröer S. The loop between helix 4 and helix 5 in the monocarboxylate transporter MCT1 is important for substrate selection and protein stability. Biochem J. 2003 Dec 1;376(Pt 2):413-22. PMID:12946269 doi:10.1042/BJ20030799
2. ↑ Reddy A, Bozi LHM, Yaghi OK, Mills EL, Xiao H, Nicholson HE, Paschini M, Paulo JA, Garrity R, Laznik-Bogoslavski D, Ferreira JCB, Carl CS, Sjøberg KA, Wojtaszewski JFP, Jeppesen JF, Kiens B, Gygi SP, Richter EA, Mathis D, Chouchani ET. pH-Gated Succinate Secretion Regulates Muscle Remodeling in Response to Exercise. Cell. 2020 Oct 1;183(1):62-75.e17. PMID:32946811 doi:10.1016/j.cell.2020.08.039
3. ↑ Wang N, Jiang X, Zhang S, Zhu A, Yuan Y, Xu H, Lei J, Yan C. Structural basis of human monocarboxylate transporter 1 inhibition by anti-cancer drug candidates. Cell. 2021 Jan 21;184(2):370-383.e13. PMID:33333023 doi:10.1016/j.cell.2020.11.043