Involvement of Human Multidrug and Toxic Compound Extrusion (MATE) Transporters in Testosterone Transport

Abstract

Multidrug and toxic compound extrusion (MATE) transporters are primarily expressed in the kidneys and liver, where they contribute to the excretion of organic cations. Our previous study suggested that pig MATE2 (class III) participates in testosterone secretion from Leydig cells. In humans, it is unclear which MATE class is involved in testosterone transport. In this study, we aimed to clarify whether human MATE1 (hMATE1) or human MATE2K (hMATE2K) mediates testosterone transport. To confirm that testosterone inhibits transporter-mediated tetraethylammonium (TEA) uptake, a cis-inhibition assay was performed using cells that stably expressed hMATE1 or hMATE2K. Docking simulations were performed to characterize differences in the binding of hMATE1 and hMATE2K to testosterone. Transport experiments in LLC-PK1 cells that stably expressed hMATE1 were used to test whether hMATE1 mediates testosterone transport. We detected differences between the amino acid sequences of the substrate-binding sites of hMATE1 and hMATE2K that could potentially be involved in testosterone binding. Testosterone and estradiol inhibited TEA uptake mediated by hMATE1 but not that mediated by hMATE2K. Transport experiments in LLC-PK1 cells indicated that testosterone might be transported via hMATE1. This study suggested that hMATE1, but not hMATE2K, is involved in human testosterone transport.

Prediction of Inhibitory Activity Against the MATE1 Transporter via Combined Fingerprint- and Physics-Based Machine Learning Models

“…Since the best balanced accuracy of this model was 0.59, the predictivity was numerically moderate; however, this research for the first time utilized structural information in MATE1 activity modelling 17 . The most recent models also used structural information: In one study performed in early 2021, although there was no construction of predictive models, the authors built a homology model of hMATE1 from PDB entry 3MKT (the multidrug transport protein NorM from Vibrio cholerae) 18 .…”

Drug Transporters in the Kidney: Perspectives on Species Differences, Disease Status, and Molecular Docking

“…dimensional structure of hMATE1 was predicted using Modeller, based on the NorM-VC (Protein Data Bank ID: 3MKT) X-ray crystal structure dataGoda et al (2021) hMATE2K inhibitor 3 compounds The three-dimensional structure of hMATE2K was predicted using Modeller, based on the NorM-VC (Protein Data Bank ID: 3MKT) X-ray crystal structure dataGoda et al (2021) MRP2 substrates 11 polyphenolic compounds The Homology modeling of MRP2 were the structure of Caenorhabditis elegans P-gp (PDB code: 4F4C) and the human MRP1 (PDB code: 2CBZ)…”