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The mitochondrial pyruvate carrier (MPC) had been studied extensively in the 1970s through 1990s by two lab groups primarily, Andrew Halestrap and Katarzyna Nalęcz, providing many predictions on the functional protein structure and the mechanism of substrate binding. (Halestrap, A P, Denton, 1974; Halestrap, 1975, 1976, 1978a, 1978b; Hildyard, Ämmälä, Dukes, Thomson, & Halestrap, 2005; K. Nałȩcz, 1994; Nałecz, Kamińska, Nałecz, & Azzi, 1992; K. A. Nałȩcz, Müller, Zambrowicz, Wojtczak, & Azzi, 1990; M. J. Nałȩcz et al., 1986) The two genes for MPC had been identified in 2012, along with evidence for pyruvate transport, but there was still doubt as to whether an MPC1 – MPC2 complex within the inner mitochondrial membrane (IMM) had pyruvate transport abilities (Bricker et al., 2012; Halestrap, 2012; Herzig et al., 2012). Recently, Halestrap and coworkers have utilized homology modeling and molecular dynamic simulations to generate 3 dimensional models of proton-linked monocarboxylate transporters (MCTs) and to identify key amino acid residues in the transport cargo and blocker binding sites (Manoharan, Wilson, Sessions, & Halestrap, 2006; Nancolas, Sessions, & Halestrap, 2015; Wilson, Meredith, Bunnun, Sessions, & Halestrap, 2009). Likewise, for MPC, still since 2012, no crystal structure has yet been registered or deposited in a protein data bank (PDB); and thus, a similar approach is reasonable. One homology model of the MPC1/2 heterodimer has been proposed using the bacterial semiSWEET (4QND.PDB) transporter as a template with indications of residues involved in the ligand binding site (Vanderperre, Bender, Kunji, & Martinou, 2015). This present report describes results for another MPC1/2 heterodimer homology model, based on a template using the E. coli respiratory complex I membrane domain B (3RKO.PDB), residues 242-366 and rmsd ranging from 2 to 9 Å. Along with the ligand docking results, this model is entirely consistent with and supports the hypothetical models proposed by both Halestrap and Nalęcz (Halestrap, 1978a, 1978b; K. Nałȩcz, 1994). The predicted amino acid sequences for human MPC1 and MPC2 from UniProt (Bateman et al., 2015) were used.
Inhibition of the MPC as a novel therapeutic target is being tested currently at Phase 2 (MSDC-0160; NCT01374438) (Shah et al., 2014) clinical trial focused on progression from mild cognitive impairment to dementia of Alzheimer’s disease, (MSDC-0602; NCT02784444) for non-alcoholic steato-hepatitis (NASH) (Chen et al., 2012; McCommis, Hodges, Brunt, et al., 2016), and diabetes mellitus (MSDC-0160; NCT00760578) (Colca, VanderLugt et al., 2013); and soon for Parkinson’s disease (MSDC-0160) (Ghosh et al., 2016). Another study on treatment to delay onset of Alzheimer’s disease is in Phase 3 (pioglitazone, aka AD-4833; NCT01931566) (Crenshaw et al., 2015) and there is some evidence that it can bind MPC but that is not the stated target for this treatment. Thiazolidinediones (TZDs), pioglitazone (a peroxisome proliferator-activated receptor-gamma, PPARγ, agonist) and MSDC-0160 and MSDC-0602 (PPARγ-sparing TZDs) (Chen et al., 2012), are the drugs being tested. Thus, any new information and insight on the mechanisms of actions of these drugs are valuable and the 3D standard data file (SDF) formats, required for ligand docking in silico, are available for each of these drugs, as well as most of the classical inhibitors used in the very early biochemical studies. This study focuses only on the two MSDC drugs.