Amino Acid Transporters as Disease Modifiers and Drug Targets

Abstract

Amino acids perform a variety of functions in cells and organisms, particularly in the synthesis of proteins, as energy metabolites, neurotransmitters, and precursors for many other molecules. Amino acid transport plays a key role in all these functions. Inhibition of amino acid transport is pursued as a therapeutic strategy in several areas, such as diabetes and related metabolic disorders, neurological disorders, cancer, and stem cell biology. The role of amino acid transporters in these disorders and processes is well established, but the implementation of amino acid transporters as drug targets is still in its infancy. This is at least in part due to the underdeveloped pharmacology of this group of membrane proteins. Recent advances in structural biology, membrane protein expression, and inhibitor screening methodology will see an increased number of improved and selective inhibitors of amino acid transporters that can serve as tool compounds for further studies.

Novel Chemical Scaffolds to Inhibit the Neutral Amino Acid Transporter B0AT1 (SLC6A19), a Potential Target to Treat Metabolic Diseases

“…the outside open conformation. The transition state of the transporter is formed by an induced fit around the substrate (Kramer, 1994;Broer, 2018). Transport inhibitors prevent the adoption of the transition state either by being too bulky (Singh et al, 2008) or by providing insufficient interactions to reduce the activation energy to form the occluded state.…”

“…Compound CB3 had its most likely pose further away from Na + 1 , suggesting a possible non-competitive mode of inhibition ( Figure 5F). Many transport inhibitors are substrate analogues that are too large to fit into the occluded substrate binding cavity, thereby blocking the conformational change required for transport (Broer, 2018). In docking studies with a homology model of the LeuT occluded structure we could not compute a docking score for E4, E18, or CB3 at the substrate binding site ( Figure 5G).…”

“…Moreover, amino acids are important signalling molecules that regulate protein biosynthesis, autophagy, ribosome biogenesis, gluconeogenesis, neurotransmitter levels, release of hormones, and many other functions. As a result, amino acid transporters are increasingly investigated as potential drug targets (Broer, 2018). The epithelial neutral amino acid transporter B 0 AT1 (SLC6A19) was initially identified as the molecule mutated in the rare condition Hartnup disorder (Kleta et al, 2004;Seow et al, 2004).…”

Glutamate transporters: a broad review of the most recent archaeal and human structures

“…As the major excitatory transmitter, glutamate has a key role in the pathogenesis of different neurological disorders [1]: excess extracellular glutamate is toxic to the surrounding neurons via overstimulation that can result in cell damage and/or death. This has been linked to epilepsy, episodic ataxia, schizophrenia and Alzheimer's disease [10], and so EAATs have attracted much attention as they represent targets for understanding and treating these disorders [11].…”

Amino Acid Transport Defects in Human Inherited Metabolic Disorders

“…An association has been found between amino acid transporter-associated diseases and metabolic disorders in instances in which transporters are closely connected to metabolism, particularly when they involve different cell types, organs, or cell compartments [17][18][19]. Table 1 summarizes the human SLC amino acid transporters that have been identified and their respective transporter genes.…”