Conclusion
The sodium dependent SLC13 transporter of di and tricarboxylates inhibitors are intended to treat various metabolic disorders including diabetes and obesity. The drugs mechanism and favorable risk-benefit ratio needs to be understood to further characterize their role against neurological disorders and cancer. In the recent past, significant efforts have been made in characterization of the proteins and discovery of novel inhibitors against these transporters. Reviewed literature revealed that in recent years there is more focus on basic residue and neutralization of it which may results in discovering the beneficial effects. The emphasis on mutation unlike from the brain alleviates the symptoms associated with the metabolic diseases. The NaCT has many functional roles to play such as glycolysis, fatty acids and cholesterol and regulating it with exogenous di and tri carboxylates regarded as potential treatment of various disorders. More specific ligands may be designed that may act as a lead molecule for future drug developments. Some of the key findings of the review are firstly, the amino acid residue Ar108 is present in highly conserved H4c domain of the NaCT receptors and neutralization of this basic residue inhibited the transport activity. Secondly crosslinking either the inwards or outward facing state of the receptors by cysteine mutants or excess HgCl2 reduced the transport activity. Thirdly mutation of amino acids presents in the transmembrane pore and citrate binding sites completely inhibited the citrate transport. Similarly, NaCT knockout mice also confirmed for reduced lipogenesis and higher energy expenditure. Fourth the 2-hydroxycarboxylate inhibitors modifications of either-OH or -COOH reduce the affinity of the transporter and Senantiomers binds efficiently while R enantiomer is devoid of any affinity. Citrate has several roles to play in the normal physiological process of the body and therefore its regulation may alleviate the symptoms associated with the cancer, inflammation, fatty liver diseases, obesity, diabetes, and CNS disorders. Consequently, both the receptor structure and the inhibitors design of new molecules needs to be taken in account to mitigate metabolic disorders.