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.