Abstract
The sodium dependent SLC13 family transporters comprise of the five
genes SLC13A1, SLC13A2 (NaDC1), SLC13A3 (NaDC3), SLC13A4 and SLC13A5
(NaCT). Among them the three NaDC1, NaDC3 and NaCT are sodium dependent
transporters such as di-carboxylates (succinate, malate,
α-ketoglutarate) and tricarboxylates (citrate). The mouse and the human
NaCT structures have still not been crystallized, the information to the
structures is taken from the related bacterial transporter of VcINDY.
Citrate in the cytosol works as precursor for the fatty acid synthesis,
cholesterol, and low-density lipoproteins. The excess citrate from the
matrix is translocated to the cytosol for fatty acid synthesis through
these receptors and thus controls the energy balance by downregulating
the glycolysis, tricarboxylic acid (TCA), and fatty acid breakdown.
These transporters play an important role in regulating various
metabolic diseases including cancer, diabetes, obesity, fatty liver
diseases and CNS disorders. These di and tricarboxylate transporters are
emerging as new targets for metabolic disorders such as obesity and
diabetes. The mutation in the function of the NaCT causes several
neurological diseases including neonatal epilepsy and impaired brain
development whereas mutation of the citrate present in the liver may
provide positive effect. Therefore, continued efforts from the earlier
work on citrate transporter are required for the development of citrate
inhibitors. In this review the structure, function, and regulation of
the NaCT receptors are discussed. The review also highlights citrate
role in diagnosing diseases such as cancer, diabetes, fatty liver, and
diabetes. The therapeutic perspective of synthetic inhibitors against
NaCT receptors are succinctly summarized.
Keywords: Citrate, dicarboxylates, NaCT, ATP citrate lyase,
citrate transporter
Introduction
Citrate, malate, succinate, and oxaloacetate are formed in steps of
Citric acid cycle. These intermediates are precursors of anabolic
pathways for fatty acids, cholesterol, glucose, pyruvate, amino acids,
and nucleotides. These also help in the regulation of important
biological processes including fatty acid synthesis and glycolysis
[1]. They act as a source for the cytosolic acetyl CoA for the
synthesis of fatty acids, cholesterol and isoprenoids [2]. Citrate
metabolite involved in tricarboxylic acid (TCA) cycle is generated in
the matrix of the mitochondria [3]. The steps involve carboxylation
of the glucose derived pyruvate and then acetylation with Acetyl CoA.
The citrate metabolite is involved in the TCA cycle to yield ATPvia generated NADH and FADH2 entering the
electron transport chain (ETC). The excess citrate in the matrix is
transported out to the cytoplasm through mitochondrial citrate carrier.
Citrate inhibits the glucose catabolism by allosterically inhibiting
phosphofructokinase-1 (rate-limiting enzyme in glycolysis) and stimulate
gluconeogenesis by activating fructose 1,6-biphosphatase. It also acts
as a carbon source for the lipid biosynthesis (fatty acids and
cholesterol) with the generation of acetyl CoA. The acetyl CoA is the
allosteric activator of the acetyl CoA carboxylase (rate limiting enzyme
for fatty acid synthesis) and generated malonyl CoA. The malonyl CoA is
the intermediate involved in the fatty acid synthesis in the cytoplasm.
Thus, citrate acts as a building bridge between the fatty acid and
carbohydrate metabolism [4] (Figure 1) . It was confirmed inMucor circinelloides where citrate produced from the TCA cycle
was translocated (mitochondrial citrate transporter) across
mitochondrial inner membrane and cleaved to oxaloacetate (OAA) and
acetyl-CoA by ATP citrate lyase. The acetyl CoA along with NADPH are
used to produce fatty acid biosynthesis in the cytosol. The two genes
responsible for coding of citrate transporters i.e., citrate transporter
and tricarboxylate transporter are overexpressed, cause increased lipid
accumulation whereas decrease in extracellular citrate concentration
[5]. The blockade of two plasma membrane malate transporter
2-oxoglutarate: malate antiporters (SoDIT-a and SoDIT-b) in the fungus
results in increased malate available for the lipid biosynthesis
[6]. The citrate transport is promoted by ΔpNa+(chemical gradient of sodium ions) and ΔpH (pH gradient across the
membrane) and not by ∆ψ (electrical potential across membrane) showing
that citrate transport is electroneutral process. The
sodium-ion-dependent citrate carrier also causes sodium counterflow in
the absence of citrate [7]. The cytosolic concentration of the
citrate also determines the rate of the fatty acid synthesis. The NaCT
(sodium-dependent citrate transporter) in liver cell plays an important
role in transporting citrate and is used as a target for anti-obesity
drugs. The extracellular citrate enters the plasma membrane of specific
cells through Na+-coupled citrate transporter (NaCT)i.e., SLC13A5 [8]. The inner mitochondrial membrane channel
is blocked by the externally bound high affinity Mg2+and may be activated by the citrate or other Mg2+chelators. The presence of exogenous MgCl2 strongly
inhibits the citrate-induced depolarization and is independent of the
presence of sodium, potassium, or chlorine ions. The exogenous citrate
in the Mg2+ free medium has been shown to suppress the
reactive oxygen species (ROS) and uncoupling of the mitochondria. It
also suppresses the H2O2 and the
stimulation of respiration of mitochondria (suppress the depolarized
mitochondria and amount of the citrate transporter)[9]. The sodium
dependent SLC13 family transporters carry these intermediates from
plasma membranes into the cells and is comprises of five genes. The
three sodium dependent transporters of the human SLC13 family includes
hNaDC1 (SLC13A2), hNaDC3 (SLC13A3), and hNaCT (SLC13A5). These receptors
are emerging as drug targets for various metabolic disorders [1].
Some of the recent patents on sodium citrate transporters are listed inTable 1 . The other two genes include SLC13 co-transporters
SLC13A1 and SLC13A4 which are involved in transportation of renal sodium
dependent anions such as selenite, sulphate, and thiosulphate [10].
Figure 1: Citrate-pyruvate shuttle and linkage of citrate as
fatty acids and carbohydrate metabolism.
Table 1: Some of the patents on sodium citrate transporters are
listed below: