Role of sodium dependent SLC13 transporter inhibitors in various metabolic disorders

Akhtar, Md. Jawaid; Khan, Shah Alam; Kumar, Bhupinder; Chawla, Pooja; Bhatia, Rohit; Singh, Kunal

doi:10.1007/s11010-022-04618-7

Cited by 11 publications

(6 citation statements)

References 73 publications

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“…Recently, Li and Wang discussed the molecular mechanisms influencing SLC13A5 expression, including the transcription factors STAT3 and cAMP-responsive element-binding protein (CREB) [ 74 ]. Expression of SLC13A5 was elevated in patients with NAFLD, obesity, and type II diabetes [ 74 , 75 ]. Xenobiotic chemical challenges such as lipopolysaccharide (LPS), benzo[a]pyrene (BaP), or rifampicin (RIF) induced the expression of SLC13A5 as well as the hormone glucagon and the cytokine IL-6 [ 14 , 76 , 77 , 78 ].…”

Section: Therapeutic Potential Of Slc13a5 /Nactmentioning

confidence: 99%

Mapping the Metabolic Niche of Citrate Metabolism and SLC13A5

2023

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The small molecule citrate is a key molecule that is synthesized de novo and involved in diverse biochemical pathways influencing cell metabolism and function. Citrate is highly abundant in the circulation, and cells take up extracellular citrate via the sodium-dependent plasma membrane transporter NaCT encoded by the SLC13A5 gene. Citrate is critical to maintaining metabolic homeostasis and impaired NaCT activity is implicated in metabolic disorders. Though citrate is one of the best known and most studied metabolites in humans, little is known about the consequences of altered citrate uptake and metabolism. Here, we review recent findings on SLC13A5, NaCT, and citrate metabolism and discuss the effects on metabolic homeostasis and SLC13A5-dependent phenotypes. We discuss the “multiple-hit theory” and how stress factors induce metabolic reprogramming that may synergize with impaired NaCT activity to alter cell fate and function. Furthermore, we underline how citrate metabolism and compartmentalization can be quantified by combining mass spectrometry and tracing approaches. We also discuss species-specific differences and potential therapeutic implications of SLC13A5 and NaCT. Understanding the synergistic impact of multiple stress factors on citrate metabolism may help to decipher the disease mechanisms associated with SLC13A5 citrate transport disorders.

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Section: Therapeutic Potential Of Slc13a5 /Nactmentioning

confidence: 99%

Mapping the Metabolic Niche of Citrate Metabolism and SLC13A5

2023

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“…provides clues to develop allosteric modulatory predrug chemicals for SLC13-related metabolic diseases, including cancer, diabetes, and even neurological disorder (41). By discerning structural discrepancies and distinct residue features, we have unveiled the intricate details underlying ACA's inhibitory effects on NaS1 and NaDC1.…”

Section: Discussionmentioning

confidence: 99%

“…The constraint induced by ACA between dimerization domain and core domain hampers the relative movement in the transport cycle. The hydrophobic binding site of ACA provides clues to develop allosteric modulatory predrug chemicals for SLC13-related metabolic diseases, including cancer, diabetes, and even neurological disorder ( 41 ). By discerning structural discrepancies and distinct residue features, we have unveiled the intricate details underlying ACA’s inhibitory effects on NaS1 and NaDC1.…”

Section: Discussionmentioning

confidence: 99%

Cryo-EM structures of the human NaS1 and NaDC1 transporters revealed the elevator transport and allosteric regulation mechanism

Chi,

Chen,

et al. 2024

Sci. Adv.

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The solute carrier 13 (SLC13) family comprises electrogenic sodium ion–coupled anion cotransporters, segregating into sodium ion–sulfate cotransporters (NaSs) and sodium ion–di- and–tricarboxylate cotransporters (NaDCs). NaS1 and NaDC1 regulate sulfate homeostasis and oxidative metabolism, respectively. NaS1 deficiency affects murine growth and fertility, while NaDC1 affects urinary citrate and calcium nephrolithiasis. Despite their importance, the mechanisms of substrate recognition and transport remain insufficiently characterized. In this study, we determined the cryo–electron microscopy structures of human NaS1, capturing inward-facing and combined inward-facing/outward-facing conformations within a dimer both in apo and sulfate-bound states. In addition, we elucidated NaDC1’s outward-facing conformation, encompassing apo, citrate-bound, and N -( p -amylcinnamoyl) anthranilic acid (ACA) inhibitor–bound states. Structural scrutiny illuminates a detailed elevator mechanism driving conformational changes. Notably, the ACA inhibitor unexpectedly binds primarily anchored by transmembrane 2 (TM2), Loop 10, TM11, and TM6a proximate to the cytosolic membrane. Our findings provide crucial insights into SLC13 transport mechanisms, paving the way for future drug design.

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“…The human NaCT is a part of the SLC13 gene family that include five members, namely, SLC13A1–SLC13A5, − which encode transporters with 8–13 transmembrane helices . SLC13 transporters are responsible for Na + -coupled anion cotransport at the plasma membrane of epithelial cells and cells within the central nervous system in mammals, and the sodium to substrate ratio is generally 3:1 or 4:1. ,, Based on their distinct functions, the SLC13 family can be classified into two groups.…”

Section: Key Proteins Of the Citrate Transport And Metabolism Pathwaymentioning

confidence: 99%

Opportunities and Challenges for Inhibitors Targeting Citrate Transport and Metabolism in Drug Discovery

Zhang

Qiu

et al. 2023

J. Med. Chem.

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Lipid metabolism disorder is closely related to metabolic diseases, inflammation, and cancer. The concentration of citrate in the cytosol has a significant impact on lipid synthesis. The expression of citrate transporters (SLC13A5 and SLC25A1) and metabolic enzymes (ACLY) proves to be substantially raised in various diseases related to disorders of lipid metabolism, such as hyperlipemia, nonalcoholic fatty liver disease, and prostate cancer. Targeting key proteins in the citrate transport and metabolic pathways is considered an effective strategy for treating various metabolic diseases. However, there is currently only one ACLY inhibitor approved for marketing, and no SLC13A5 inhibitor has entered clinical research. Further development of drugs targeting citrate transport and metabolism is needed for the treatment of metabolic diseases. This perspective summarizes the biological role, therapeutic potential, and research progress of citrate transport and metabolism and then discusses the achievements and prospects of modulators targeting citrate transport and metabolism for therapeutic applications.

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Role of sodium dependent SLC13 transporter inhibitors in various metabolic disorders

Cited by 11 publications

References 73 publications

Mapping the Metabolic Niche of Citrate Metabolism and SLC13A5

Mapping the Metabolic Niche of Citrate Metabolism and SLC13A5

Cryo-EM structures of the human NaS1 and NaDC1 transporters revealed the elevator transport and allosteric regulation mechanism

Opportunities and Challenges for Inhibitors Targeting Citrate Transport and Metabolism in Drug Discovery

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