# SLC22A6

## Overview
SLC22A6 is a gene that encodes the protein solute carrier family 22 member 6 (OAT1), which is a crucial component of the renal organic anion transport system. This protein is a transmembrane transporter, specifically classified under the Major Facilitator Superfamily (MFS), and is primarily expressed in the kidney. OAT1 functions as an organic anion/dicarboxylate exchanger, facilitating the renal excretion and reabsorption of various endogenous and exogenous organic anions, including metabolic wastes and numerous drugs. The protein's structure includes 12 transmembrane alpha-helices and operates independently of sodium ions, utilizing an outwardly directed concentration gradient of α-ketoglutarate or glutarate for the transport process (Koepsell2013The). Genetic variations in SLC22A6 can significantly affect the transporter's function, impacting drug efficacy and safety, and are thus of clinical importance in pharmacokinetics and personalized medicine (Cheong2011Screening).

## Structure
The human organic anion transporter 1 (hOAT1), encoded by the SLC22A6 gene, is a protein that exhibits a complex molecular structure integral to its function in transporting organic anions across cell membranes. The protein is characterized by a 12-transmembrane alpha-helical topology, which is typical of the Major Facilitator Superfamily (MFS) of transporters. This topology includes two six-helix bundles connected by a long loop, forming the primary structure of the protein (Tsigelny2011Conformational).

The secondary structure of hOAT1 features these transmembrane helices, which are crucial for the formation of the protein's tertiary structure. The tertiary structure is noted for its 'V'-shape conformation in the outward-facing state and a 'Λ'-shape in the inward-facing state, which are essential for the function of the transporter in the substrate transport cycle (Janaszkiewicz2022Insights).

Post-translational modifications of hOAT1 include glycosylation and phosphorylation. Glycosylation occurs at known sites within the extracellular loop between transmembrane helices 1 and 2, although it is not essential for the transporter's function. Phosphorylation, particularly at serine residues, plays a regulatory role in the transport activity of specific substrates like p-aminohippurate (Vávra2022Functional).

The quaternary structure of hOAT1 suggests that it may be organized as a homo-oligomer, possibly forming a homotrimer or containing a higher number of subunits, which could influence its functional dynamics and substrate binding properties (Vávra2022Functional).

## Function
The SLC22A6 gene encodes the Organic Anion Transporter 1 (OAT1), which is primarily expressed in the kidney and plays a crucial role in the renal excretion and reabsorption of various endogenous and exogenous organic anions. OAT1 is localized to the basolateral membrane of the renal proximal tubules, where it functions as an organic anion/dicarboxylate exchanger. This exchange process is sodium-independent and driven by an outwardly directed concentration gradient of α-ketoglutarate or glutarate (Koepsell2013The).

OAT1 facilitates the uptake of organic anions from the bloodstream into the kidney cells, a critical step in their subsequent excretion into the urine. This transporter is essential for the clearance of a wide range of compounds, including therapeutic drugs such as beta-lactam antibiotics, loop diuretics, non-steroidal anti-inflammatory drugs, and antiviral nucleoside analogs (Fujita2005Functional). Additionally, OAT1 mediates the renal excretion of urate and other endogenous anions, as well as many anionic drugs, contributing significantly to the detoxification and clearance processes in the body (Koepsell2013The). 

The expression of OAT1 is regulated by hepatocyte nuclear factors HNF-1 and HNF-4, and its activity can be modulated by phosphorylation of serine residues, which affects the transport of specific substrates like p-aminohippurate (Koepsell2013The). Genetic variations in SLC22A6, such as the R50H variant, can lead to kinetic differences in the transport of substrates, impacting the efficacy and safety profile of drugs (Cheong2011Screening).

## Clinical Significance
Mutations in the SLC22A6 gene, which encodes the organic anion transporter 1 (OAT1), have been linked to significant clinical implications, particularly affecting renal function and drug pharmacokinetics. Variants such as p.P104L and p.A190T in SLC22A6 have been studied for their impact on uric acid transport, which is crucial in the context of diseases like gout and hyperuricemia (Vávra2022Functional). These mutations can alter the transporter's efficiency, potentially leading to altered drug efficacy and increased susceptibility to drug-induced nephrotoxicity. For instance, the R50H mutation has been associated with kinetic differences in the transport of nucleoside phosphonate analogs, which are critical in the treatment of viral infections (Cheong2011Screening).

Furthermore, genetic variability in SLC22A6 affects the disposition of substrates like methotrexate and various antiviral drugs, influencing the effectiveness and safety of pharmacological treatments (Cheong2011Screening). This variability underscores the importance of personalized medicine approaches in managing drug responses, especially in diverse ethnic populations, to mitigate potential toxicities and optimize therapeutic outcomes. Additionally, alterations in noncoding regions of SLC22A6 might influence the transcription levels of the gene, further affecting the functional protein levels and the body's ability to handle drugs and toxins (Bhatnagar2006Analyses).

## Interactions
SLC22A6, also known as Organic Anion Transporter 1 (OAT1), is involved in significant protein-protein interactions that affect its function and localization. It has been identified to form homo-oligomers, a type of multiprotein complex where identical proteins bind together. This oligomerization was initially detected as a double-sized band on western blots and further characterized using techniques such as gel filtration and immunoprecipitation (Zhang2019Protein-protein). The presence of a peptide corresponding to its transmembrane domain 6 (TMD6) has been shown to reduce OAT1 oligomerization and decrease its expression on the cell membrane, which subsequently reduces the maximum velocity (Vmax) of substrate uptake (Zhang2019Protein-protein). Additionally, mutations in the GXXXG motifs in TMD1 and TMD5 significantly affect OAT1's expression and membrane localization, underscoring the importance of these motifs in its oligomerization and proper membrane trafficking (Zhang2019Protein-protein). These interactions are crucial for the transporter's function in renal handling of organic anions and its role in pharmacokinetics and drug-drug interactions.


## References


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[8. (Zhang2019Protein-protein) Yuchen Zhang and Bruno Hagenbuch. Protein-protein interactions of drug uptake transporters that are important for liver and kidney. Biochemical Pharmacology, 168:384–391, October 2019. URL: http://dx.doi.org/10.1016/j.bcp.2019.07.026, doi:10.1016/j.bcp.2019.07.026. (21 citations) 10.1016/j.bcp.2019.07.026](https://doi.org/10.1016/j.bcp.2019.07.026)