article.json

[
  {
    "title": "ABCC11",
    "content": "",
    "hierarchy": "ABCC11"
  },
  {
    "title": "Overview",
    "content": "The ABCC11 gene encodes the ATP-binding cassette subfamily C member 11 protein, a transmembrane efflux transporter that plays a critical role in the transport of various lipophilic compounds across cell membranes. This protein is part of the larger family of ATP-binding cassette (ABC) transporters, which utilize the energy from ATP hydrolysis to translocate substrates. ABCC11 is involved in several physiological processes, including the secretion of cerumen in the ear and apocrine sweat in the axillae, which affects body odor characteristics. The protein's functionality is influenced by genetic polymorphisms, notably the SNP 538G>A, which has implications in conditions like axillary osmidrosis and influences the pharmacogenetics of certain drugs (Ishikawa2013Pharmacogenetics; Toyoda2009Earwax).",
    "hierarchy": "ABCC11 > Overview"
  },
  {
    "title": "Structure",
    "content": "The ABCC11 protein, encoded by the ABCC11 gene, is a complex molecule primarily involved in the transport of various substances across cellular membranes. Structurally, ABCC11 is characterized by 12 transmembrane helices and two ATP-binding cassettes, which are crucial for its function as a transporter (Ishikawa2013Pharmacogenetics; Toyoda2009Earwax). These transmembrane helices form the core through which substrates are translocated across the cell membrane.  ABCC11 also features two sets of Walker A and Walker B motifs, along with two ABC signature sequences, known as 'C motifs', which are typical of ATP-binding cassette (ABC) transporters (Yabuuchi2001Multiple). The protein's topology indicates that both the N-terminus and C-terminus are located on the cytoplasmic side of the membrane, suggesting a specific orientation within the lipid bilayer (Toyoda2016Regulation).  A significant post-translational modification of ABCC11 is N-linked glycosylation, particularly at asparagine residues Asn838 and Asn844, which is essential for the protein's stability and proper functioning (Toyoda2009Earwax; Toyoda2016Regulation). This glycosylation helps in stabilizing the protein structure and maintaining its functionality within the cellular environment.  Additionally, there are splicing variants of ABCC11, such as variant A, which lacks 38 amino acids in the second ATP-binding cassette due to the absence of exon 28, potentially altering its functional capabilities (Yabuuchi2001Multiple). This variant still retains the 12 membrane-spanning domains, indicative of its role in transport but with possibly modified transporter activity.",
    "hierarchy": "ABCC11 > Structure"
  },
  {
    "title": "Function",
    "content": "The ABCC11 gene encodes the ATP-binding cassette sub-family C member 11 protein, a crucial component of the ATP-binding cassette (ABC) transporter family. This protein functions as an efflux transporter, utilizing ATP hydrolysis to transport various lipophilic anions across cell membranes. These substrates include cyclic nucleotides, glutathione conjugates, steroid sulfates, glucuronides, and bile acids, which are vital for cellular detoxification and the regulation of metabolic processes (Toyoda2016Diagnosis; Ishikawa2013Pharmacogenetics).  ABCC11 is expressed in a wide range of tissues, including apocrine glands, where it plays a significant role in the secretion processes. In the apocrine glands of the axillae, ABCC11 influences the secretion of precursor compounds for axillary odor, which are metabolized by skin bacteria into odor-causing compounds (Toyoda2010Pharmacogenomics). The protein is also involved in the secretion of ceruminous materials in the cerumen glands, impacting the type of earwax produced (Toyoda2009Earwax).  The functionality of ABCC11 is modulated by genetic polymorphisms, notably the SNP 538G>A, which can lead to variations in protein stability and function. The wild-type form of the protein undergoes N-linked glycosylation, which is essential for its stability and proper localization within the cell. In contrast, certain variants resulting from this SNP are prone to misfolding and degradation, affecting the protein's function in secretion processes (Toyoda2009Earwax). This genetic variability underscores the importance of ABCC11 in physiological processes and its implications in conditions such as axillary osmidrosis and the pharmacogenetics of drug response.",
    "hierarchy": "ABCC11 > Function"
  },
  {
    "title": "Clinical Significance",
    "content": "Mutations in the ABCC11 gene, specifically the 538G>A single nucleotide polymorphism (SNP), have significant clinical implications. This SNP results in an amino acid change from Glycine (Gly180) to Arginine (Arg180), affecting the protein's stability and function. The 538G>A mutation is associated with axillary osmidrosis, a condition characterized by strong body odor due to increased secretion from apocrine glands, and is covered by national health insurance in Japan due to its recognition as a disease (Toyoda2016Diagnosis; Toyoda2010Pharmacogenomics).  Furthermore, the ABCC11 gene is linked to variations in earwax type, with the 538G allele correlating with wet earwax and the 538A allele with dry earwax. These phenotypes are also associated with different risks for axillary osmidrosis (Toyoda2009Earwax).  Additionally, ABCC11 has implications in breast cancer risk. Studies have shown that the presence of the 538G allele is more frequent in breast cancer patients compared to controls, suggesting a moderate association between this allele and increased breast cancer risk (Ishikawa2013Pharmacogenetics).  The gene's role in drug metabolism also affects chemotherapy efficacy. Variants of ABCC11 can influence the efflux of nucleoside-based anticancer drugs, impacting treatment outcomes in chemotherapy (Toyoda2010Pharmacogenomics). This highlights the importance of considering ABCC11 genotypes in personalized medicine approaches for cancer treatment.",
    "hierarchy": "ABCC11 > Clinical Significance"
  },
  {
    "title": "Interactions",
    "content": "ABCC11, also known as Multidrug Resistance Protein 8 (MRP8), is involved in various physical interactions that are crucial for its function as a transporter. The protein interacts with ATP to facilitate the transport of substrates across cellular membranes, a process that is energy-dependent and crucial for its role in multidrug resistance and physiological transport mechanisms (Chen2004Transport). ABCC11 has been shown to form complexes with other proteins, although specific partner proteins are not detailed in the provided sources. The interactions likely involve transient associations with other cellular proteins that regulate its transport activity or stability.  The protein's interaction with nucleotides and substrates is also a key aspect of its function. ABCC11 binds to cyclic nucleotides like cGMP and ATP, which are essential for the conformational changes required for substrate translocation from the intracellular to the extracellular space (Honorat2013Localization). These interactions are not only crucial for the transport function but also for the regulation of the protein's activity in response to cellular energy levels and the presence of substrates.  Overall, while the specific details of multiprotein complexes or interactions with other nucleic acids are not extensively documented in the provided sources, the known interactions underline the functional complexity and regulatory mechanisms of ABCC11 in cellular transport processes.",
    "hierarchy": "ABCC11 > Interactions"
  },
  {
    "title": "References",
    "content": "[1. (Yabuuchi2001Multiple) Hikaru Yabuuchi, Hidetada Shimizu, Shin-ichiro Takayanagi, and Toshihisa Ishikawa. Multiple splicing variants of two new human atp-binding cassette transporters, abcc11 and abcc12. Biochemical and Biophysical Research Communications, 288(4):933–939, November 2001. URL: http://dx.doi.org/10.1006/bbrc.2001.5865, doi:10.1006/bbrc.2001.5865. (148 citations) 10.1006/bbrc.2001.5865](https://doi.org/10.1006/bbrc.2001.5865)  [2. (Honorat2013Localization) Mylène Honorat, Raphaël Terreux, Pierre Falson, Attilio Di Pietro, Charles Dumontet, and Lea Payen. Localization of putative binding sites for cyclic guanosine monophosphate and the anti-cancer drug 5-fluoro-2′-deoxyuridine-5′-monophosphate on abcc11 in silico models. BMC Structural Biology, May 2013. URL: http://dx.doi.org/10.1186/1472-6807-13-7, doi:10.1186/1472-6807-13-7. (66 citations) 10.1186/1472-6807-13-7](https://doi.org/10.1186/1472-6807-13-7)  [3. (Toyoda2016Regulation) Yu Toyoda, Tappei Takada, Hiroshi Miyata, Toshihisa Ishikawa, and Hiroshi Suzuki. Regulation of the axillary osmidrosis-associated abcc11 protein stability by n-linked glycosylation: effect of glucose condition. PLOS ONE, 11(6):e0157172, June 2016. URL: http://dx.doi.org/10.1371/journal.pone.0157172, doi:10.1371/journal.pone.0157172. (16 citations) 10.1371/journal.pone.0157172](https://doi.org/10.1371/journal.pone.0157172)  [4. (Toyoda2016Diagnosis) Yu Toyoda, Tsuneaki Gomi, Hiroshi Nakagawa, Makoto Nagakura, and Toshihisa Ishikawa. Diagnosis of human axillary osmidrosis by genotyping of the humanabcc11gene: clinical practice and basic scientific evidence. BioMed Research International, 2016:1–9, 2016. URL: http://dx.doi.org/10.1155/2016/7670483, doi:10.1155/2016/7670483. (22 citations) 10.1155/2016/7670483](https://doi.org/10.1155/2016/7670483)  [5. (Ishikawa2013Pharmacogenetics) Toshihisa Ishikawa, Yu Toyoda, Koh-ichiro Yoshiura, and Norio Niikawa. Pharmacogenetics of human abc transporter abcc11: new insights into apocrine gland growth and metabolite secretion. Frontiers in Genetics, 2013. URL: http://dx.doi.org/10.3389/fgene.2012.00306, doi:10.3389/fgene.2012.00306. (47 citations) 10.3389/fgene.2012.00306](https://doi.org/10.3389/fgene.2012.00306)  [6. (Toyoda2010Pharmacogenomics) Yu Toyoda and Toshihisa Ishikawa. Pharmacogenomics of human abc transporter abcc11 (mrp8): potential risk of breast cancer and chemotherapy failure. Anti-Cancer Agents in Medicinal Chemistry, 10(8):617–624, October 2010. URL: http://dx.doi.org/10.2174/187152010794473975, doi:10.2174/187152010794473975. (49 citations) 10.2174/187152010794473975](https://doi.org/10.2174/187152010794473975)  [7. (Chen2004Transport) Zhe-Sheng Chen, Yanping Guo, Martin G. Belinsky, Elena Kotova, and Gary D. Kruh. Transport of bile acids, sulfated steroids, estradiol 17-β-d-glucuronide, and leukotriene c4 by human multidrug resistance protein 8 (abcc11). Molecular Pharmacology, 67(2):545–557, November 2004. URL: http://dx.doi.org/10.1124/mol.104.007138, doi:10.1124/mol.104.007138. (115 citations) 10.1124/mol.104.007138](https://doi.org/10.1124/mol.104.007138)  [8. (Toyoda2009Earwax) Yu Toyoda, Aki Sakurai, Yasumasa Mitani, Masahiro Nakashima, Koh-ichiro Yoshiura, Hiroshi Nakagawa, Yasuo Sakai, Ikuko Ota, Alexander Lezhava, Yoshihide Hayashizaki, Norio Niikawa, and Toshihisa Ishikawa. Earwax, osmidrosis, and breast cancer: why does one snp (538g>a) in the human abc transporter abcc11 gene determine earwax type? The FASEB Journal, 23(6):2001–2013, April 2009. URL: http://dx.doi.org/10.1096/fj.09-129098, doi:10.1096/fj.09-129098. (66 citations) 10.1096/fj.09-129098](https://doi.org/10.1096/fj.09-129098)",
    "hierarchy": "ABCC11 > References"
  }
]