In view of the documented association of solute carrier family 19 member 1 (SLC19A1) G80A (R27H) polymorphism with the risk for different types of cancers and systemic lupus erythematosus (SLE), we have reanalysed the case-control study on breast cancer to ascertain the conditions in which this polymorphic variant exerts the risk of breast cancer. Association statistics have revealed that this polymorphism exerts the risk for breast cancer under the conditions of low folate intake, and in the absence of well-documented protective polymorphism in cytosolic serine hydroxymethyltransferase. To substantiate this observation, we have developed a homology model of SLC19A1 using glycerol-3-phosphate transporter (d1pw4a) as a template where 73% of the residues were modelled at 90% confidence while 162 residues were modelled ab initio. The wild and mutant proteins shared same topology in S3, S5, S6, S7, S11 and S12 transmembrane domains. The topology varied at S1 (28-43 residue vs 28-44 residue), S2 (66-87 residue vs 69-87 residue), S4 (117-140 residue vs 117-139 residue), S8 (305-325 residue vs 305-324 residue), S9 (336-356 residue vs 336-355residue), and S10 (361-386 residue vs 361-385 residue) transmembrane domains between wild versus mutant proteins. S2 domain is shortened by three amino acid residues in the mutant while in other domains the difference corresponds to one amino acid residue. The 3DLigandSite analysis revealed that the metallic-ligand-binding sites at 273Trp, 277Asn, 379Leu, 439Phe and 442Leu are although unaffected, there is a loss of active sites corresponding to nonmetallic ligand binding. Tetrahydrofolate and methotrexate have lesser affinity towards the mutant protein than the wild protein. To conclude, the R27H polymorphism affects the secondary and tertiary structures of SLC19A1 with the significant loss in ligand-binding sites.

中文翻译：

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在计算机上分析SLC19A1 R27H多态性的结构和功能含义。

鉴于溶质载体家族19成员1（SLC19A1）G80A（R27H）多态性与不同类型的癌症和系统性红斑狼疮（SLE）风险相关的文献记载，我们重新分析了乳腺癌的病例对照研究，以确定这种多态性变异体会增加患乳腺癌的风险。协会的统计数据表明，在叶酸摄入量低的情况下，并且在没有充分证明的胞浆丝氨酸羟甲基转移酶保护性多态性的情况下，这种多态性会增加患乳腺癌的风险。为了证实该观察结果，我们使用3-磷酸甘油转运蛋白（d1pw4a）作为模板建立了SLC19A1的同源性模型，其中73％的残基以90％置信度建模，而162个残基从头开始建模。野生蛋白和突变蛋白在S3，S5，S6，S7，S11和S12跨膜结构域中共享相同的拓扑。拓扑在S1（28-43残基vs 28-44残基），S2（66-87残基vs 69-87残基），S4（117-140残基vs 117-139残基），S8（305-325残基vs 305-324残基），S9（336-356残基对336-355残基）和S10（361-386残基对361-385残基）跨膜结构域。S2结构域在突变体中被三个氨基酸残基缩短，而在其他结构域中，差异对应于一个氨基酸残基。3DLigandSite分析显示，虽然273Trp，277Asn，379Leu，439Phe和442Leu的金属-配体结合位点不受影响，但与非金属配体结合的活性位点却丢失了。四氢叶酸和甲氨蝶呤对突变蛋白的亲和力小于野生蛋白。总之，R27H多态性影响SLC19A1的二级和三级结构，配体结合位点明显减少。