Sheikh Ishfaq Ahmad, Beg Mohd Amin, Yasir Muhammad
King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia
King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia.
Anticancer Res. 2017 Nov;37(11):6245-6249. doi: 10.21873/anticanres.12075.
BACKGROUND/AIM: Lactoperoxidase (LPO) is an antimicrobial protein present in milk, saliva, gastric secretions, tears and upper respiratory tract secretions. LPO constitutes an important enzyme of the human immune defense system. However, LPO has also been suggested to be involved in breast cancer etiology through production of reactive free radicals and activation of carcinogenic aromatic compounds. Aromatic compounds are generally highly lipophilic and thus accumulate in highly fatty breast tissues. The aromatic compounds 4-aminobiphenyl (ABP) and 4,4'-diaminobiphenyl (BZ) are known to have carcinogenic properties. LPO catalyzes their oxidation and converts them into reactive products which bind to DNA and form adducts. These DNA adducts subsequently lead to breast cancer.
The crystal structure of LPO was obtained from Protein Data Bank. Structures of ABP and BZ were retrieved from PubChem database. Induced Fit Docking was performed using glide module from Schrodinger.
The present study reports the structural binding of ABP and BZ with LPO using in silico approaches. The amino acid residues of LPO involved in the binding with the two aromatic ligands were characterized and binding energy values were calculated.
Both ABP and BZ were placed in the substrate binding site present in the distal heme cavity of LPO with good affinity. The binding mode mimicked that of the natural substrate since these compounds did not disturb the water molecule that plays an important role in the oxidation reaction. Thus, the water molecule is potentially available for facilitating the subsequent activation of the aromatic amines to reactive species which may form DNA adducts leading to breast cancer.
背景/目的：乳过氧化物酶（LPO）是一种存在于牛奶、唾液、胃分泌物、眼泪和上呼吸道分泌物中的抗菌蛋白。LPO是人体免疫防御系统的一种重要酶。然而，也有研究表明LPO通过产生活性自由基和激活致癌芳香化合物参与乳腺癌的病因学。芳香化合物通常具有高度亲脂性，因此会在高脂肪的乳腺组织中积累。已知芳香化合物4-氨基联苯（ABP）和4,4'-二氨基联苯（BZ）具有致癌特性。LPO催化它们的氧化并将它们转化为与DNA结合并形成加合物的反应性产物。这些DNA加合物随后导致乳腺癌。
LPO的晶体结构从蛋白质数据库中获得。ABP和BZ的结构从PubChem数据库中检索。使用Schrodinger的glide模块进行诱导契合对接。
本研究报告了使用计算机方法ABP和BZ与LPO的结构结合。对LPO中与这两种芳香配体结合的氨基酸残基进行了表征，并计算了结合能值。
ABP和BZ都以良好的亲和力位于LPO远端血红素腔中的底物结合位点。结合模式模仿了天然底物的结合模式，因为这些化合物没有干扰在氧化反应中起重要作用的水分子。因此，水分子可能有助于随后将芳香胺激活为可能形成导致乳腺癌的DNA加合物的反应性物种。
