Catalytic Signature of a Heat-Stable, Chimeric Human Alkaline Phosphatase with Therapeutic Potential
Catalytic Signature of a Heat-Stable, Chimeric Human Alkaline Phosphatase with Therapeutic Potential
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DOI：
10.1371/journal.pone.0089374
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发表时间：
2014-02-24
期刊：
影响因子：
3.7
通讯作者：
Millan, Jose Luis
中科院分区：
文献类型：
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作者：
Kiffer-Moreira, Tina;Sheen, Campbell R.;Millan, Jose Luis
重组碱性磷酸酶正在成为预防骨骼矿化缺陷、炎症性肠病和治疗急性肾损伤的有前景的蛋白质治疗剂。通过用人胎盘同工酶（PLAP）的柔性冠状结构域取代人肠碱性磷酸酶（IAP）的柔性冠状结构域，我们产生了嵌合酶（ChimAP），其保留了IAP的结构折叠，但显示出大大增加的稳定性、活性位点Zn 2+结合、增加的转磷酸化、更高的转换数和更窄的底物特异性，对细菌脂多糖（LPS）具有可比的选择性，比亲本IAP同工酶高。ChimAP显示出作为一种蛋白质治疗剂用于炎症性肠病、肠道生态失调和急性肾损伤等适应症的前景。
Recombinant alkaline phosphatases are becoming promising protein therapeutics to prevent skeletal mineralization defects, inflammatory bowel diseases, and treat acute kidney injury. By substituting the flexible crown domain of human intestinal alkaline phosphatase (IAP) with that of the human placental isozyme (PLAP) we generated a chimeric enzyme (ChimAP) that retains the structural folding of IAP, but displays greatly increased stability, active site Zn2+ binding, increased transphosphorylation, a higher turnover number and narrower substrate specificity, with comparable selectivity for bacterial lipopolysaccharide (LPS), than the parent IAP isozyme. ChimAP shows promise as a protein therapeutic for indications such as inflammatory bowel diseases, gut dysbioses and acute kidney injury.