Human serum transferrin: is there a link among autism, high oxalate levels, and iron deficiency anemia?
Human serum transferrin: is there a link among autism, high oxalate levels, and iron deficiency anemia?
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DOI：
10.1021/bi401190m
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发表时间：
2013-11-19
期刊：
影响因子：
2.9
通讯作者：
Mason, Anne B.
中科院分区：
文献类型：
--
作者：
Luck, Ashley N.;Bobst, Cedric E.;Kaltashov, Igor A.;Mason, Anne B.
先前已经提出，血浆中的高草酸盐可以通过与双叶铁转运蛋白转铁蛋白（hTF）结合而在自闭症中发挥作用，从而通过抑制铁向细胞的递送而干扰铁代谢。通过研究草酸盐取代hTF各叶中生理上利用的协同碳酸根阴离子的效果，我们试图提供支持或反对这种作用的分子基础。我们的工作清楚地表明，定性（6 M尿素凝胶）和定量（动力学分析通过停流荧光光谱法），草酸盐的存在下，在每个结合位点的hTF的碳酸盐确实大大干扰铁从每个叶（无论是在特定的hTF受体的存在和不存在）。然而，我们也清楚地表明，一旦铁结合在hTF的每个叶内，两个阴离子都不能取代另一个。此外，如通过尿素凝胶和电喷雾质谱法所验证的，完全均匀的hTF-阴离子复合物的形成需要首先去除所有铁，然后在碳酸盐或草酸盐的存在下用铁重新装载hTF。重要的是，本文所述的实验显示碳酸盐是优选的结合配偶体，即，即使在铁负载过程中可获得等量的每种阴离子，也会形成hTF-碳酸盐络合物。
It has been previously suggested that high amounts of oxalate in plasma could play a role in autism by binding to the bilobal iron transport protein transferrin (hTF) thereby interfering with iron metabolism by inhibiting iron delivery to cells. By examining the effect of the substitution of oxalate for the physiologically utilized synergistic carbonate anion in each lobe of hTF we sought to provide a molecular basis for or against such a role. Our work clearly shows both qualitatively (6 M urea gels) and quantitatively (kinetic analysis by stop flow spectrofluorimetry) that the presence of oxalate in place of carbonate in each binding site of hTF does indeed greatly interfere with iron removal from each lobe (both in the absence and presence of the specific hTF receptor). However, we also clearly demonstrate that once the iron is bound within each lobe of hTF, neither anion can displace the other. Additionally, as verified by urea gels and electrospray mass spectrometry, formation of completely homogeneous hTF-anion complexes requires that all iron must first be removed and hTF then reloaded with iron in the presence of either carbonate or oxalate. Of significance, experiments described herein show that carbonate is the preferred binding partner, i.e., even if an equal amount of each anion is available during the iron loading process the hTF-carbonate complex is formed.
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