Mims Martha P, Prchal Josef T
Division of Hematology/Oncology, Baylor College of Medicine, One Baylor Plaza 802E, Houston, TX 77030, USA.
Hematology. 2005 Aug;10(4):339-45. doi: 10.1080/10245330500093419.
In the last few years, the field of iron metabolism has exploded with the discovery of many new proteins including ferroportin, hephaestin, hepcidin, duodenal cytochrome b and the topic of this review, divalent metal ion transporter 1 (DMT1). DMT1 functions in transport of ferrous iron, and some, but not all divalent metal ions across the plasma membrane and/or out of the endosomal compartment. DMT1 mRNA has been found in every cell type in which it has been sought and its structure is highly conserved in evolution with similar proteins expressed in plants, insects, microorganisms and vertebrate animals. Rodents with defects in iron absorption and utilization were identified long before it was determined that the defect was due to a single nucleotide mutation in DMT1. Study of these animals reveals that transport of iron and other divalent metal ions by DMT1 is pH dependent, but the exact manner in which pH exerts its effect is unknown. The structure of the DMT1 gene is complex. Alternative usage of 3' exons, results in forms with and without iron responsive elements (IREs), while alternative usage of 5' exons and less well defined products of alternative splicing results in an array of isoforms with incompletely defined function. Expression of some isoforms is tissue specific and appears to affect subcellular targeting of the protein. At least one signal for DMT1 expression appears to be intracellular iron status, however, other, as yet undefined signals may also contribute to DMT1 expression. Interestingly, DMT1 function may differ subtly between humans and other animals; the spontaneous DMT1 mutation found in mice and rats appears to limit iron uptake in the intestine and iron utilization in red cell precursors, whereas the only known human mutation has its primary effect on iron utilization by erythroid cells. The importance of DMT1 function at the level of the whole organism and the individual cell and mechanisms of its regulation on a molecular scale are only beginning to be understood; an appreciation of these process will lead to an understanding of the role of iron in various cellular processes and improved treatments for both anemia and iron-overload.
在过去几年里，随着许多新蛋白质的发现，铁代谢领域取得了飞速发展，这些新蛋白质包括铁转运蛋白、铁氧化还原蛋白、铁调素、十二指肠细胞色素b以及本综述的主题——二价金属离子转运蛋白1（DMT1）。DMT1负责亚铁离子以及部分（而非全部）二价金属离子跨质膜和/或从内体区室输出的转运。在所有被检测的细胞类型中均发现了DMT1 mRNA，其结构在进化过程中高度保守，在植物、昆虫、微生物和脊椎动物中都有表达类似的蛋白质。早在确定铁吸收和利用缺陷是由DMT1中的单核苷酸突变所致之前，就已鉴定出存在此类缺陷的啮齿动物。对这些动物的研究表明，DMT1对铁和其他二价金属离子的转运依赖于pH值，但其发挥作用的确切方式尚不清楚。DMT1基因的结构很复杂。3'外显子的选择性使用会产生带有和不带有铁反应元件（IRE）的形式，而5'外显子的选择性使用以及选择性剪接产生的定义不太明确的产物会导致一系列功能未完全明确的异构体。某些异构体的表达具有组织特异性，似乎会影响该蛋白质的亚细胞定位。至少有一个DMT1表达信号似乎是细胞内铁状态，然而，其他尚未明确的信号可能也会影响DMT1的表达。有趣的是，DMT1的功能在人类和其他动物之间可能存在细微差异；在小鼠和大鼠中发现的自发DMT1突变似乎会限制肠道对铁的吸收以及红细胞前体中铁的利用，而唯一已知的人类突变主要影响红系细胞对铁的利用。DMT1在整个生物体和单个细胞水平上的功能重要性及其分子水平的调控机制才刚刚开始被理解；对这些过程的认识将有助于理解铁在各种细胞过程中的作用，并改善对贫血和铁过载的治疗。
