The evolving biology of the proton-coupled folate transporter: New insights into regulation, structure, and mechanism.
The evolving biology of the proton-coupled folate transporter: New insights into regulation, structure, and mechanism.
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DOI：
10.1096/fj.202101704r
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Matherly LH
中科院分区：
文献类型：
--
作者：
Hou Z;Gangjee A;Matherly LH
人类质子偶联叶酸转运蛋白(PCFT；SLC46A1)或hPCFT在2006年被确定为参与膳食叶酸肠道吸收的主要叶酸转运蛋白。一种罕见的常染色体隐性遗传性叶酸吸收不良综合征可归因于人类SLC46A1变异。HPCFT在许多肿瘤中高表达的认识激发了人们对其潜在的细胞毒性药物靶向的浓厚兴趣，因为它在酸性pH条件下具有高水平的转运活性，这是许多肿瘤的特征，而且它在大多数正常组织中的表达水平很低。为了更好地了解包括人类肿瘤在内的组织之间hPCFT水平差异的基础，研究人员研究了hPCFT的转录调控，包括CpG超甲基化和关键转录因子和顺式元件的作用。另一个重点是确定hPCFT转运蛋白的关键结构和功能决定因素，与基于细菌转运蛋白GlpT和Lacy结构同源性的同源模型相结合，使人们能够获得新的结构和机制见解。最近报道了鸡PCFT在无底物状态和与抗叶酸培美曲塞形成复合体中的冷冻电子显微镜结构，为进一步了解PCFT识别(抗)叶酸的决定因素和PCFT调节(抗)叶酸转运的机制提供了进一步的结构信息。像许多主要的促进蛋白一样，hPCFT以同源寡聚体的形式存在，有证据表明hPCFT单体蛋白的同源寡聚化可能对其细胞内转运和/或转运功能起重要作用。更好地了解hPCFT的结构、功能和调控，应该有助于合理开发与叶酸缺乏和癌症相关的新的治疗策略。
The human proton‐coupled folate transporter (PCFT; SLC46A1) or hPCFT was identified in 2006 as the principal folate transporter involved in the intestinal absorption of dietary folates. A rare autosomal recessive hereditary folate malabsorption syndrome is attributable to human SLC46A1 variants. The recognition that hPCFT was highly expressed in many tumors stimulated substantial interest in its potential for cytotoxic drug targeting, taking advantage of its high‐level transport activity under acidic pH conditions that characterize many tumors and its modest expression in most normal tissues. To better understand the basis for variations in hPCFT levels between tissues including human tumors, studies have examined the transcriptional regulation of hPCFT including the roles of CpG hypermethylation and critical transcription factors and cis elements. Additional focus involved identifying key structural and functional determinants of hPCFT transport that, combined with homology models based on structural homologies to the bacterial transporters GlpT and LacY, have enabled new structural and mechanistic insights. Recently, cryo‐electron microscopy structures of chicken PCFT in a substrate‐free state and in complex with the antifolate pemetrexed were reported, providing further structural insights into determinants of (anti)folate recognition and the mechanism of pH‐regulated (anti)folate transport by PCFT. Like many major facilitator proteins, hPCFT exists as a homo‐oligomer, and evidence suggests that homo‐oligomerization of hPCFT monomeric proteins may be important for its intracellular trafficking and/or transport function. Better understanding of the structure, function and regulation of hPCFT should facilitate the rational development of new therapeutic strategies for conditions associated with folate deficiency, as well as cancer.
影响因子：
3.7
作者：
Duddempudi PK;Goyal R;Date SS;Jansen M
通讯作者：
Jansen M