小柯机器人

科学家揭示NNT的结构与机制
2019-08-29 14:44

奥地利科学技术研究所Leonid A. Sazanov研究组一项最新研究,揭示了线粒体质子转位转氢酶(NNT)的结构与机制。这一研究成果2019年8月28日在线发表于《自然》。

研究人员提出了在不同构象状态下的完整哺乳动物NNT冷冻电镜结构。他们揭示了NADP(H)结合结构域如何打开质子通道到膜的对侧,并提供这两种状态的结构。他们还描述了膜和可溶性结构域之间的催化过程中重要界面和接头,及其在核苷酸交换过程中的作用。这些结构使他们提出了一种修订的NNT藕联过程机制,这与先前大量的生物化学工作是一致的。他们的研究结果可以联系到目前还没有研发出来的NNT抑制剂,这些抑制剂可能在贫血后输血损伤、代谢综合征和某些癌症中具有治疗潜力。

据了解,NNT存在于细菌的质膜和真核生物的线粒体内膜中。 NNT催化NADH和NADP +之间的氢化物转移,并伴随着一个质子穿过膜。其主要的生理功能是产生NADPH,NADPH是合成代谢反应的基质和氧化状态的调节剂。然而,NNT也可以微调三羧酸循环。 NNT缺陷导致人类家族性糖皮质激素缺乏和小鼠代谢异常,类似于II型糖尿病。已经提出的NNT的催化机理涉及整个NADP(H)结合结构域的约180°旋转,其交替参与氢化物转移和质子通道门控。但是,此前由于缺乏完整NNT的高分辨率结构,这一过程的细节并不清楚。

附:英文原文

Title: Structure and mechanism of mitochondrial proton-translocating transhydrogenase

Author: Domen Kampjut, Leonid A. Sazanov

Issue&Volume: 2019-08-28

Abstract: Proton-translocating transhydrogenase (also known as nicotinamide nucleotide transhydrogenase (NNT)) is found in the plasma membranes of bacteria and the inner mitochondrial membranes of eukaryotes. NNT catalyses the transfer of a hydride between NADH and NADP+, coupled to the translocation of one proton across the membrane. Its main physiological function is the generation of NADPH, which is a substrate in anabolic reactions and a regulator of oxidative status; however, NNT may also fine-tune the Krebs cycle1,2. NNT deficiency causes familial glucocorticoid deficiency in humans and metabolic abnormalities in mice, similar to those observed in type II diabetes3,4. The catalytic mechanism of NNT has been proposed to involve a rotation of around 180° of the entire NADP(H)-binding domain that alternately participates in hydride transfer and proton-channel gating. However, owing to the lack of high-resolution structures of intact NNT, the details of this process remain unclear5,6. Here we present the cryo-electron microscopy structure of intact mammalian NNT in different conformational states. We show how the NADP(H)-binding domain opens the proton channel to the opposite sides of the membrane, and we provide structures of these two states. We also describe the catalytically important interfaces and linkers between the membrane and the soluble domains and their roles in nucleotide exchange. These structures enable us to propose a revised mechanism for a coupling process in NNT that is consistent with a large body of previous biochemical work. Our results are relevant to the development of currently unavailable NNT inhibitors, which may have therapeutic potential in ischaemia reperfusion injury, metabolic syndrome and some cancers7,8,9.

DOI: 10.1038/s41586-019-1519-2

Source: https://www.nature.com/articles/s41586-019-1519-2

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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