He Science of Sirtuins(蛋白酶)

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he Science of Sirtuins

去乙酰化酶的科学

Sirtuins help regulate your cellular health. Here’s what you need to know about how they work, what they can do for your body, and why they rely on NAD+ to function.

去乙酰化酶帮助调节你的细胞健康。以下是你需要知道的关于它们如何工作,它们能为你的身体做什么,以及为什么它们依赖 NAD + 来工作。

Sci101 Sirtuins Lead

Sirtuins are a family of proteins that regulate cellular health. Sirtuins play a key role in regulating cellular homeostasis. Homeostasis involves keeping the cell in balance. However, sirtuins can only function in the presence of NAD+, nicotinamide adenine dinucleotide, a coenzyme found in all living cells.

去乙酰化酶是一类调节细胞健康的蛋白质。去乙酰化酶在调节细胞内环境稳态中起着关键作用。内环境平衡包括保持细胞的平衡。然而,去乙酰化酶只有在 NAD + ,烟酰胺腺嘌呤二核苷酸,一种存在于所有活细胞中的辅酶的存在下才能发挥作用。

How Sirtuins Regulate Cellular Health with NAD+

去乙酰化酶如何通过 NAD + 调节细胞健康

Think of your body’s cells like an office. In the office, there are many people working on various tasks with an ultimate goal: stay profitable and fulfill the mission of the company in an efficient manner for as long as possible. In the cells, there are many pieces working on various tasks with an ultimate goal, too: stay healthy and function efficiently for as long as possible. Just as priorities in the company change, due to various internal and external factors, so do priorities in the cells. Someone has to run the office, regulating what gets done when, who’s going to do it and when to switch course. In the office, that would be your CEO. In the body, at the cellular level, it’s your sirtuins.

把你的身体细胞想象成一间办公室。在办公室里,有许多人在从事各种各样的工作,他们的最终目标是: 保持盈利并尽可能长时间有效地完成公司的使命。在这些细胞中,有许多部分在从事各种各样的工作,它们的最终目标也是: 尽可能长时间地保持健康和高效地工作。正如公司的优先级会因为各种内部和外部因素而发生变化一样,细胞的优先级也会发生变化。必须有人来管理办公室,规范什么时候做什么,谁来做什么,什么时候转变方向。在办公室里,那就是你的 CEO。在身体里,在细胞水平上,是你的抗衰老蛋白。

Sirtuins are a family of seven proteins that play a role in cellular health. Sirtuins can only function in the presence of NAD+, nicotinamide adenine dinucleotide, a coenzyme found in all living cells. NAD+ is vital to cellular metabolism and hundreds of other biological processes. If sirtuins are a company’s CEO, then NAD+ is the money that pays the salary of the CEO and employees, all while keeping the lights on and the office space rent paid. A company, and the body, can’t function without it. But levels of NAD+ decline with age, limiting the function of sirtuins with age as well. Like all things in the human body, it’s not that simple. Sirtuins manage everything that happens in your cells.

去乙酰化酶是七种蛋白质的家族,在细胞健康中起着重要作用。去乙酰化酶只有在 NAD + ,烟酰胺腺嘌呤二核苷酸,一种存在于所有活细胞中的辅酶的存在下才能发挥作用。NAD + 对细胞新陈代谢和数百种其他生物过程至关重要。如果 sirtuins 是一家公司的 CEO,那么 NAD + 就是支付 CEO 和员工薪水的钱,同时还要保持灯光亮度和支付办公室租金。没有它,公司和整个机构就无法运转。但是 NAD + 的水平随着年龄的增长而下降,也限制了去乙酰化酶的功能。就像人体内的所有东西一样,事情并没有那么简单。去乙酰化酶控制细胞内发生的一切。

Sirtuins Are Proteins. What Does That Mean?

去乙酰化酶是蛋白质,这意味着什么?

Sirtuins are a family of proteins. Protein might sound like dietary protein — what’s found in beans and meats and well, protein shakes — but in this case we’re talking about molecules called proteins, which work throughout the body’s cells in a number of different functions. Think of proteins as the departments at a company, each one focusing on its own specific function while coordinating with other departments.

去乙酰化酶是一类蛋白质。蛋白质听起来可能像膳食蛋白质——在豆类、肉类和蛋白质奶昔中发现的蛋白质——但在这里,我们讨论的是一种叫做蛋白质的分子,它在人体细胞中发挥多种不同的功能。把蛋白质想象成一个公司的部门,每个部门在与其他部门协调的同时,专注于自己特定的功能。

A well-known protein in the body is hemoglobin, which is part of the globin family of proteins and is responsible for transporting oxygen throughout your blood. The myoglobin is the hemoglobin’s counterpart, and together they make up the globin family.

人体中一种众所周知的蛋白质是血红蛋白,它是蛋白质家族的一部分,负责在血液中输送氧气。肌红蛋白是血红蛋白的对应物,它们共同构成了球蛋白家族。

Your body has nearly 60,000 families of proteins — a lot of departments! — and sirtuins are one of those families. While hemoglobin is one in a family of two proteins, sirtuins are a family of seven.

你的身体有将近60,000个蛋白质家族ーー很多部门!Sirtuins 就是其中之一。虽然血红蛋白是两种蛋白家族中的一种,去乙酰化酶是七种蛋白家族中的一种。

Of the seven sirtuins in the cell, three of them work in the mitochondria, three of them work in the nucleus and one of them works in the cytoplasm, each playing a variety of roles. The basic role of sirtuins, however, is that they remove acetyl groups from other proteins.

在细胞中的七种去乙酰化酶中,有三种在线粒体中工作,三种在细胞核中工作,一种在细胞质中工作,每种都扮演着不同的角色。然而,去乙酰化酶的基本作用是从其他蛋白质中去除乙酰基。

Acetyl groups control specific reactions. They’re physical tags on proteins that other proteins recognize will react with them. If proteins are the departments of the cell and DNA is the CEO, the acetyl groups are the availability status of each department head. For example, if a protein is available then the sirtuin can work with it to make something happen, just as the CEO can work with an available department head to make something happen.

乙酰基控制特定的反应。它们是蛋白质上的物理标记,其他蛋白质识别出来的蛋白质会与它们发生反应。如果说蛋白质是细胞的部门,DNA 是首席执行官,那么乙酰基群就是每个部门领导的可用状态。例如,如果一种蛋白质是可用的,那么 sirtuin 就可以与它一起工作,使某些事情发生,就像 CEO 可以与一个可用的部门领导一起工作,使某些事情发生。

Sirtuins work with acetyl groups by doing what’s called deacetylation. This means they recognize there’s an acetyl group on a molecule then remove the acetyl group, which tees up the molecule for its job. One way that sirtuins work is by removing acetyl groups (deacetylating) biological proteins such as histones. For example, sirtuins deacetylate histones, proteins that are part of a condensed form of DNA called chromatin. The histone is a large bulky protein that the DNA wraps itself around. Think of it as a Christmas tree, and the DNA strand is the strand of lights. When the histones have an acetyl group, the chromatin is open, or unwound.

去乙酰化酶与乙酰基一起工作,这被称为去乙酰化。这意味着他们认识到一个分子上有一个乙酰基,然后去除乙酰基,这个分子为它的工作增加了分子。去乙酰化酶的一种工作方式是去除乙酰基(去乙酰化)生物蛋白,如组蛋白。例如,去乙酰化去乙酰化组蛋白,它是一种浓缩的 DNA 的一部分,叫做染色质。组蛋白是一种巨大的蛋白质,被 DNA 包裹着。把它想象成一棵圣诞树,DNA 链就是一串灯。当组蛋白含有一个乙酰基群时,染色质是开放的或未开放的。

This unwound chromatin means the DNA is being transcribed, an essential process. But it doesn’t need to remain unwound, as it’s vulnerable to damage in this position, almost like the Christmas lights could get tangled or the bulbs can get damaged when they’re unwieldy or up for too long. When the histones are deacetylated by sirtuins, the chromatin is closed, or tightly and neatly wound, meaning gene expression is stopped, or silenced.

这种未缠绕的染色质意味着 DNA 正在被转录,这是一个必不可少的过程。但是它不需要一直待在原地,因为它在这个位置很容易受到损坏,就像圣诞节的灯会缠在一起,或者灯泡会因为太笨重或者太长时间不能使用而受损。当组蛋白被去乙酰化去乙酰化后,染色质被关闭,或者紧密而整齐地缠绕,这意味着基因表达被停止,或者被沉默。

We’ve only known about sirtuins for about 20 years, and their primary function was discovered in the 1990s. Since then, researchers have flocked to study them, identifying their importance while also raising questions about what else we can learn about them.

我们对去乙酰化酶的了解只有20年左右,它们的主要功能是在20世纪90年代被发现的。从那时起,研究人员成群结队地研究它们,确定它们的重要性,同时提出关于我们还能从中了解到什么的问题。

The Discovery and History of Sirtuins

去乙酰化酶的发现与历史

Geneticist Dr. Amar Klar discovered the first sirtuin, called SIR2, in the 1970s, identifying it as a gene that controlled the ability of yeast cells to mate. Years later, in the 1990s, researchers found other genes that were homologous — similar in structure — to SIR2 in other organisms like worms, fruit flies, and these SIR2 homologues were then named sirtuins. There were different numbers of sirtuins in each organism. For example, yeast has five sirtuins, bacteria has one, mice have seven, and humans have seven.

遗传学家 Amar Klar 博士在20世纪70年代发现了第一个 sirtuin,称为 SIR2,确定它是一个控制酵母细胞交配能力的基因。几年后,在20世纪90年代,研究人员发现了其他与 SIR2同源的基因(在结构上相似) ,存在于其他生物体中,如蠕虫、果蝇,这些 SIR2同源基因后来被命名为 sirtuins。每种生物体中去乙酰化酶的数量不同。例如,酵母菌有五种去乙酰化酶,细菌有一种,老鼠有七种,人类有七种。The fact that sirtuins were found across species means they were “conserved” with evolution. Genes that are “conserved” have universal functions in many or all species. What was yet to be known, though, was how important sirtuins would turn out to be. 去乙酰化酶是在不同物种间发现的这一事实意味着它们在进化过程中是“保守的”。“保守”的基因在许多或所有物种中具有普遍的功能。然而,我们还不知道去乙酰化酶到底有多重要

In 1991, Elysium co-founder and MIT biologist Leonard Guarente, alongside graduate students Nick Austriaco and Brian Kennedy, conducted experiments to better understand how yeast aged. By chance, Austriaco tried to grow cultures of various yeast strains from samples he had stored in his fridge for months, which created a stressful environment for the strains. Only some of these strains could grow from here, but Guarente and his team identified a pattern: The strains of yeast that survived the best in the fridge were also the longest lived. This provided guidance for Guarente so he could focus solely on these long-living strains of yeast.

1991年,Elysium 联合创始人、麻省理工学院生物学家伦纳德 · 瓜伦特与研究生尼克 · 奥地利和布莱恩 · 肯尼迪一起进行了实验,以更好地了解酵母的衰老过程。一次偶然的机会,奥地利阿科试图从他在冰箱里存放了几个月的样本中培养出各种酵母菌株,这给菌株创造了一个紧张的环境。这些菌株中只有一部分可以在这里生长,但是瓜伦特和他的团队确定了一个模式: 在冰箱中存活得最好的酵母菌株也是最长寿的。这为瓜伦特提供了指导,因此他可以专注于这些长寿酵母菌株。

This led to the identification of SIR2 as a gene that promoted longevity in yeast. It’s important to note that to date there is not yet evidence that this study can be extrapolated to humans and more research is needed on SIR2’s effects in humans. The Guarente lab thus found that removing SIR2 shortened yeast life span dramatically, while most importantly, increasing the number of copies of the SIR2 gene from one to two increased the life span in yeast. But what activated SIR2 naturally had yet to be discovered.

这导致了 SIR2作为一个促进酵母长寿的基因的鉴定。值得注意的是,到目前为止还没有证据表明这项研究可以外推到人类身上,还需要对 SIR2对人类的影响进行更多的研究。瓜伦特实验室因此发现去除 SIR2大大缩短了酵母的寿命,而最重要的是,将 SIR2基因的拷贝数从一个增加到两个,延长了酵母的寿命。但是天然激活的 SIR2还没有被发现。

This is where acetyl groups come into play. It was initially thought that SIR2 might be a deacetylating enzyme — meaning it removed those acetyl groups — from other molecules, but no one knew if this were true since all attempts to demonstrate this activity in a test tube proved negative. Guarente and his team were able to discover that SIR2 in yeast could only deacetylate other proteins in the presence of the coenzyme NAD+, nicotinamide adenine dinucleotide.

这就是乙酰基群发挥作用的地方。最初人们认为 SIR2可能是一种去乙酰化酶ーー这意味着它从其他分子中去除了那些乙酰基群,但是没有人知道这是否正确,因为所有在试管中证明这种活性的尝试都被证实为阴性。和他的团队发现,酵母中的 SIR2只能在辅酶 NAD + ,烟酰胺腺嘌呤二核苷酸的存在下脱乙酰其他蛋白质。

In Guarente’s own words: “Without NAD+, SIR2 does nothing. That was the critical finding on the arc of sirtuin biology.”

用瓜伦特自己的话说: “如果没有 NAD + ,SIR2就什么也做不了。这是关于 sirtuin 生物学弧线的重要发现。”

The Future of Sirtuins

Sirtuins 的未来

Sirtuins research has largely been tied to aging and metabolic activity. “There are maybe 12,000 papers on sirtuins now,” Guarente’s said. “At the time we discovered the NAD+ dependent deacetylase activity the number of papers was in the 100s.”

去乙酰化酶的研究主要与衰老和代谢活动有关。“现在关于 sirtuins 的论文大概有12000篇,”瓜伦特说。“当我们发现 NAD + 依赖的脱乙酰基酶活性时,论文数量在100篇左右。”

As the sirtuins field continues to expand, this leaves room for incredible research opportunities into how activating sirtuins with NAD+ precursors can lead to more exciting discoveries.

随着去乙酰化酶领域的不断扩大,这为不可思议的研究机会留下了空间,研究如何通过 NAD + 前体激活去乙酰化酶从而导致更令人兴奋的发现。

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