国际科学委员会的化学研究：调查电子的盗窃
Once a year, biochemist Lisa Landino makes a scientific pilgrimage to Virginia’s great pork-packing center of Smithfield, coming home with eight or ten fresh pig brains.
“I know; it sounds lovely,” Landino says. “They’re a buck each, with a minimum of fifty. I only need ten, but I have to pay fifty bucks.” She runs the brains through a blender (“I really do.”), then the “pig-brain milkshake” goes into a centrifuge. 得到的液体，分出并冷冻，代表了足够的原材料，足以让兰迪诺和她的学生们对大脑中蛋白质的氧化损伤进行为期一年的深入研究。
Many diseases such as Alzheimer’s, Parkinson’s and amyotrophic lateral sclerosis, also known as Lou Gehrig’s Disease, have beginnings in the chemistry of our own body. Landino威廉玛丽大学的化学副教授，研究这些神经退行性疾病的化学根源。 她的佳博体育专注于氧化损伤一种被称为微管蛋白的蛋白质。
成千上万的蛋白质
微管蛋白只是我们体内数千种不同蛋白质中的一种。 大多数，如果不是全部，都处于一个24/7的破坏和修复循环的某个阶段，涉及我们自己身体产生的分子毒素。
“We all breathe oxygen. Most of the time, our bodies process the oxygen into water,” Landino said. “But not all of the time.” An unavoidable percentage of the oxygen we breathe is processed into what chemists call reactive oxygen species—molecular structures that are “really quite toxic,” as Landino says.
活性氧具有介于氧和水之间的化学结构。 “Reactive,” in chemical terms, means that these ions or small molecules have an unpaired electron in their outer—or valence—shells. 如果大自然厌恶真空，那么它也厌恶带着紫色激情的未配对电子。 Their unfilled outer electron shell makes them chemically prone to react with something nearby, Landino says, so they “steal an electron” to make their outer shell complete and stable.
Often, the victim of electron theft is one of the body’s own proteins. 细胞分子成分之间的电子损失，如果不加以控制，就会损害蛋白质，当然也会损害细胞本身。
窃取电子的分子肇事者也被称为自由基。 当你食用富含抗氧化剂的食物或膳食补充剂时，这些自由基就是你的目标。 Landino explained that antioxidants act as molecular sacrificial lambs: “If you eat a blueberry, it gives these reactive species something else to steal an electron from, rather than targeting the proteins in your cells.”
专注于修复
Landino’s work concentrates less on antioxidants and more on the cell’s abilities to repair oxidative damage to its own proteins—especially tubulin. 她解释说，神经元中15%到20%的蛋白质是微管蛋白，微管蛋白的功能就像支架一样，赋予每个细胞三维结构。
“Tubulin also acts as a kind of intracellular railroad track,” she explained, “because some proteins use the tubulin as a walkway to get around inside the cell.”
兰蒂诺解释说，微管蛋白以两种状态存在：二聚体和聚合物。 二聚体是由两部分组成的分子，就像两个粘在一起的粘土球。 为了使微管蛋白发挥脚手架和铁轨的功能，二聚体将自己排列在聚合物微管中，形成由蛋白质组成的空心细丝。
The tubulin molecule, she said, has amino-acid “arms” that are vulnerable to electron theft by free radicals. These arms consist of a sulfur and a hydrogen atom, known to chemists as a thiol, or, in chemical notation, as an –SH group. 一个急于窃取电子的活性氧离子或分子，把这些硫醇臂看作是一辆没有上锁、马达还在运转的汽车的化学等价物。
“If this guy loses an electron, what will commonly happen in a protein is that it now has an S with a little dot,” Landino said. “If two of these S-dot guys are close to each other, they will form a new bond called a disulfide where they are now linked together.” Another result of electron theft could be that two different proteins—each missing an electron—will form an unwanted covalent bond with each other. Enough of this damage, Landino explains, can cause the tubulin filaments to dissolve, the polymer microtubules crumbing into a set of loose tubulin dimers.
“There are proteins that like to associate with these polymer microtubules, and if those proteins don’t have anything to grab onto, it changes the organization of the cell,” Landino said. “And so if you get rid of a main structural component, there’s a blip in time where the proteins don’t know who they’re supposed to interact with. It can be enough to turn on a process called programmed cell death, where cells actually pause and say something’s just not right here. And the cell will begin the process of just…dying. In a disease like Alzheimer’s, if you have a sufficient number of those cells that just die, you start having big holes in your brain.”
In addition, Landino says dissolved tubulin may be implicated in neurofibrillary tangles, the signature protein clumps found in and between neurons of Alzheimer’s patients. 这些缠结是由一种叫做tau的蛋白质的结块组成的，这种蛋白质通常与微管蛋白结合。
“My theory is that if something fundamentally bad happens to tubulin, well, then tau’s got nothing to do but bind to itself,” she explained.
The good news, Landino says, is that oxidative damage to proteins is reversible—and usually is reversed. 以微管蛋白为例，松散的二聚体重新组装成微管，这样细胞就恢复了结构，蛋白质序列就开始按时运行。 坏消息是，由于某种原因，随着我们年龄的增长，对蛋白质的氧化损伤会增加。
问题是老龄化
“Every cell in your body has some defense against those reactive oxygen species. So you have a number of different proteins in your body that protect you from damage,” Landino said. “But the biggest concern with oxidative damage has to do with getting older. As you age, it’s been shown that you produce more of these intermediates that can be toxic—and you have fewer defenses against them.”
她拥有她所知道的唯一一个研究微管蛋白氧化损伤的佳博体育，并且在理解这一过程方面已经取得了很大的进展。 Using off-the-shelf chemicals—and even temperature—she can induce and reverse oxidative damage in the lab, causing the protein microtubules to dissolve into loose dimers and then to re-assemble. At present, Landino’s lab is searching for the specific protein or group of proteins in the neuron that provides the chemical signal for reconstruction.
“The reason I’m interested in this type of damage is that it is reversible. 你可以很容易地把它反过来。 That’s what your body does when it repairs damage normally.”