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Extracellular
protein crosslinks and how to get rid of them
细胞外蛋白质交联及其排除
All
the proteins inside our cells are destroyed and rebuilt quite regularly, as a
way to keep them in a generally undamaged state. Some of the proteins outside
our cells, however, are laid down early in our life and then never recycled
at all, and some others are only recycled very very slowly. 我们细胞外所有的蛋白质，都经常被破坏和重建，如同有一种方法把它们保持在一种未损伤状态。然而，某些细胞外蛋白质，在我们生命早期就有，此后完全不更换，另有一些更换得非常非常慢。 These
long-lived proteins are susceptible to chemical reactions. Luckily, the
function of long-lived proteins tends to be very simple -- they don't
catalyse chemical reactions, for example, the way that enzymes do. In general
they have a biophysical function -- they give a tissue elasticity (as in the
artery wall) or transparency (as in the lens of the eye) or high tensile
strength (as in ligaments). 这些长寿蛋白质易受化学反应影响。幸运的是，长寿蛋白质的功能往往很简单—例如，它们没有像酶那样会催化化学反应。 Occasional
chemical reactions with other molecules in the extracellular space don't
affect these functions very much -- at first. But in the long run, they can
matter a lot, especially in the case of the artery wall, which becomes much
more rigid and leads to high blood pressure. 这些长寿蛋白质在细胞外空间与其他分子的偶然化学反应，起先其功能不太受影响。但是长此以往，它们可以关系重大，特别是在动脉壁的场合，它变得僵硬并导致高血压。 The
type of chemical reaction that causes this loss of elasticity is one that
results in a chemical bond (a cross-link) between two nearby proteins that
were previously able to slide across or along each other. 引起这种弹性丧失的化学反应类型，是在本来能横向滑动或彼此并排的相邻两个蛋白质之间产生一种化学键（交联键）。 Luckily,
it happens that a lot of the cross-links that accumulate in this way have
very unusual chemical structures, not found in proteins or other molecules
that the body makes on purpose. 幸运的是，以这种方式积累的很多交联键，有着很不寻常的化学结构，没有发现于为构成身体而产生的蛋白质或其他分子中。 This
means that it is theoretically possible to identify chemicals that can react
with the cross-links and break them, without reacting with anything that we
don't want to break. And indeed, several years ago a group of chemists found
such a molecule, which has now been tested in many different animals and also
in humans and seems to lower blood pressure quite substantially. 这意味着，在理论上能够鉴定出诸多化学物质，它们可以同交联键反应、破坏交联键，同时又不与我们不想破坏的任何东西起反应。确实，几年前一组化学家发现了这样的一种分子，这种分子现在已在很多不同动物中测试过，也在人类中测试过，似乎能实实在在地降低血压。 These
chemists formed a company (named Alteon) to market the drug (named ALT-711),
but it is still in clinical trials. We
need more work in this area. There are plenty of other types of cross-link
that ALT-711 doesn't break, so we need other chemicals that will complement
what ALT-711 does. 这些化学家建立了一个公司（称为Alteon公司）把该药品（称为ALT-711）投放市场，但该药品仍然还在临床试验中。我们需要在这个领域做更多的工作。有很多其他类型的交联键是ALT-711不能破坏的，所以我们需要其他的化学物质来补充 ALT-711。 Some
such crosslinks are probably too stable to be breakable catalytically by any
non-toxic small molecule; here it may be necessary to find enzymes that can
couple the link-breakage to hydrolysis of ATP (which might need the enzyme to
shuttle back and forth across the cell membrane, as there is very little ATP
in the extracellular space) or else to use the concept of
"one-shot" proteins, such as the DNA repair protein MGMT, which
react with a stable molecule but thereby inactivate themselves. 有些这样的交联键可能太稳定，不能被任何非毒性小分子所催化破坏；很可能需要发现一些酶，它们可以把连接-裂口，偶联于ATP的水解（ATP水解可能需要酶类来回穿梭于细胞膜内外，因为细胞外空间几乎没有ATP），或者也可利用"一次性"蛋白质概念，例如DNA修复蛋白MGMT能同稳定的分子反应，但也因此而使它们自己失活。 This
is a feasible approach because of the very low rate of formation of the
relevant cross-links: the cellular energy budget would not be significantly
impacted. 这是一个可行的方案，因为有关的交联键形成得很慢：细胞能量预算不会受到很大冲击。 Talks
on this topic at IABG 10: 以这个题目在IABG 10上讲话：Lakatta |
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