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Lead With A Poisonous Electron Shield

Main Category: Biology / Biochemistry News
Article Date: 19 Jan 2007 - 3:00 PST
ローマ帝国滅亡の要因の一つは鉛製コンテナー内のぶどうジュースとの主張がある。
単純な酵素モデルの量子化学による研究の成果が明らかになった。
鉛は神経系、腎臓、肝臓、脳及び血液にに重大な打撃を与える。
研究は２種類のタンパク質に注目
Calmodulinは体内のカルシウム陽イオンの統制と輸送に有用な役割を果たす。
d-Aminolevulinic acid dehydrataseはヘモグロビンのバイオ合成に必須である。
これら２種類の酵素内での鉛の異なる動きが以下のことを示している。すなわち、鉛が金属分子結合内の複合体内に入り込み、全方向に進むか、一方の半球内にのみ入るかし、その際、他の半球は自由電子ペアで満たされることになるという。
It has been speculated that lead poisoning may have played a role in the fall of the Roman Empire: it is thought to have been caused by the concentration of grape juice in lead containers. Though the introduction of lead-free gasoline has reduced damage to the environment, the annual production of lead continues to increase worldwide because lead is still used in batteries, glass, and electronic components. However, there has thus far been little research into what, at a molecular level, causes the toxic effects of lead.

French researchers have now applied quantum chemistry to very simple enzyme models and gained new insights. As they have reported in Angewandte Chemie, it seems that the lead's "electron shield" is the main culprit.

Lead does the most damage to the nervous system, kidneys, liver, brain, and blood. These kinds of damage are especially severe for children as they can be irreversible. Complexation agents that grab onto the metal cations are used as antidotes. However, these agents are not lead-specific, meaning that they also remove other important metal cations from the body.

C. Gourlaouen and O. Parisel (Laboratoire de Chimie Théorique, Université Paris 6) took a closer look at two proteins to which lead likes to bind. Calmodulin, a calcium-binding protein, plays an important role in regulating and transporting the calcium cation in the human body. A calcium ion binds to seven ligands at the active centers of the enzyme. If one of the four possible calcium ions of calmodulin is replaced by lead, the lead ion remains roughly heptacoordinated, but this active center becomes distorted and inefficient; the three remaining sites get a reduced efficiency.

d-Aminolevulinic acid dehydratase is essential for the biosynthesis of hemoglobin. Inhibition of this enzyme disrupts the formation of blood to the point of anemia. At the active center, a zinc ion binds to four ligands, three of which involve a sulfur atom. When lead replaces zinc, it only binds to the three sulfur atoms. The reason for this is the emerging free electron pair of the lead cation. It acts as an electronic shield on one side, pushing away the fourth ligand. Such a dramatic geometrical distortion at the active center could explain why lead inhibits this enzyme.

The different behavior of lead in these two enzymes demonstrates that it can enter into complexes in which the metal-ligand bonds can either point in all directions, or into only one hemisphere, while the other hemisphere is filled by the free electron pair.
この研究結果は将来、鉛専門の解毒剤設計に有効となる可能性が有る。
This observation may help in the design of future lead-specific antidotes.