ACTIVE-SITE ZINC LIGANDS AND ACTIVATED H2O OF ZINC ENZYMES

被引:413
作者
VALLEE, BL
AULD, DS
机构
[1] HARVARD UNIV,SCH MED,DEPT PATHOL,BOSTON,MA 02115
[2] BRIGHAM & WOMENS HOSP,BOSTON,MA 02115
关键词
D O I
10.1073/pnas.87.1.220
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The x-ray crystallographic structures of 12 zinc enzymes have been chosen as standards of reference to identify the ligands to the catalytic and structural zinc atoms of other members of their respective enzyme families. Universally, H2O is a ligand and critical component of the catalytically active zinc sites. In addition, three protein side chains bind to the catalytic zinc atom, whereas four protein ligands bind to the structural zinc atom. The geometry and coordination number of zinc can vary greatly to accommodate particular ligands. Zinc forms complexes with nitrogen and oxygen just as readily as with sulfur, and this is reflected in catalytic zinc sites having a binding frequency of His > > Glu > Asp = Cys, three of which bind to the metal atom. The systematic spacing between the ligands is striking. For all catalytic zinc sites except the coenzyme-dependent alcohol dehydrogenase, the first two ligands are separated by a "short spacer" consisting of 1 to 3 amino acids. These ligands are separated from the third ligand by a "long spacer" of ≈ 20 to ≈ 120 amino acids. The short spacer enables formation of a primary bidentate zinc complex, whereas the long spacer contributes flexibility to the coordination sphere, which can poise the zinc for catalysis as well as bring other catalytic and substrate binding groups into apposition with the active site. The H2O is activated by ionization, polarization, or poised for displacement. Collectively, the data imply that the preferred mechanistic pathway for activating the water - e.g., zinc hydroxide or Lewis acid catalysis - will be determined by the identity of the other three ligands and their spacing. (amino acid sequence/metalloenzymes/metalloproteins/structure-function/x-ray crystallography).
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页码:220 / 224
页数:5
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