Transcript Slide 1 - Elsevier

Chapter 12
Zinc  Lewis Acid and Gene
Regulator
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FIGURE 12.1 Zinc-binding sites in enzymes can be catalytic, structural, or cocatalytic. The protein
ligands are indicated by smaller filled circles.
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FIGURE 12.2 The zinc-bound water can either be ionised to zinc-bound hydroxide, polarised by a
general base to generate a nucleophile for catalysis or displaced by the substrate.
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FIGURE 12.3 The active site of human carbonic anhydrase.
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FIGURE 12.4 The main features of the mechanism of carbonic anhydrase.
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FIGURE 12.5 Active sites of thermolysin and carboxypeptidases A and B.
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FIGURE 12.6 Two possible reaction pathways for carboxypeptidase A. (Adapted from Wu et al., 2010.)
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FIGURE 12.7 MMP catalytic domain structure. (a) Stereographic Richardson plot of the catalytic domain of human MMP-8
(Phe79eGly242) shown in standard orientation (PDB 1JAN). The repetitive secondary structure elements (orange arrows
for -strands, IV; cyan ribbons for -helices, AC) and the four cations (two zinc ions in magenta and two calcium
ions in red) are depicted. The side chains of the zinc-binding histidines, the general base/acid glutamate, the Met-turn
methionine, and residues engaged in key electrostatic interactions (grey dots) within the C-terminal subdomain are shown
as stick models with yellow carbons and labeled. A substrate of sequence ProLeuGlyLeuAla, modeled based on
published inhibitor structures, is shown as a stick model with grey carbons. Additional relevant chain segments are shown
in distinct colours and labeled (Met-turn in green; specificity loop in red; S10-wall-forming segment in blue; S-loop in purple;
and bulge-edge segment in magenta). (b) Topology scheme of MMP-8 in the same orientation as in (A). (c) Close-up view
of (A) depicting the side chains engaged in zinc-binding and those shaping the specificity pocket, which are labeled. (From
Tallant, Marrero, & Gomis-Ru¨th, 2010. Copyright 2010 with permission from Elsevier.)
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FIGURE 12.8 Catalytic mechanism of MMPs. Scheme for the cleavage mechanism proposed for
MMPs, with the catalytic zinc ion as a sphere and hydrogen bonds as dashed lines. The three histidine
ligands are represented by sticks. One conceivable alternative is that the second proton is transferred
directly from the gem-diolate to the leaving amine in II and not via the general base/acid glutamate.
This proton transfer could hypothetically occur before or after scissile-bond cleavage. (Adapted from
Tallant et al., 2010.)
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FIGURE 12.9 Reactions catalysed by SDR enzymes. (Adapted from Kavanagh, O¨rnvall, Persson, &
Oppermann, 2008.)
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FIGURE 12.10 The essential features of the catalytic cycle of liver alcohol dehydrogenase. (Adapted
from Parkin, 2004.)
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FIGURE 12.11 Specific attachment of a prochiral centre to an enzyme-binding site enables the
enzyme to distinguish between prochiral methylene protons in ethanol. (Adapted from Voet & Voet,
2004.)
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FIGURE 12.12 Some other active site coordination motifs in mononuclear zinc enzymes: from left to
right bacteriophage T7 lysozyme, 5-aminolaevulinate dehydratase, Ada DNA repair protein. (Adapted
from Parkin, 2004.)
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FIGURE 12.13 Repair of damaged DNA by sacrificial alkylation of one of the zinc cysteine thiolate
ligands of the Ada DNA repair protein. (Adapted from Parkin, 2004.)
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FIGURE 12.14 The zinc-binding sites of subclass B1 (BCII from B cereus), B2 (CphA from A.
hydrophila), and B3 (FEZ1 L. gormanii) -lactamases. (From Bebrone, 2007. Copyright 2007 with
permission from Elsevier.)
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FIGURE 12.15 Drawings of the active sites of the leucine aminopeptidases BlLAP (Protein Data Bank
[PDB]: 1LAM), AAP (PDB: 1AMP), and SAP (PDB: 1CP7) based on X-ray crystallography. (Adapted
from Holz, Bzymek, & Swierczek, 2003.)
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FIGURE 12.16 Proposed general mechanism for the hydrolysis of a peptide, catalysed by a
metallopeptidase with a cocatalytic active site where R1, R2, R3 are substrate side chains and R is an Nterminal amine or a C-terminal carboxylate. This mechanism is based on the proposed mechanism for the
aminopeptidase from Aeromonas proteolytica. (Adapted from Holz et al., 2003.)
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FIGURE 12.17 Metal coordination sites in trinuclear zinc enzymes. (Adapted from Parkin, 2004.)
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FIGURE 12.18 Coordination of the dinuclear site in kidney bean purple acid phosphatase. (Adapted
from Parkin, 2004.)
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FIGURE 12.19 (Left) Schematic representation of tandemly repeated zinc finger motif with their
tetrahedrally coordinated Zn2+ ions. Conserved amino acids are labeled and the most probable DNAbinding side chains are indicated by balls. (Right) A ribbon diagram of a single zinc finger motif in a
ribbon diagram representation. (From Voet & Voet, 2004. Copyright 2004 with permission from John
Wiley and Sons.)
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FIGURE 12.20 (a) TFIIIA binds to 5S rRNA promoter sequences using zinc fingers 13, 5, and 79
which recognise respectively box C (green), the IE sequences (red), and box A (orange). (b) TFIIIA
binds to 5S rRNA using primarily zinc fingers 46. Finger 4 binds to sequences in loop E, finger 5 to
backbone atoms in helix V, and finger 6 binds to sequences in loop A. (From Hall, 2005. Copyright
2005 with permission from Elsevier.)
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FIGURE 12.21 DNA and RNA recognition by the fifth zinc finger of TFIIIA. (a) The zinc finger recognises
bases in the major groove of 5S rRNA promoter DNA (b) The finger recognises the phosphate groups of
5S rRNA. (From Hall, 2005. Copyright 2005 with permission from Elsevier.)
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UnnFIGURE 12.1
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