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Catalysis by approximation Bringing two substrates together *Nucleoside monophosphate (NMP) kinases *Adenylate kinase, guanylate kinase *Challenge to promote.

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Presentation on theme: "Catalysis by approximation Bringing two substrates together *Nucleoside monophosphate (NMP) kinases *Adenylate kinase, guanylate kinase *Challenge to promote."— Presentation transcript:

1 Catalysis by approximation Bringing two substrates together *Nucleoside monophosphate (NMP) kinases *Adenylate kinase, guanylate kinase *Challenge to promote phosphoryl transfer from NTP to NMP without promoting NTP hydrolysis

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3 NMP kinases Conserved NTP binding domain *Central -sheet surrounded by -helices *Loop between first -strand and first helix *Gly-X-X-X-X-Gly-Lys *P-loop, also present in a wide variety of important nucleotide-binding proteins

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6 NMP kinases ATP- Mg 2+ complex true substrate *Enhances the binding energy *Reduces non-specific ionic interactions between enzyme and ATP *Hold nucleotide in well-defined conformation

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9 NMP kinases ATP binding induces large conformational changes *Classical example of induced fit *P-loop closes down on top of the ATP chain *Movement of P-loop permits the top domain of the enzyme to move down to form a lid over the bound nucleotide *Binding of second substrate (NMP) induces additional conformational changes bringing the reactive parts of the two substrates close together *Prevents the wasteful transfer of the phosphoryl group to water

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12 Multienzyme catalysis Bringing enzymes together *Structural integration of different kinds of enzymes makes the coordinated catalysis of a complex reaction possible *The proximity of one enzyme to another increases the overall reaction rate and minimizes side reactions *Pyruvate dehydrogenase complex

13 Pyruvate dehydrogenase complex Member of a family of homologous giant complexes with molecular masses ranging from 4-10 million daltons * -ketoglutarate dehydrogenase *branched chain -ketoacid dehydrogenase *acetoin dehydrogenase

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23 Dihydrolipoyl transacetylase (E2) Core of the complex *8 catalytic trimers *N-terminal domain contains a bound lipoamide cofactor that acts as a swinging arm *Flexible arm has the ability to call on each active site of E1, E2 and E3 in turn

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35 Fatty acid synthase Multifunctional enzyme complex in eukaryotes *All enzyme components linked in a large polypeptide chain *Mammalian enzyme: dimer 2x260 kDa *Three domains joined by flexible regions

36 Mammalian fatty acid synthase 7 different catalytic sites present on a single polypeptide chain *Domain 1: substrate entry and condensation unit *Domain 2: reduction unit *Domain 3: palmitate release unit The arenas of catalytic action are the interfaces between domains on opposite chains

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38 Mammalian fatty acid synthase Flexibility and 20-Å maximal length of the phosphopantetheinyl moiety are critical for the function of the multienzyme complex *No large structural rearrangements needed *Substrate is on a long, flexible arm that can reach each of the numerous active sites *Enhanced efficiency because intermediates are directly transferred from one active site to the next

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40 Multienzyme complexes Many eukaryotic multienzyme complexes are multifunctional proteins in which different enzymes are linked covalently Advantages *Synthetic activity of different enzymes is coordinated *Covalently joined enzymes are more stable than one formed by noncovalent attractions


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