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Aulani " Biokimia Enzim" Presentasi 11 Enzyme Phosphorylation Aulanni’am Biochemistry Laboratory Chemistry Department Brawijaya University.

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Presentation on theme: "Aulani " Biokimia Enzim" Presentasi 11 Enzyme Phosphorylation Aulanni’am Biochemistry Laboratory Chemistry Department Brawijaya University."— Presentation transcript:

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2 Aulani " Biokimia Enzim" Presentasi 11 Enzyme Phosphorylation Aulanni’am Biochemistry Laboratory Chemistry Department Brawijaya University

3 Aulani " Biokimia Enzim" Presentasi 11 Enzyme regulation: How to control the activity of a pathway in response to the needs of the cell or body

4 Aulani " Biokimia Enzim" Presentasi 11 Multiple ways of controlling enzyme activity Control of enzyme availability –Amount of enzyme in the cell Control of enzyme synthesis Control of enzyme degradation –Location of enzyme in the cell On/off membrane Inside/outside organelle

5 Aulani " Biokimia Enzim" Presentasi 11 Multiple ways of controlling enzyme activity Control of enzyme activity –Allosteric activation or inactivation: interaction of small molecule with enzyme, but not at active site

6 Aulani " Biokimia Enzim" Presentasi 11 “Feedback” control of metabolic pathways is often accomplished by allosteric mechanisms ABCDEFG (Excess G)

7 Aulani " Biokimia Enzim" Presentasi 11 Carbamoyl phosphate + aspartate N-carbamoyl aspartate ATCase CTP Allosteric modulation of aspartate transcarbamylase, the first unique step in the biosynthesis of pyrimidines (C, T, U) ATP

8 Aulani " Biokimia Enzim" Presentasi 11 The reaction catalyzed by aspartate transcarbamoylase carbamoyl phosphate aspartate N-carbamoyl aspartate H 2 PO 4 -

9 Aulani " Biokimia Enzim" Presentasi 11 Activity of aspartate transcarbamoylase (and many allosteric enzymes is cooperative with respect to aspartate [aspartate] v0v0 Sigmoid (S- shaped) curve

10 Aulani " Biokimia Enzim" Presentasi 11 Cooperativity in enzymatic activity Multimeric enzymes Binding of S to one protomer causes change in adjacent protomer, increasing the affinity of both protomers for the substrate

11 Aulani " Biokimia Enzim" Presentasi 11 Cooperativity of enzymatic activity: multiple states of the enzyme E LA E MA (T state) Less active Lower affinity for S (R state) More active Higher affinity for S

12 Aulani " Biokimia Enzim" Presentasi 11 What good is cooperativity in enzymatic activity? v0v0 [S] (Same V max and v 0 at 1/2 V max ) Steeper slope ensures greater sensitivity to variations in substrate concentration

13 Aulani " Biokimia Enzim" Presentasi 11 ATP and CTP are positive and negative modulators of aspartate transcarbamoylase [substate] v0v0 positive negative Effects of positive and negative modulators on cooperative enzymes

14 Aulani " Biokimia Enzim" Presentasi 11 Allosteric activators and inhibitors stabilize different states of the enzyme (ATCase) E LA E MA (T state) Less active Lower affinity for S Stabilized by CTP (R state) More active Higher affinity for S Stabilized by ATP

15 Aulani " Biokimia Enzim" Presentasi 11 Allostery is accomplished by conformational changes in ATCase and other enzymes Red: upper catalytic trimer Blue: lower catalytic trimer Green: regulatory dimers (bind ATP and CTP )

16 Aulani " Biokimia Enzim" Presentasi 11 Other about allosterism Allosteric modulators can change K m or V max or both Not all allosteric enzymes are cooperative Allosteric modulation renders an enzyme sensitive to metabolites other than its own substrates and products (e.g., ATCase is sensitive to endproducts of purine and pyrimidine biosynthesis).

17 Aulani " Biokimia Enzim" Presentasi 11 Multiple ways of controlling enzyme activity Control of enzyme activity –Allosteric activation or inactivation: interaction of small molecule with enzyme, but not at active site –Interaction with a large molecule, usually another protein Example: Thrombin and thrombomodulin

18 Aulani " Biokimia Enzim" Presentasi 11 Modification of thrombin activity by thrombomodulin Thrombomodulin (on cell surface of vascular endothelium) –Decreases activity of thrombin toward fibrinogen –Increases ability of thrombin to activate Protein C, an inhibitor of clotting

19 Aulani " Biokimia Enzim" Presentasi 11 Modification of thrombin activity by thrombomodulin clot Thrombin Protein C > Thrombomodulin Protein C zymogen (contains Gla)

20 Aulani " Biokimia Enzim" Presentasi 11 Multiple ways of controlling enzyme activity Control of enzyme activity –Allosteric activation or inactivation –Interaction with another protein –Reversible covalent modification Example: phosphorylation

21 Aulani " Biokimia Enzim" Presentasi 11 Modulation by phosphorylation Enzyme X (inactive) PO 3 2- Enzyme X (active) Phosphorylation may also result in inactivation, depending on the enzyme kinase ATPADP phosphatase H2OH2O PiPi

22 Aulani " Biokimia Enzim" Presentasi 11 Multiple ways of controlling enzyme activity Control of enzyme activity –Allosteric activation or inactivation –Interaction with another protein –Reversible covalent modification –Irreversible modification Example: zymogen activation

23 Aulani " Biokimia Enzim" Presentasi 11 Multiple ways of controlling a single enzyme: Glycogen phosphorylase Gene expression –Multiple genes, tissue-specific expression –Rates transcription vary Protein activity –Allosteric control –Reversible phosphorylation

24 Aulani " Biokimia Enzim" Presentasi 11


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