Ch 8.5

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  1. ·         Small molecules can __ and __ enzymes--> control
    ·         Can be __ or __ binding
    o   __ dissociates slowly from its target enzyme because it becomes __ to the enzyme, either __ or __, like __
    • bind and inhibit enzymes
    • irreversible or reversible
    • Irreversible inhibitor
    • tightly bound
    • covalently or noncovalently
    • penicillin
  2. o   __: characterized by a rapid dissociation of the enzyme-inhibition complex
    §  Competitive inhibition: __

    Competitive inhibitor __
    • Reverse inhibition
    • an enzyme binds to substrate (forming ES complex) or inhibitor (EI) but not both (ESI)
    • resembles the substrate and binds tot the active site of the enzyme. The substrate is thereby prevented from binding to the same active site
  3.    A competitive inhibitor diminishes the rate of catalysis by __
    ·         Can be relieved by __
    • reducing the proportion of enzyme molecules bound to a substrate
    • increasing the substrate concentration so that the substrate competes for the active site
  4. §  Uncompetitive inhibition is distinguished by the fact that the inhibitor does what? It is created only on interaction of the __ and __
    • binds only to the enzyme substrate complex
    • enzyme and substrate
  5. §  Noncompetitive inhibition (__)
    ·         Can bind __ or __
    ·         A noncompetitive inhibitor acts by __ rather than __
    o   Net effect: __
    • the inhibitor and substrate can bind simultaneously to an enzyme molecule at different binding sites
    • free enzyme or the enzyme-substrate complex
    • decreasing the concentration of functional enzyme
    • by diminishing the proportion of enzyme molecules that are bound to substrate 
    • decrease the turnover number
  6. Noncompetitive inhibition cannot be overcome by __. 

    Mixed inhibition is produced when?
    • o   Net effect: decrease the turnover number
    • ·         Cannot be overcome by substrate increase
    • o   Mixed inhibition is produced when a single inhibitor both hindiers the binding of substrate and decreases the turnover number of the enzyme
  7. ·         Reversible inhibitors are _distinguishable
    o   Measurements of __ and __ serve to distinguish the three inhibitions
    §  In competitive inhibition, what happens? The smaller the Ki, the more __the inhibition
    • kinetically 
    • the rates of catalysis at different concentrations of substrate and inhibitor
    • the inhibitor competes with the substrate for the active site
    • potent
  8. ·         The hallmark of competitive inhibition is that it can __
    ·         The effect of a competitive inhibitor is to __, meaning more substrate is needed to obtain the same reaction rate
    ·         At a sufficiently high concentration, virtually all the active sites are __, and the enzyme is fully operative
    • be overcome by a sufficiently high concentration of substrate
    • increase the apparent value of KM
    • filled by substrate
  9. §  In uncompetitive inhibition, the __. This __ does not form any product. Because some __ will always be present, Vmax will be __ than in its absence
    • inhibitor binds only to the ES complex
    • enzyme-substrate-inhibitor complex ESI
    • unproductive ESI complex
    • lower in the presence of inhibitor
  10. ·         The uncompetitive inhibitor lowers the apparent value of KM because __
    ·         To maintain equilibrium between E and ES, __. Thus, __ is required to form __ and the apparent value of KM is reduced
    • the inhibitor binds to ES to form ESI, depleting ES
    • more S binds to E
    • a lower concentration of S
    •  half of the maximal concentration of ES
  11. §  In noncompetitive inhibition, substrate can still __. But, enzyme-inhibitor-substrate complex does not __. The value of __ is decreased to a new value called __, whereas the value of KM is unchanged. 
    • bind to enzyme-inhibitor complex
    • proceed to form product
    •  V­max
    • Vampapx
  12. ·         The reason Vmax is lowered though KM remains unchanged is because the __.The resulting solution behaves as a more dilute solution of enzyme does.
    ·         Noncompetitive inhibition cannot be overcome by __.
    • inhibitor simply lowers the concentration of functional enzyme. 
    • increasing the substrate concentrations
  13. §  The presence of the competitive inhibitor does what?
    §  In uncompetitive inhibition, the inhibitor only __.
    §  In noncompetitive inhibition, the inhibitor can combine with either the __ and __. 
    • cuts the reaction rate in half at this substrate concentration
    • combines with the enzyme-substrate complex
    • enzyme or the enzyme-substrate complex
  14. ·         In pure noncompetitive inhibition, the values of the __ of the inhibitor and enzyme and of the inhibitor and enzyme-substrate complex are equal
    o   The value of Vmax is decreased to the new __; and so, the intercept on the __ is increased
    §  The new slope, which is equal to __ is larger by the same factor. In contrast with Vmax, __ is not affected by pure noncompetitive inhibition
    • dissociation constants
    • value V^(app)max
    • vertical axis
    • KM/V^appmax
    • KM
  15. o   The first step in obtaining a chemical mechanism of an enzyme is to __--> __ of the enzyme bound to its substrate or __ or __ that covalently bond to the enzyme as the inhibitors modify the __, which can then be identified
    determine what functional groups are required for enzyme activity

    X-ray crystallography

    • substrate analog or irreversible inhibitors
    • functional groups
  16. §  Irreversible inhibitors can be divided into three categories: _
    group-specific reagents, reactive substrate analogs (affinity labels) and suicide inhibitors
  17. Group-specific reagents
    ·         react with specific side chains of amino acids (ex: DPIF)
  18. Affinity labels (reactive substrate analogs):
    ·         molecules that are structurally similar to the substrate for an enzyme and that covalently bind to active-site residues. They are more specific for the enzyme’s active site than are group specific reagents
  19. Suicide inhibitors (mechanism-based inhibitors): 
    • ·         modified substrates that provide the most specific means for modifying an enzyme’s active site. The inhibitor binds to the enzyme as a substrate and is initially processed by the normal catalytic mechanism. The mechanism f catalysis then generates a chemically reactive intermediate that inactivates the enzyme through covalent modification 
    • suggests that the covalently modified group on the enzyme is vital for catalysis
  20. ·         __ are potent inhibitors of enzymes
    o   Compounds that resemble the transition state of a catalyzed reaction should be __ and are called __
    §  The inhibition of proline __is an example:
    • Transition-state analogs
    • effective ihibitors and are called transition-state analogs
    • racemase
  21. §  In general, highly potent and specific inhibitors of enzymes can be produced by synthesizing compounds that more closely resemble the __ than the __ itself. The inhibitory power of transition-state analogs underscores the essence of catalysis: __
    • transition state than the substrate itself
    • selective binding of the transition state
  22. ·         Catalytic antibodies demonstrate the importance of __ to __
    o   Antibodies that recognize transition states should function as __

    • selective binding of the transition state to enzymatic activity
    • catalysts
  23. o   Catalytic antibodies (__) can indeed be produced by using __ as __ 
    §  Antibodies catalyzing many other kinds of chemical reactions—exemplified by __ and __, amide-bond formation, __, photoinduced cleavage, photo-induced dimerization, decarboxylation, and oxidation—have been produced with the use of similar strategies
    • abzymes
    • transition-state analogs as antigens
    • ester and amide hydrolysis
    • transesterification
  24. §  Enzymes can function by assuming a conformation in the active site that is __
    ·         The power of transition-state analogs is now evident: (1) __, (2) __ , and (3) __
    • complementary in structure to the transition state
    • they are sources of insight into catalytic mechanisms
    • they can serve as potent and specific inhibitors of enzymes
    • they can be used as immunogens to generate a wide range of novel catalysts
  25. §  Penicillin irreversibly does what?
    ·         It consists of a __fused to a __ to which a __ is attached by a peptide bond. The __ is very labile; and this instabilitiy is closely tied to the antibiotic afction of penicillin
    • inactivates a key enzyme in bacterial cell-wall synthesis
    • thiazolidine ring 
    • beta-lactam ring
    • variable R group
    • beta-lactam ring
  26. ·         Penicillin works by doing what?
    interfering with the synthesis of the cell walls, which is made of peptidoglycan, which consists of linear polysaccharide chains that are cross-linked by short peptides (pentaglycines and tetrapeptides)
  27. o   __ catalyzes the formation of the cross-links that make the peptidoglycan so stable. Bacterial cell walls are unique in containing __, which form cross-links by a mechanism different from that used to synthesize proteins 
    • Glycopeptide transpeptidase
    • D amino acids
  28. ·         Penicillin inhibits the __, which normally forms an __ with the __.
    o   This intermediate then reacts with the __ in another peptide to form the __
    • cross-linking transpeptidase
    • acyl intermediate
    • second to last D-alanine residue of the D-Ala-D-Ala peptide
    • amino group of the terminal glycine
    • cross-link
  29. o   Penicillin is welcomed into the active site of the __ because it mimics the __ moiety of the normal substrate
    o   Bound penicillin then forms a __ with a __ at the active site of the enzyme
    §  This __ does not react further. Hence, the __is irreversibly inhibited and __cannot take place. 
    • transpeptidase
    • D-Ala-D-Ala
    • covalent bond
    • serine residue
    • transpeptidase 
    • cell-wall synthesis
  30. ·         Why is penicillin such an effective inhibitor of the transpeptidase? 
    • o   The highly strained, four-membered bta-lactam ring of penicillin makes it especially reactive
    • o   On binding to the transpeptidase, the serine residue at the active site attacks the carbonyl carbon atom of the lactam ring to form the penicilloyl-serine derivative.
    • o   Because the peptidase participates in its own inactivation, penicillin acts as a suicide inhibitor. 
  31. ·         Characteristics of enzymes require an enzyme prepared in a __ solution
    ·         When we determine an enzyme property such as the value of KM in ensemble studies, that value is of necessity an __
    o   However, __, the ability of a molecule to assume several different structures that differ slightly in stability, is an inherent property of all biomolecules
    • buffered 
    • average value of all of the enzymes present
    • molecular heterogeneity
  32. ·         If we were to perform an experiment to determine enzyme activity under a particular set of conditions with the use of ensemble methods, e would get a __, which would represent the __. However, performing a sufficient number of single molecule experiments, we’d discover that the enzyme has __ with very different activities
    • single value
    • average of the heterogeneous assembly
    • three different molecular forms
Card Set:
Ch 8.5
2014-10-14 16:47:07
Test Two
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