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Regulatory Strategies

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Regulatory Strategies Enzymes and Hemoglobin Regulatory Strategies What are the four ways in which enzymes are regulated? allosteric regulation enzymes exist in ... – PowerPoint PPT presentation

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Title: Regulatory Strategies


1
Regulatory Strategies
  • Enzymes and Hemoglobin

2
Regulatory Strategies
  • What are the four ways in which enzymes are
    regulated?
  • allosteric regulation
  • enzymes exist in multiple forms (isoenzymes)
  • covalent modification
  • proteolytic cleavage

3
Allosteric Regulation
  • What are some of the characteristics of this form
    of regulation?
  • Activity influenced by non-covalent binding of
    metabolite called a modulator
  • May be inhibitory or stimulatory
  • May have one (monovalent) or several (polyvalent)
    modulators
  • Binding induces shape change in enzyme
  • Enzymes are large two or more subunits
  • Exhibit homotropic or heterotropic control

4
Allosteric Regulation
  • enzyme may be part of a sequence in which the end
    product inhibits allosteric enzyme
  • enzyme does not show Michaelis-Menten kinetics

5
Aspartate Transcarbamoylase
  • What is the reaction catalyzed by this enzyme?

6
Aspartate Transcarbamoylase
  • CTP is a negative modulator and ATP is a positive
    modulator
  • feedback inhibition

7
Aspartate Transcarbamoylase
  • How do we know that the catalytic and regulatory
    sites on this enzyme are distinct?
  • treat with
  • p-hydroxymercuribenzoate

8
Aspartate Transcarbamoylase
  • Catalytic subunit consists of 3 chains (c3) and
    regulatory subunit consists of 2 chains (r2)

9
Aspartate Transcarbamoylase
  • Allosteric modulators alter the quaternary
    structure of the enzyme

10
Aspartate Transcarbamoylase
  • What is the difference between the T state and
    the R state of the enzyme?
  • T tense lower affinity for substrate
  • R relaxed higher affinity for substrate
  • Binding of substrate or substrate analog converts
    enzyme from T to R state
  • positive cooperativity
  • homotropic control

11
Aspartate Transcarbamoylase
  • How does CTP act as a negative modulator?
  • Why is this an example of heterotropic modulation?

12
Aspartate Transcarbamoylase
  • How does ATP act as a positive modulator?
  • Does this represent homo or heterotropic
    modulation?

13
Aspartate Transcarbamoylase
  • Why is the mechanism just described called the
    concerted model?
  • All subunits must be in same conformation, T or R

14
Allosteric Regulation
  • An alternative, the sequential model has been
    proposed

15
Allosteric Regulation
  • How does the sequential model differ from the
    concerted model?
  • Subunits may undergo individual sequential
    changes in conformation
  • Subunits can interact even in different
    conformations
  • Change induced by binding of substrate to one
    subunits can increase or decrease substrate
    binding to other subunits
  • positive or negative homotropic effects
  • finer tuning

16
Allostery and Hemoglobin
  • Binding of O2 to hemoglobin represented by a
    sigmoidal curve similar to allosteric enzymes
  • Cooperativity promotes efficient O2 delivery

17
Allostery and Hemoglobin
  • What part of the hemoglobin molecule binds O2?

18
Allostery and Hemoglobin
  • How does the binding of O2 affect the structure
    of heme?

19
Allostery and Hemoglobin
  • How does O2 binding influence the quaternary
    structure of hemoglobin?

20
Allostery and Hemoglobin
  • How does 2,3 bisphosphoglycerate affect O2
    affinity of hemoglobin?
  • How is this effect brought about?

21
Allostery and Hemoglobin
  • How is fetal hemoglobin different from maternal
    hemoglobin?
  • How can this be explained?

22
Allostery and Hemoglobin
  • What is the Bohr effect?
  • What is the chemical basis of this effect?

23
Allostery and Hemoglobin
  • CO2 also stabilizes deoxyhemoglobin by forming
    carbamate groups

24
Isozymes
  • What are isozymes or isoenzymes?
  • enzymes that have differences in amino acid
    sequence but catalyze the same reaction
  • Example lactate dehydrogenase
  • Two different chains, M and H, exist
  • Enzyme consists of 4 subunits
  • H4, H3M, H2M2, HM3, M4
  • Each form has different Km and Vmax

25
Isozymes
  • M4 functions best in anaerobic environment while
    H4 in aerobic environment

26
Covalent Modification
  • Enzymes exist in active and inactive forms
  • Interconvertable by covalent modification
  • Catalyzed by other enzymes
  • Most modifications are reversible

27
Covalent Modification
28
Covalent Modification
  • What are the most common forms of covalent
    modification?
  • Phosphorylation and dephosphorylation
  • Which enzymes catalyze phosphorylation?
  • protein kinases
  • Which enzymes catalyze dephosphorylation?
  • protein phosphatases

29
Covalent Modification
  • What donates the phosphate group?

30
Covalent Modification
  • Why is phosphorylation an effective way to
    regulate proteins?
  • Phosphate group adds negative charges
  • Phosphate group can form hydrogen bonds
  • Free energy of phosphorylation is large
  • Can occur rapidly or slowly as needed
  • Can achieve amplification
  • Linked to energy status of cell

31
Covalent Modification
  • Example glycogen phosphorylase
  • Two forms a and b
  • A active 4 subunits each with a serine residue
    phosphorylated at OH group
  • B inactive removal of PO4 groups causes
    protein to separate into two half molecules

32
Covalent Modification
  • What is the connection between c-AMP and protein
    kinases?
  • PKA activated by c-AMP in cells

33
Zymogens
  • What are zymogens?
  • inactive precursors of enzymes
  • How are they activated?
  • proteolytic cleavage

34
Zymogens
35
Zymogens
  • What are some other examples?
  • Blood clotting
  • Insulin
  • Conversion of procollagenase to collaginase in
    metamorphosis
  • Conversion of procaspases to caspases in apoptosis

36
Zymogens
  • Activation of chymotrypsinogen to chymotrypsin

37
Zymogens
  • Why is trypsin a key enzyme in zymogen activation?

38
Zymogens
  • Why do proteolytic enzymes have specific
    inhibitors?
  • To prevent premature activation of the enzyme
  • Activation of trypsin in pancreas could destroy
    pancreatic tissue

39
Zymogens
  • How are zymogens involved in the formation of
    blood clots?
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