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Semester 1 - MCBG > 16. Regulation Of Protein Function > Flashcards

16. Regulation Of Protein Function Flashcards

1
Q

What are the short term regulations of enzyme activity?

A
  1. Substrate and product concentration
  2. Change in enzyme conformation
    A. Allosteric regulation
    B. Covalent modification
    C. Proteolytic cleavage
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2
Q

What are the long term regulations of enzyme activity?

A
  1. Change in rate of protein synthesis

2. Change in rate of protein degradation

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3
Q

How does the substrate concentration affect the rate of enzyme activity?

A

Increasing the substrate concentration increases the enzyme activity until the enzymes are saturated

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4
Q

What are isoenzymes?

A

Isoenzymes are different forms of the same enzyme that have different kinetic properties

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5
Q

Why do isoenzymes have different kinetic properties?

A

They have different kinetic properties as they have different amino acid sequences as they have different roles in the cell

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6
Q

How do coenzymes regulate enzyme activity?

A

Some coenzymes will have limited availability e.g. NAD/NADH. So if an enzyme needs a high concentration of a coenzyme, then a low concentration will slow the enzyme activty

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7
Q

How can product inhibition regulate enzyme activity?

A

Accumulation of the product of a reaction inhibits the forward reaction

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8
Q

What is allosteric regulation?

A

binding of a molecule away from the active site that causes an effect on the overall enzyme activity

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9
Q

What kind of curve do allosteric enzymes show?

A

Allosteric enzymes show a sigmoid relationship between rate and substrate concentration, instead of the rectangular hyperbola seen for simple enzymes

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10
Q

What are the 2 conformations that allosteric enzymes can exist in?

A

Can exist in 2 different conformations
• T state
• R state

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11
Q

Is the T state low affinity or high affinity?

A

Low affinity

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12
Q

Is the R state low or high affinity?

A

High affinity

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13
Q

How do allosteric activators affect the enzyme activity?

A

Increases the proportion of enzyme in the R state so increases the rate of reaction

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14
Q

How do allosteric inhibitors affect the enzyme activity?

A

Increases the proportion of enzyme in the T state so slows down the rate of reaction

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15
Q

Give an enzyme in glycolysis that is an allosteric enzyme?

A

Phosphofructokinase

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16
Q

What are two activators of Phosphofructokinase?

A

AMP, fructose-2,6- bisphosphate

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17
Q

What are 3 inhibitors of Phosphofructokinase?

A

ATP, citrate, H+

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18
Q

Give a types of covalent modification

A

Phosphorylation

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19
Q

Is phosphorylation reversible or irreversible?

A

Reversible

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20
Q

What is the function of protein kinases in phosphorylation?

A

transfer the terminal phosphate from ATP to the –OH group of Ser, Thr, Tyr

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21
Q

What is the function of protein phosphatases in phosphorylation?

A

reverse the effects of kinases by catalysing the hydrolytic removal of phosphoryl groups from proteins.

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22
Q

How can phosphorylation as covalent modification regulate enzyme activity?

A

If we regulate phosphorylation by regulating the protein kinases, then we can regulate how active the enzyme(protein) is

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23
Q

Why is protein phosphorylation so effective?

A
  • Adds 2 negative charges • A phosphoryl group can make H-bonds
  • Rate of phosphorylation/dephosphorylation can be adjusted
  • Links energy status of the cell to metabolism through ATP
  • Allow for amplification effects
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24
Q

Describe amplification by enzyme cascades

A

When an enzyme activate enzymes, the number of affected molecules increases geometrically in an enzyme cascade

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25
Q

Give 5 examples of when Enzymes Are Activated by Specific Proteolytic Cleavage

A
  1. Digestive enzymes are synthesized as zymogens in the stomach and pancreas.
  2. Some protein hormones (e.g. insulin) are synthesised as inactive
    precursors.
  3. Blood clotting is mediated by a cascade of proteolytic activations
    that ensures a rapid and amplified response.
  4. Many developmental processes are controlled by the activation of
    zymogens to contribute to tissue remodelling.
  5. Programmed cell death (apoptosis) is mediated by proteolytic
    enzymes, caspases, which are synthesised in inactive (procaspase)
    form.
26
Q

What are zymogen?

A

inactive

precursors

27
Q

Why is regulation by proteolytic cleavage important?

A

It ensures that enzymes such as digestive enzymes and enzymes for programmed cell death are only active at locations where it should be. If digestive enzymes where released in the active form, it would digest proteins inside the cell which is not wanted. Therefore the enzymes only become activated by proteolytic cleavage at sites where it is needed.

28
Q

Is proteolytic cleavage reversible?

A

No it is an irreversible process - cannot reform peptide bond

29
Q

Which enzyme activates zymogen by proteolytic cleavage?

A

Trypsin

30
Q

What is an inhibitor of trypsin?

A

a1-antitrypsin

31
Q

What disease does deficiency of a1-antitrypsin cause?

A

EMPHYSEMA- Destruction of alveolar walls by elastase

32
Q

In long term regulation, how does change in rate of protein synthesis regulate enzyme activity?

A

Change in rate of protein synthesis changes the amount of enzyme present so leads to Enzyme induction/repression

33
Q

Which pathway is involved in changing the rate of protein degradation?

A

Ubiquitin-proteasome pathway

34
Q

In the blood clotting cascade, what is the intrinsic pathway?

A

Damaged endothelial lining of blood cells promotes binding of factor XII

35
Q

In the blood clotting cascade, what is the extrinsic pathway?

A

Trauma releases tissue factor (factor III)

36
Q

Describe the cascade that both the intrinsic and extrinsic pathway lead to?

A

FACTOR X ACTIVATION (Common endpoint for both pathways) ——>
——> THROMBIN ACTIVATION ——>
FORMATION OF FIBRIN CLOT

37
Q

Why is a cascade used for blood clotting?

A

Cascade allows rapid formation of a clot from activation of very small amounts of the initial factor

38
Q

What are two necessary things of blood clot formation?

A

That it is rapidly formed and is formed at the correct location

39
Q

Where is the serine protease function of prothrombin contained?

A

The protease function (the thrombin part) is contained in the C-terminal
domain.

40
Q

What is the function of the Kringle domain in the prothrombin?

A

The two kringle domains help keep prothrombin in the inactive form The two kringle domains help keep prothrombin in the inactive form. It Ensures that the prothrombin folds up so that there’s no serine protease activity

41
Q

What is the function of the Gla domain in prothrombin?

A

Gla domains target it to appropriate sites for its activation

42
Q

Why is thrombin needed to be in the inactive form of prothrombin?

A

In its pro form, thrombin completely lacks activity because you don’t want thrombin to be forming fibrin inappropriately as it leads to formation of blood clot inappropriately

43
Q

What happens to activate prothrombin to thrombin?

A

For activation, the N terminal part containing the GLA and Kringle domains are removed so that only the fully functional c terminus remains

44
Q

How, where and when are g-carboxyglutamate (Gla) residues formed?

A
  • Post-translational modification of factors II, VII, IX, X in the liver
  • Addition of COOH groups to glutamate residues to form carboxyglutamate (Gla)
  • Allows interaction with sites of damage and brings together clotting factors
45
Q

How does the addition of COOH groups to glutatamate to form carboxyglutamate (Gla) help in interacting with sire of damage?

A
  • The addition of COOH gives it negative charges
  • Negative charges are attracted to the positive calcium ions to the site of damage so helps to navigate the clotting factors to where they are needed
46
Q

Describe the structure of fibrinogen

A

• 340kDa protein
• 2 sets of tripeptides , a, b, g, joined at N-termini by disulphide
bonds
• 3 globular domains linked by rods

47
Q

What part of fibrinogen help prevent aggregation of fibrinogen?

A

N-terminal regions of a and b chains are highly negatively charged and prevent aggregation of fibrinogen

48
Q

Describe formation of fibrin clot

A

(1) Thrombin cleaves fibrinopeptides A and B from the central globular
domain of fibrinogen.
(2) Globular domains at the C-terminal ends of the b and g chains
interact with exposed sequences at the N-termini of the cleaved b
and a chains to form a fibrin mesh or clot.

49
Q

How is the newly formed clot stabilised?

A

The newly formed clot is stabilised by the formation of amide bonds between the side chains of lysine and glutamine residues in different monomers.
This cross-linking reaction is catalysed by transglutaminase, which is activated from protransglutaminase by thrombin.

50
Q

What causes classic haemophilia?

A

Classic haemophilia is a defect in factor VIII.

Factor VIII (‘antihaemophilic factor’) is not a protease, but markedly
stimulates the activity of factor IX a
, a serine protease.

51
Q

What increases the activity of factor VIII and why is it useful?

A

The activity of factor VIII is markedly increased by limited proteolysis by thrombin and factor Xa. This positive feedback
amplifies the clotting signal and accelerates clot formation.

52
Q

How is classic haemophilia treated?

A

Treated with recombinant factor VIII

53
Q

Why is the clotting arcade a self sustaining loop?

A
  • Thrombin feeds back and activates previous steps in the pathway
  • once thrombin is activated, do not need the initial damage to continue the cascade
54
Q

What are the 3 ways in stopping the clotting process?

A
  1. Localisation of (pro)thrombin
  2. Digestion by proteases
  3. Specific inhibitors
55
Q

How does localisation of thrombin stop the clotting process?

A

Dilution of clotting factors by blood flow, and removal by liver

56
Q

Describe how digestion by proteases can stop the clotting process?

A
  • for example, factors Va and VIIIa are degraded by

protein C so factor Xa not activated so thrombin not activated so fibrinogen not converted to fibrin

57
Q

How is protein c activated?

A

protein C is activated by thrombin binding to endothelial receptor, thrombomodulin

58
Q

What does defects in protein C cause?

A

Thrombotic disease

59
Q

Give an example of a specific inhibitor that stops the clotting process

A 
Antithrombin III (AT3) - stops thrombin working 
- Enhanced by heparin binding
60
Q

Describe fibrinolysis

A
  • Breaking down fibrin clot using plasmin
  • Plasmin is made in the inactive form as plasminogen
  • T-PA stimulates activation of plasminogen
  • Streptokinase also enhances the activation of plasminogen
61
Q

What are the 7 control points in blood clotting?

A
  1. Inactive zymogens present at low concentration.
  2. Proteolytic activation.
  3. Amplification of initial signal by cascade mechanism.
  4. Clustering of clotting factors at site of damage.
  5. Feedback activation by thrombin ensures continuation of clotting.
  6. Termination of clotting by multiple mechanisms.
  7. Clot breakdown controlled by proteolytic activation.
62
Q

Summarise blood clotting

A
  • injury to a blood vessel sets in motion a cascade of clotting factors that ultimately result in a blood clot
  • clotting factors are all proteases or cofactors needed for the activation of the next step
  • proteolytic cleavage of the fibrinogen molecule to form fibrin which aggregate to form clots
  • clot formation is tightly controlled and can be reversed by proteolytic cleavage of fibrin by the enzyme plasmin
  • the clotting process can be disrupted in certain genetic disease

Semester 1 - MCBG (18 decks)

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