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YEAR 2 HUMAN BIOCHEMISTRY > Regulation of Metabolism > Flashcards

Regulation of Metabolism Flashcards

1
Q

Why does metabolism require control?

A
  • To co-ordinate metabolic processes
  • Vital that some of the enzymes involved in these processes are subject to strict controls
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2
Q

What are 4 factors that may be involved in the regulation of biochemical pathways?

A
  1. Concentrations of substrates and products
  2. Modifications
  3. Endocrine signals
  4. Other enzymes
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3
Q

General Mechanisms of Enzyme Regulation: What did Leonor Michaelis and Maud Menten propose?

A
  • That the enzyme reversibly combines with its substrate
  • To form an ES complex that subsequently breaks down to product, regenerating free enzyme
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4
Q

What does the Michaelis-Menten equation describe?

A

Describes how reaction velocity varies with substrate concentration

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5
Q

What is the Michaelis-Menten equation for the formation of an ES complex?

A
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6
Q

What is the Michaelis-Menten equation for how velocity varies with substrate concentration?

A
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7
Q

What are the assumptions of the Michaelis-Menten Equation (3 points)

A
  • [S] is small, much greater than [E], so that the amount of substrate bound by the enzyme at any one time is small.
  • [ES] does not change with time as it is in ‘steady state’
  • Only initial velocities are used in analysis of enzyme reactions, as it is only at this time when the reaction is linear with time
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8
Q

What is The Michaelis constant

A

Km

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9
Q

What is Km characteristic of and what does it reflect?

A
  • characteristic of an enzyme and its substrate
  • reflects the affinity of the enzyme for that substrate
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10
Q

What is Km numerically equal to?

A

Numerically equal to [S] at which the reaction velocity is at ½Vmax

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11
Q

Km does NOT vary with with what?

A

Km does not vary with the concentration of enzyme

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12
Q

What does a numerically small Km (low) reflect?

A
  • reflects a high affinity of the enzyme for substrate
    -because a low concentration of substrate is needed to half-saturate the enzyme
  • i.e. to reach ½Vmax. ​
  • Enzymes like this are usually targeted for regulation
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13
Q

What does a numerically large Km (high) reflect?

A
  • reflects a low affinity for the substrate
  • because a high concentration is required to half-saturate the enzyme
  • Enzymes like this are not usually targeted for regulation
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14
Q

What is the rate of reaction for the Michaelis-Menten Equation directly proportional to?

A

The enzyme concentration [S]

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15
Q

What is the order of reaction for enzyme regulation?

A

When [S] is much less than Km:

-The velocity of the reaction is roughly proportional to [S]
-The rate is said to be first order with respect to substrate

When [S] is much greater than Km:
- The velocity is constant and equal to Vmax
- The rate of reaction is then independent of [S]
- Is said to be zero order with respect to substrate concentration.

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16
Q

Allosteric Modification

Some molecules may bind non-covalently to an enzyme…. What does this result in and what are these molecules called?

A
  • Inhibits the activity of said enzyme
  • Molecules that do this are called effectors​
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17
Q

What are the two types of effectors?

A
  1. Homotropic Effectors​
  2. Heterotropic Effectors​
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18
Q

What are the main characteristics of Homotropic Effectors​?

A
  • When the substrate is an effector​
  • They are usually positive​
  • Significance: Km is decreased several fold for a small increase in [S].​
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19
Q

What are the main characteristics of Heterotropic Effectors​?

A
  • The effector is not the substrate​
  • May have a stimulatory or inhibitory effect​
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20
Q

What is a very rapid (instantaneous) form of regulation?

A

Allosteric modification

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21
Q

What does induction and Repression of Synthesis represent?

A
  • Represents adaptive regulation - whereby enzyme synthesis is either enhanced or decreased by certain physiological situations
  • Slow (days) mechanism of regulation
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22
Q

How are the processes of glycogen synthesis and glycogen breakdown reciprocally regulated

A
  • allosterically
  • covalently
  • induction/repression of synthesis​
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23
Q

What are the key regulatory enzymes in glycogen metabolism?

A

SYNTHESIS: Glycogen Synthase​

BREAKDOWN: Glycogen Phosphorylase

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24
Q

Fed state of glycogen metabolism:

Glucose converts to? ——->

A

Glucose—–>Glycogen

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25
Q

Fasted state of glycogen metabolism:

Glycogen converts to? ——->

A

Glycogen—–>Glucose

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26
Q

What does glucose 6-phosphate activate and inhibit in glycogen metabolism (allosteric regulation)

A

Glucose 6-phosphate….

Activates:Glycogen Synthase

Inhibits:Glycogen phosphorylase

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27
Q

Allosteric regulation:

What is AMP and how is it generated?

A
  • AMP= Adenosine Monophosphate
  • AMP is generated when skeletal muscle uses ATP to contract
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28
Q

AMP has no effect on glycogen synthase but does what instead?

A

Allosterically activates Glycogen phosphorylase – very important in exercising skeletal muscle

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29
Q

Allosteric regulation:
What does a high concentration of ATP mean?

A
  • Means the energy status of the cell is very high
  • Hence there is no requirement to breakdown Glycogen
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30
Q

ATP has no effect on glycogen synthase but does what?

A
  • ATP allosterically inhibits Glycogen phosphorylase
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31
Q

In a fed state, there is an increase of glucose concentration.

So there is no need for what?

A
  • no need to continue breaking down glycogen for glucose production
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32
Q

What does glucose allosterically inhibit?

A
  • Allosterically inhibits glycogen phosphorylase
  • with no effect on Glycogen Synthase
    -very important for the liver
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33
Q

Allosteric regulation of enzymes is classified as what type of regulation?

A

‘Within the cell’ regulation

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34
Q

Allosteric regulation involves the binding of what? and what does this result in?

A
  • Involves the binding of an effector molecule to the enzyme

-Thereby altering its activity

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35
Q

Covalent regulation of metabolic processes is usually in response to what? and give an example.

A

An extracellular stimulus

  • Such as from a hormone which then binds to an extracellular receptor
  • leads to a cascade of biochemical events leading to an effect on the target enzymes
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36
Q

What are the 6 components of hormone action to consider in general terms, before we can look at what happens to glycogen synthase and glycogen phosphorylase?

A
  1. Signal
  2. Receptor
  3. Coupling
  4. Amplification
  5. Effect
  6. Termination
37
Q

Hormones: 1=signal

What are the 3 categories of hormones?

A
  1. Peptides or polypeptides
  2. Steroid hormones
  3. Amino acid derivatives
38
Q

Hormones: 2= The receptor

What are hormones unable to stimulate?

A

Hormones cannot stimulate a metabolic process directly

39
Q

What do hormones have to bind to in the first instance? And give 2 examples.

A
  • Have to bind to a specific receptor​

Steroids:
- Intracellular receptors interact with chromatin and effect mRNA transcription – not discussed further

Others:
– Bind to receptors located on the external surface of the plasma membrane​

40
Q

Extracellular receptors are usually what?

A

Glycoprotiens

41
Q

N-linked region of extracellular receptors contain oligosaccharides on the extracellular surface: What do these convey?

A

– these convey specificity​

42
Q

Receptor distribution is dependent on what?

A

– dependent upon the tissue

43
Q

Hormones: 3= Coupling and G proteins

Binding of a hormone to its receptor is not sufficient on its own to affect what?

A

Metabolic pathways

44
Q

What is hormone receptor binding coupled to?

A

Hormone-Receptor binding is coupled to:

  • An intracellular event
44
Q

Peptide and amino acid hormone receptors are coupled to what? and where is it found?

A
  • A specific ‘Guanyl-stimulatory binding protein’ (GS-protein)
  • Found on the intracellular surface of the plasma membrane​
44
Q

How many subunits does GS consist of and what are they?

A

GS consists of 3 subunits:​

α subunit (45 kDa)​
β subunit (35 kDa)
γ subunit (7kDa)

44
Q

Hormones: 3= Coupling and G proteins

α-subunit can interconvert between what 2 forms? and what does this depend on?

A
  1. a form which binds GDP
  2. a form that binds GTP

Depending on whether there is a hormone signal or not

44
Q

When there is no hormone signal what does the α-subunit do?

A
  • The α-subunit ‘rests’ in the GDP binding form
  • There is no interaction between the unoccupied receptor and GS-protein
44
Q

Hormones: 3= Coupling and G proteins

When there is a hormone signal, the α-subunit does what?

A
  • changes its conformation and loses the GDP and instead binds GTP
44
Q

Fill in the blanks:

The α-GTP subunit ——— from the ———— and binds to and ————-, an enzyme called ———- which is located within the ———–.

A
  1. Dissociates
  2. Rest of the GS-protein
  3. Activates
  4. Adenylate cyclase
  5. Plasma membrane

The α-GTP subunit dissociates from the rest of the GS-protein and binds to and activates an enzyme called adenylate cyclase which is located within the plasma membrane.​

44
Q

In the absence of further hormone stimulation , what happens?

A
  • The GTP is hydrolysed to GDP
  • And the α-GDP subunit dissociates from adenylate cyclase and re-associates with the rest of the GS-protein subunits
44
Q

The βγ subunit does not undergo what type of change? and what does it do instead?

A

-The βγ subunit does not undergo a conformational change

  • Acts as its own signalling molecule activating and inhibiting various enzymes
44
Q

Hormones: 4= Amplification and cAMP

When bound to the α-GTP subunit of the GS-protein, adenylate cyclase is activated and is able to do what?

A
  • Able to catalyse the formation of cyclic AMP (cAMP) from ATP. ​
44
Q

Hormones: 4= Amplification and cAMP

Hundreds of molecules of cAMP are produced for every activated molecule of adenylate cyclase. What is the term used to describe this?

A

– this is the amplification of the hormone signal

45
Q

Hormones: 5=Effect by protein kinases

What is cyclic AMP called?

A

Cyclic AMP is called a second messenger

45
Q

Hormones: 5=Effect by protein kinases

cAMP is a potent activator of another enzyme, what is it?

A

– Protein Kinase A

cAMP-dependent protein kinase

46
Q

Protein Kinase A is a……??

And is made up of what?

A

Protein Kinase A is a tetramer

  • 2 regulatory subunits
  • 2 catalytic subunits
47
Q

What do the two free catalytic subunits do?

A
  • They catalyse the phosphorylation of specific serine or threonine residues on target proteins
47
Q

Phosphorylated proteins may do what 3 things?

A
  1. Activate enzymes
  2. Inactivate enzymes
  3. Modulate the activity of cellular ion channels
47
Q

Protein kinase A can phosphorylate what? and what does this cause?

A

-Can phosphorylate specific proteins that bind topromoter regions of DNA

  • Causing increased expression ofspecific genes
47
Q

Hormones: 6=Termination

What happens during termination?

A
  1. Loss of hormone signal​
  2. Dephosphorylation of proteins​
  3. Hydrolysis of cAMP
48
Q

Explain what happens in the process of dephosphorylation of proteins.

A
  • The phosphate groups added to proteins by protein kinases areremoved

-They are removed by the actions of phosphoprotein phosphatases: enzymesthat hydrolytically cleave phosphate esters

  • This ensures that changes in enzymatic activity induced by proteinphosphorylation are not permanent
48
Q

Hydrolysis of cAMP​:

cAMP is readily hydrolysed to what?

A

cAMP is readily hydrolysed to 5’-AMP byphosphodiesterase.

48
Q

5’-AMP is not what type of molecule?

A

5’-AMP is not an intracellular signalling molecule

48
Q

What is the target enzyme in the Inhibition of synthesis by a cAMP cascade?

A

Target enzyme = GlycogenSynthase​

49
Q

Inhibition of synthesis by a cAMP cascade:

Glycogen synthase exists in what 2 forms? and give key features of each

A
  1. “A” form:
    - NOTphosphorylated
    - Is the most activeform
  2. “B” form:
    - ISphosphorylated
    - Inactive
49
Q

Inhibition of synthesis by a cAMP cascade:

Glycogen synthase is converted from A to B form by what?

A

By phosphorylation’s ata numberofsites on theenzyme.​

50
Q

After the conversion from A to B form the level of inactivation is proportional to what?

A

It’s degree ofphosphorylation

50
Q

Inhibition of synthesis by a cAMP cascade:

What 3 things result in the activation of adenylate cyclase?

A
  1. Binding of the hormone glucagon to hepatocyte receptors
  2. Binding of the hormone adrenaline tohepatocyte receptors
  3. Binding of adrenaline to muscle cell receptors
50
Q

Inhibition of synthesis by a cAMP cascade:

cAMP is synthesised, what does this activate?

A
  • Activates protein kinase A
50
Q

After protein kinase A is activated, what does this result in protein kinase A doing?

A
  • Protein kinase A phosphorylates glycogen synthase A toglycogen synthase B
  • Therefore inactivates glycogensynthesis
50
Q

Glycogen synthase B can be transformed back to glycogen synthase A by what?

A
  • By removing the phosphate groups hydrolytically using phosphoprotein phosphatase type 1
50
Q

– Activation of breakdown by a cAMP cascade

The binding of glucagon or adrenaline to receptors, signalsthe need for what?

A

Signalsthe need for glycogen to be degraded:

– Either to elevateblood glucose levels (contributed by liver glycogen)
- Or toprovide energy in exercising muscle

50
Q

Activation of breakdown by a cAMP cascade

What 3 things are activated during this process?

A
  • Activation of protein kinase A​
  • Activation of phosphorylase kinase​
  • Activation of glycogen phosphorylase
51
Q

Activation of breakdown by a cAMP cascade:

How is phosphorylase kinase activated?

A
  • Active protein kinase A phosphorylates the inactive form ofphosphorylase kinase, resulting in its activation
52
Q

Activation of breakdown by a cAMP cascade:

Explain the process of the activation of glycogen phosphorylase.

A
  • Glycogen phosphorylase exists in an inactive “B” form and an active“A” form
  • Active phosphorylase kinase, phosphorylates glycogen phosphorylaseb.
  • Converting it into active glycogen phosphorylase A, which beginsglycogen breakdown.​
  • Phosphorylase A is reconverted to phosphorylase B. Byphosphoprotein phosphatase type 1
53
Q

Summary of the reciprocal regulation of glycogen synthesis and degradation:

Glycogen synthesis and degradation are both regulated by the same what?

A

Both regulated by the same hormonal signals

54
Q

Summary of the reciprocal regulation of glycogen synthesis and degradation:

What do the following things result in:

  1. Elevated insulin levels
  2. Elevated Glucagon/Adrenaline levels
A
  1. Elevated insulin level=overall increased glycogen synthesis
  2. Elevated glucagon/adrenaline=cause increased glycogen degradation
55
Q

Summary of the reciprocal regulation of glycogen synthesis and degradation:

What do cyclic AMP levels fluctuate in response to?

A

Fluctuate in response to hormonal stimuli

56
Q

Summary of the reciprocal regulation of glycogen synthesis and degradation:

What do cAMP levels in cells increase and decrease in response to?

A

cAMP levels increase=in response to hormonal stimuli

cAMP levels decrease= in the presence of insulin

57
Q

Summary of the reciprocal regulation of glycogen synthesis and degradation:

Give an example of hormonal stimuli that would increase cAMP levels.

A
  1. Glucagon and adrenaline in liver
  2. Adrenaline in muscle
58
Q

Summary of the reciprocal regulation of glycogen synthesis and degradation:

What are key enzymes phosphorylated by?

A

A family of kinases
Only some of which are cAMP dependent

59
Q

Summary of the reciprocal regulation of glycogen synthesis and degradation:

What does phosphorylation of an enzyme cause?

A
  • Causes a conformational change
  • That affects the active site
  • And can greatly increase or decrease the catalytic activity of some enzymes
60
Q

Phosphorylase kinase can also be activated how?

A
  • Allosterically in muscle
61
Q

Phosphorylase kinase can also be activated allosterically in muscle. Step 1:

Muscles contract because of the release of what?

A
  • Release of Ca2+ release
  • From sarcoplasmic reticulum
62
Q

Phosphorylase kinase can also be activated allosterically in muscle. Step 2:

Ca2+ binds to a subunit of phosphorylase kinase called what?

A

Calmodulin

63
Q

Phosphorylase kinase can also be activated allosterically in muscle. Step 3:

Ca2+-Calmodulin activates phosphorylase kinase: This thereby activates what?

The glucose release from this then fuels what process?

A
  • Thereby activating glycogen phosphorylase and hence causing glycogen breakdown
  • Glucose released then fuels muscle contractions
64
Q

Phosphorylase kinase can also be activated allosterically in muscle. Step 4:

When muscle relaxes, Where does Ca2+ return to?

What then happens to the phosphorylase kinase and glycogen phosphorylase A?

A
  • Ca2+ returns to the sarcoplasmic reticulum
  • Phosphorylase kinase=becomes inactive
  • Glycogen phosphorylase A = converted to the inactive, glycogen phosphorylase B

YEAR 2 HUMAN BIOCHEMISTRY (12 decks)

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