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BioChem > MT 1 > Flashcards

MT 1 Flashcards

1
Q

What do lipid structure forms depend on

A
  1. Type of lipid
  2. Concentration
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2
Q

What are the types of structures formed by lipids?

A
  1. Micelles
  2. Liposomes
  3. Bilayers
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3
Q

What are membranes?

A

Complex lipid-based structures that form pliable sheets.

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4
Q

What are membranes composed of?

A

Lipids and proteins

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5
Q

Describe the fluid mosaic model of membranes.

A

Lipids form a viscous, two-dimensional solvent into which proteins are inserted and integrated more or less deeply. Constantly changing.

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6
Q

Define integral proteins.

A

Proteins firmly associated with the membrane, often spanning the bilayer. Have asymmetry. Hydrophobic stretches in the protein interact with hydrophobic area of membrane.

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7
Q

Define peripheral proteins.

A

Found next to the membrane, can be easily separated. Based on charge.

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8
Q

How are peripheral proteins attached?

A
  1. Associate with the polar head groups of membranes.
  2. Loosely associated by noncovalent interactions.
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9
Q

How do membrane compositions differ?

A
  1. Ratio of lipid to protein
  2. Types of phospholipids
  3. Abundance and type of sterols (includes cholesterol).
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10
Q

How does the membrane of archaea differ?

A
  1. Monolayer
  2. No resonance so more stable (isoprenoid tetra esters vs. esters like in ours)
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11
Q

Describe how membrane bilayers are asymmetric.

A
  1. The two leaflets have different lipid compositions.
  2. Outer leaflet is usually more positively charged.
  3. Outer leaflet has phosphatidylserine.
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12
Q

What is the function of phosphatidylserine on the outer leaflet?

A
  1. Activates blood clotting in platelets
  2. Marks cells for destruction.
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13
Q

What are the functions of proteins in membranes?

A
  1. Receptors
  2. Channels, gates and pumps
  3. Enzymes
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14
Q

Give examples of how membrane proteins act as receptors.

A
  1. Opsin responds to light
  2. Hormones (insulin receptor)
  3. Neurotransmitters (ACh)
  4. Pheromones (taste and smell receptors)
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15
Q

Give examples of how membrane proteins act as channels, gates or pumps.

A
  1. Nutrients (maltoporin)
  2. Ions (K-channel)
  3. Neurotransmitters (serotonin reuptake protein)
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16
Q

Give examples of how membrane proteins act as enzymes.

A
  1. Lipid biosynthesis (some acyltransferases)
  2. ATP synthesis (ATPase)
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17
Q

How are peripheral proteins removed?

A
  1. High salt
  2. Change in pH
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18
Q

How are integral proteins removed?

A

By using detergents that disrupt the membrane.

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19
Q

Define amphitropic protein.

A

Integrated into the membrane but then part can be cleaved off leaving some of the protein in the membrane.

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20
Q

How many types of integral membrane proteins are there?

A

6

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21
Q

Where are charged amino acids found?

A

In aqueous domains.

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22
Q

Which amino acids cluster at nonpolar/polar interface?

A

Tyr & Trp

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23
Q

Describe a lipoprotein

A

Membrane protein with a covalently linked lipid molecule which can become part of the membrane. Anchors the protein to the membrane.

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24
Q

Give examples of a covalently linked lipid molecule.

A
  1. Long-chain F.A.
  2. Isoprenoids
  3. Sterols
  4. Glycosylated phosphatidylinositol
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25
Q

Discuss lipid anchors.

A
  1. Reversible process.
  2. Allows targeting of proteins.
  3. Some are found only on the outer face of the membrane.
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26
Q

Define farnesylation.

A

The process by which proteins can be targeted to the inner leaflet of the membrane.

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27
Q

What is the signature for farnesylation?

A

CaaX where C is a conserved Cyst, a is usually an aliphatic amino acid and X is Met, Ser, Glu or Ala

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28
Q

What enzyme catalyzes farnesylation?

A

Farnesyl tranferase

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29
Q

What happens to nonfarnesylated proteins?

A
  1. They do not go to the membrane
  2. They are inactive.
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30
Q

How does the concept of farnesylation relate to disease?

A

A protein must have the farnesylation sequence. This can become a means for disease or a means to target disease.

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31
Q

How do lipids contribute to membrane asymmetry?

A

Outer and inner leaflets have different lipid compositions.

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32
Q

How do proteins contribute to membrane asymmetry?

A
  1. Individual peripheral membrane proteins are only associated with one side of the membrane.
  2. Integral membrane proteins have different domains on different sides of the membrane.
  3. Specific lipid modification of proteins targets the protein to a specific leaflet.
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33
Q

How do carbohydrates contribute to membrane asymmetry?

A

They are only on the outside of the cell. Are marker for blood type, glycocalyx, cell-cell recognition.

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34
Q

List the physical properties of membranes.

A
  1. Dynamic and flexible.
  2. Exist in various phases and undergo phase transitions.
  3. Not permeable to large polar solutes and ions.
  4. Permeable to small polar solutes and non polar compounds.
  5. permeability can be artificially increased by chemical treatment.
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35
Q

What are the membrane phases?

A
  1. Gel phase
  2. Fluid phase
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36
Q

Describe the gel phase of a membrane.

A

Individual molecules do not move around

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37
Q

Describe the fluid phase of a membrane.

A

Individual molecules can more around.

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38
Q

What changes the gel phase to a fluid phase

A

Heat.

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39
Q

What phase must the membrane exhibit for proper function?

A

Fluid phase.

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40
Q

What determines membrane fluidity?

A

Fatty acid composition

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41
Q

What type of fatty acids result in more fluid membranes?

A

Shorter and unsaturated fatty acids.

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42
Q

How does the f.a. composition of a membrane adjust to higher temperatures?

A

More saturated f.a.’s to maintain integrity.

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43
Q

How do sterols and hopanols effect membrane rigidity and permeability?

A

They increase it.

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44
Q

Eukaryote cell membranes contain?

A

Sterols.

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45
Q

What type of sterol is found in animal membranes?

A

Cholesterol.

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46
Q

What type of sterol is found in plant membranes?

A

Phystosterols.

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47
Q

What type of sterol is found in fungi membranes?

A

Ergosterol.

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48
Q

What do membranes of aerobic prokaryotes contain?

A

Hopanols.

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49
Q

Discuss lateral diffusion in membrane dynamics.

A

Individual lipids move laterally within the leaflet. Happens very fast.

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50
Q

Discuss Transfers diffusion in membrane dynamics.

A

Spontaneous flips from one leaflet to another. Very slow. Rare because of the polar head having to pass through the hydrophobic area.

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51
Q

What enzymes catalyze transverse diffusion?

A

Flippases.

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52
Q

What are the 3 types of flippy enzymes?

A
  1. Flippases
  2. Floppies
  3. Scramblases
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53
Q

What technique allows us to monitor lateral diffusion?

A

Fluorescence Recovery After Photobleaching (FRAP)

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54
Q

How does FRAP work?

A
  1. Fluorescent probes on lipids
  2. View surface and measure fluorescence.
  3. Laser beam bleaches an area of the membrane.
  4. Track how long it takes for bleached are to become diffused with fluorescent probes.
    **The overall fluorescence decreases the same amount as the bleached area.
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55
Q

What is a membrane raft?

A

Lipid distribution in a single leaflet that is not random or uniform.

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56
Q

What are membrane rafts composed of?

A

Phospholipids PLUS clusters of glycosphingolipids with longer than usual tails. Specific doubly or triply acylated proteins.

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57
Q

What is the function of membranes rafts?

A
  1. Lock proteins together so they can work efficiently.
  2. Add to the asymmetry of the membrane.
  3. Allows segregation of proteins.
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58
Q

What protein plays an important role in membrane rafts?

A

Caveolin.

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59
Q

What type of membrane protein is caveolin?

A

Integral

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60
Q

How can caveolin be removed from the membrane

A

Break open membrane.

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61
Q

What is the function of caveolin as a protein membrane?

A

Forces membrane curvature.

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62
Q

What are 3 other modes of membrane curvature?

A
  1. Interaction between positively charged concave surface and negatively charged head groups.
  2. Protein with amphipathic helices crowds lipids into a leaflet, forcing membrane to bend.
  3. BAR domains can polymerize into a superstructure that favours the curvature.
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63
Q

What are examples of protein mediated fusion?

A
  1. Entry of virus into host cell.
  2. Release of neurotransmitters at synapses.
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64
Q

Describe fusion in neurotransmitter release.

A

Neurotransmitter filled vesicle approached plasma membrane.
2. v-SNARE and t-SNARE bind, zip up from a.a. termini and draw the membranes together.
3. Zipping causes curvature and lateral tension favouring hemifusion between outer leaflets.
4. Hemifusion - inner leaflets of both membranes come into contact.
5. Complete fusion creates a fusion pore.
6. Pore widens and vesicle contents are released outside of the cell.

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65
Q

What types of proteins provide alternative diffusion paths?

A

Transporters or permeases.

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66
Q

What type of solutes require transporters?

A

Polar.

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67
Q

What are the 3 types of transport systems?

A
  1. Uniporter
  2. Symporter
  3. Antiporter
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68
Q

Which types of transporters are considered cotransporters?

A

Symport and Antiport

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69
Q

What are 2 of the types of glucose transporters and where are they found on the membrane?

A
  1. Na+glucose symporter
  2. Glucose uniporter
    Found on opposite sides of epithelial cells.
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70
Q

Give an example of an anti porter.

A

Bicarbonate transporter in RBC

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71
Q

Describe how the bicarbonate transporter works.

A

First the CO2 in the blood enters the RBC, combines with water and via carbonic anhydrase is converted to bicarbonate and H+. The bicarbonate anti porter facilitates bicarbonate out of the RBC and Cl- into the RBC. Once the RBC gets to the lungs the anti porter works in the opposite direction so that the bicarbonate is converted back to CO2 and released from the body.

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72
Q

What are the 2 types of active transport?

A

Primary and secondary

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73
Q

What is the function of ATPase?

A

Controls pH in the cell by using the energy from ATP hydrolysis to drive proteins through the membrane.

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74
Q

What can the difference in proton gradient be used for in the mitochondria?

A

ATP synthesis

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75
Q

What enzyme catalyzes ATP synthesis?

A

ATP synthase.

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76
Q

What structures allow for rapid water passage through membranes?

A

Aquaporins

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77
Q

How do aquaporins work?

A

They allow for the transfer of H+ from outside the cell to inside where it is picked up by OH-

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78
Q

What type of channels maintain gradients for active transport?

A

Ion channels

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79
Q

How are membranes important for life?

A
  1. Define the external boundaries of cells.
  2. Control the molecular traffic across the boundary.
  3. Divide internal space into compartments to segregate processes and components.
  4. Organize complex reaction sequences.
  5. Central to energy conservation and cell to cell communication.
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80
Q

Describe glucose transport across the cell membrane.

A
  1. Glucose transporter: A uniporter.D-Glucose interacts with the receptor, changing the shape of the transporter so that the glucose is then released on the inside of the cell. The conformation of the transporter changes back to the original shape and is ready to accept a new glucose molecule from the extracellular environment.
  2. Na+Glucose transporter. A Symporter. 2 Na+ and 1 glucose molecule move from outside the cell to inside the cell. This is driven by the high extracellular concentration of Na+.
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81
Q

What are the roles of signal transduction?

A
  1. Differentiation
  2. Antibody production
  3. Growth
  4. Sexual vs asexual cell division
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82
Q

What types of signals do cells receive?

A
  1. Antigens
  2. Hormones
  3. Neurotransmitters
  4. Light
  5. Touch
  6. Pheromones
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83
Q

Define receptor

A

A membrane-bound or soluble protein or protein complex, which exerts a physiological effect (intrinsic effect) after binding its natural ligand.

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84
Q

What are the 5 types of receptors?

A
  1. G-protein coupled receptors
  2. Enzyme-linked receptors (tyrosine kinase/guanylyl cyclase)
  3. Ligand-gated ion channels
  4. Adhesion receptors
  5. Nuclear receptors
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85
Q

Give an example of a G-protein coupled receptor

A

Epinephrine receptor - cascade

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86
Q

Give an example of an enzyme-linked receptor

A

Insulin receptor

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87
Q

Give an example of a ligand-gated ion channel.

A

Nicotinic acetylcholine receptor

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88
Q

Give an example of a nuclear receptor.

A

Steroid receptors. Nuclear receptors have their own category due to being in the nucleus and their function.

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89
Q

Give an example of an ‘other’ membrane receptor.

A

Integrin

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90
Q

What are the 5 features of signal-transducing systems?

A
  1. Specificity
  2. Amplification
  3. Modularity
  4. Desensitization/adaptation
  5. Integration
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91
Q

Describe specificity as it pertains to signal-transducing systems.

A

Signal molecule fits binding site on its complementary receptor. Other signals do not fit.

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92
Q

Discuss amplification as it pertains to signal-transducing systems.

A

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

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93
Q

Discuss modularity as it pertains to signal-transducing systems.

A

Proteins with multivalent affinities form diverse signalling complexes from interchangeable parts. Phosphorylation provides reversible points of interaction. Unique to biological systems. Switching one element leads to a different result from the signalling pathway.

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94
Q

Discuss desensitation/adaptation as it pertains to signal-transducing systems.

A

Receptor activation triggers a feedback circuit that shuts off the receptor or removes it from the cell surface. (Shuts off or slows down)

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95
Q

Discuss integration as it pertains to signal-transducing systems.

A

When two signals have opposite effects on a metabolic characteristic, they regulate the final effect. The net effect of up regulation of one signal and down regulation of the other signal. Allows for unique responses to changes in environment.

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96
Q

List and give examples of the types of typical ligands.

A
  1. Small ions - Ferric ion to the bacterial ferric receptor
  2. Organic molecules - Adrenalin to the epinephrine receptor
  3. Polysaccharides - Heparin to the fibroblast growth factor
  4. Peptides - Insulint to the insulin receptor
  5. Proteins - Vascular endothelial growth factor to its receptor
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97
Q

Briefly explain how G protein-coupled receptors function.

A

External ligand binds to receptor.
This activates an intracellular GTP binding protein (G).
G protein regulates an enzyme.
Enzyme generates an intracellular second messenger.

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98
Q

Briefly describe how receptor tyrosine kinase functions.

A

Ligand binds.
Tyrosine kinase becomes autophosphorylated - activated.
Kinase cascade occurs.
Kinase activates transcription factor altering gene expression

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99
Q

Briefly describe how the receptor guanylyl cylcase functions.

A

Ligand binds to extracellular domain of enzyme.
This stimulates formation of a second-messenger, cyclic GMP

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100
Q

Briefly describe how gated ion channel receptors function.

A

Open or close in response to concentraion of ligand or membrane potential.

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101
Q

Briefly describe how adhesion receptors, such as integrin function.

A

Bind with molecules in extracellular matrix.
This changes the conformation which alters how it interacts with cytoskeleton.

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102
Q

Describe G-protein structure and general function.

A

a-helical integral membrane proteins. Heterotrimeric membrane associated proteins that bind GTP. Mediate signal transduction from receptors to other target proteins.

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103
Q

Describe the epinephrine pathway.

A

In general:
Epinephrine released from adrenal glands.
Binding to receptors in mucle or liver cells induced glycogen breakdown.
Binding to receptors in adipose cells induces lipid hydrolysis.
Binding to receptors in heart cells increases heart rate.
Mediates stress response, mobilization of energy.

Specific:
Binding of epinephrine to receptor causes GDP to be replaced by GTP, activating Gsa
Activated Gsa moves to adenylyl cyclase and activates it.
Adenylyl cyclase catalyzes formation of cAMP which then activates PKA
Activation of PKA causes cellular response to epinephrine

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104
Q

What is the role of cAMP

A

It is a secondary messenger.
Allosterically activates protein kinase A (PKA)
PKA activation leads to activation of enzymes that produce glucose from glycogen.

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105
Q

Describe signal amplification in the epinephrine cascade.

A

Activation of few GPCRs leads to activation of few andenylyl cyclase enzymes.
Each adenylyl cyclase enzymes makes several cAMP molecules.
cAMP molecules active several PKA enzymes.
PKA enzymes activate thousands of glycogen-degrading enzymes in the liver.
Tens of thousands of glucose molecules are released into bloodstream.

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106
Q

Describe self-inactivation in G-protein signaling.

A

Epinephrine is meant to be short lived.
Organism must stop glucose synthesis if no need to fight or flight.
Down-regulation of cAMP happens due to hydrolysis of GTP in the a subunit of the G-protein.
The Gsa has an intrinsic GTPase whcih hydrolyzes the GTP to GDP and the subunit heads back to the GPCR to start again when needed.

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107
Q

What 2 proteins cause desensitization in the epinephrine cascade?

A

B-ARK (beta-andrenergic receptor kinase)
B-ARR (beta-arrestin)

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108
Q

Describe the process of desensitization in the epinephrine cascade pathway.

A

When epinephrine continues to occupy the receptor, B-ARK phosphorylates the C terminus of the receptor due to the changes in the G-protein complex.
B-ARR binds to the phosphorylated C terminus which prevents further interaction between the G-protein and the receptor. So, even though the GTPase is intrinsic and replenishing GDP for the beginning of the cycle the G complex is not responsive to the receptor conformation change. B-ARR also initiates endocytosis that brings the receptor protein into the cell so it is no longer accessible to epinephrine. The receptors are eventually de-phosphorylated and returned to the plasma membrane.

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109
Q

How is cAMP able to mediate multiple signals?

A

PKA is localized to particular areas of the cell by anchoring proteins (AKAPs).
Anchors the “raft” to the area where the PKAs are going to phosphorylate the components of that area.

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110
Q

Name 2 other secondary messenger molecules used by GPCRs.

A
  1. Inositol-1,4,5-triphosophate
  2. Ca2+
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111
Q

What does Ca2+ use to modulate the function of enzymes?

A

Calmodulin

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112
Q

What are the most common type of enzyme-linked membrane receptors?

A

Tyrosine kinase

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113
Q

What do tyrosine kinases do?

A

Adds a phosphate group to itself (auto phosphorylation), which causes a conformational change that allows binding and catalytic phsophorylation of specific target proteins.
Adds a phosphate group to tyrosine in specific target proteins.

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114
Q

What else do some catalytic domains of enzyme-linked membrane receptors have?

A

Guanylyl cyclase activity which converts GTP to cGMP (a secondary messenger)

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115
Q

What is the most commonly studied enzyme-linked membrane receptor?

A

Insulin receptors

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116
Q

Where is insulin produced and what is it produced in response to?

A

Produced in the B-cells of islets of Langerhans in the pancreas in resonse to increased glucose levels.

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117
Q

Where are insulin target cells?

A

Liver, muscle and fat tissue

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118
Q

What is the overall effect of insulin binding to the insulin receptor?

A

Increased glucose uptake and metabolism.

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119
Q

What is the response of the RTK to insulin?

A

RTK is a transmembrane protein.
The extracellular alpha-domains bind with insulin. (pinchers)
The binding activates one cytosolic active Beta-domain which is the tyrosine kinase.
Tyrosine kinase phophorylates 3 tyrosine domains on the other beta subunit.
This autophosphorylation opens up the active site so that tyrosine residues on target proteins can then be phosphorylated. (protein IRS-1)

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120
Q

Describe the insulin signalling cascade.

A

The phosphorylated IRS protein indirectly interacts with the Ras protein which then initiates a series of additional protein phosphorylations.
ERK (one of the additional phosphorylated proteins in the cascade) enters the nucleus and upregulates Elk1 to express GLUT4 (glucose transporter)

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121
Q

Discuss the JAK-STAT signaling system.

A

JAK is a protein kinase (on an enzyme-mediated receptor)
Erythropoietin binds to the EPO receptor, causing the receptor to dimerize and then binds and activates JAK.
The activated JAK phosphorylates Tyr residues on the cytoplasmic domain of the EPO receptor.
JAK also phosphorylates STATs, allowing them to move to the nucleus upregulating genes for erythrocyte maturation.

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122
Q

Describe cross-talk as it pertains to insulin and epinephrine pathways.

A

1.Insulin binds to the receptor and, in addition to it’s independent pathway, also phosphorylates the GPCR for epinephrine. This initiates a clathrin regulated process that takes the GPCR out of service. (Insulin = glucose into the cell, epinephrine = glucose out of the cell, so this helps insulin do it’s job better)
2. Cross talk also results in 5-10 times greater expression of the ERK protein.

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123
Q

What properties is the Na+ voltage gated channel specific to?

A
  1. Size
  2. Charge
  3. Voltage sensor
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124
Q

What ions pass through the nicotinic acetylcholine receptor?

A
  1. Na+
  2. Ca2+
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125
Q

How does the acetylcholine receptor function?

A

Hydrophobic Leu side chains of helices block (close) the channel.
Binding of 2 Acth molecules causes twisting of the helices opening the channel and exposing small polar residues that line it.

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126
Q

Describe how Integrins mediate cell adhesion.

A

Extracellular domain interacts with collagen, fibrinogen, fibronectin etc. (Arg-Gly-Asp)
Triggers cytoskeleton to rearrange and triggers gene expression.
Newly expressed genes bind to intracellular domain triggering extracellular response; cell adhesion and migration, assembly of extracellular matrix.

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127
Q

What type of receptors mediate sensory perception?

A

GPCRs

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128
Q

What regulates the cell cycle intracellularly?

A

Cyclin-dependent protein kinases (CDKs)

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129
Q

What regulates cyclin-dependent kinases (CDKs)?

A

Phosphorylation and proteolysis

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130
Q

How can CDKs contribute to cancer

A

CDKs are only active if there is cyclin. CDKs are highly regulated as they are important for controling cell division. If a CDK is unregulated it can continue to uncontrolled cell division and/or growth.

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131
Q

What is the concern with targeting protein kinase inhibitors as a treatment for cancer?

A

Due to multiple pathways there would be many side effects.

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132
Q

The release of what molecule triggers apoptosis?

A

Cytochrome C

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133
Q

What does the term steady state refer to?

A

Rate of metabolite synthesis = Rate of metabolite breakdown.

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134
Q

What part of pathways is regulated to maintain homeostasis?

A

Flow of metabolites.

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135
Q

What inhibits the commitment step of glycolysis?

A

ATP

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136
Q

What do rates of biochemical reactions depend on?

A
  1. Concentration of reactants vs. products
  2. Concentration of the enzyme
  3. Instrinsic activity of the enzyme
  4. Concentration of effectors (regulators, competing substrates)
  5. pH, ionic environment
  6. Temperature
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137
Q

What factors determine the activity of enzymes?

A
  1. Quantity of enzyme
  2. Degradation of enzyme
  3. Phosphorylation/dephosphorylation
  4. Allosteric effectors
  5. Regulatory proteins
  6. Sequestration
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138
Q

Enzyme kinetics

A

When [S] = 1/2 Vmax this is the Km (affinity)
Rate changes 10x’s when below Km
v = Vmax[S] / Km + [S]

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139
Q

At what speed do most enzymes operate and why?

A

1/2 Vmax, good for homeostasis

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140
Q

What is significant about key enzymes as regulators

A

They operate far from equilibrium, this controls flow through the pathway.

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141
Q

How can you tell which is the regulatory step from looking at a Velocity chart.

A

The forward and backward reactions have the greatest ratio difference between them.
e.g. 10.01/.01 vs 200/190

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142
Q

Which two molecules are key cellular regulators?

A

ATP and AMP

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143
Q

What does a 10% decrease in [ATP] affect?

A
  1. Activity of ATP utilizing enzymes
  2. leads to a dramatic increase in AMP
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144
Q

Why do we artificially maintain low [AMP]?

A

So that any change in [ATP] has a drastic effect on [AMP]

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145
Q

What activates AMPK?

A

1.Increase [AMP]
2.decrease [ATP]
3. Leptin or adiponectin
4. SNS

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146
Q

What organs does AMPK effect and what are those effects?

A
  1. Hypothalamus - increase food intake
  2. Heart - FA oxidation, glucose uptake, glycolysis
  3. Adipose tissue - stops FA synthesis and lipolysis
  4. Liver - stops FA and cholesterol synthesis
  5. Skeletal mm - FA uptake, oxidation, glucose uptake, mitochondrial biogenesis
  6. Pancrease - stops insulin secretion
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147
Q

What effects might regulated enzymes have on pathways?

A
  1. Control flux through the pathway
  2. Regulate steady state concentration in response to changes in flux.
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148
Q

What controls flow to glycogen synthase

A

Glucose uptake and phosphorylation

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149
Q

What are the 2 hexokinase enzymes we need to know and list their functions.

A

HK I - tends to be located in mitochondria, phosphorylates glucose to G6P
HK IV - expressed in liver, not inhibited by G6P so can function at a higher [glucose], functions to clear blood glucose at high [glucose] for storage as glycogen.

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150
Q

What is an isozyme?

A

Different enzymes that catalyse the same reaction. Allow us to regulate different pathways and not have to start at the beginning.

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151
Q

How is HK IV regulated?

A

Sequestration (regulatory protein puts it to bed when F6P is high) and transcription.

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152
Q

What is the commitment step in glycolysis?

A

F6P to F 1,6-bisphosphate

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153
Q

What regulates phosphofructokinase-1?

A

ATP. It is a substrate and also a negative effector, if lots of ATP, no need to use up more glucose.

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154
Q

What are two alternative fates for pyruvate?

A
  1. New source of glucose; store energy as glycogen, generate NADPH via pentose phosphate pathway
  2. Source of acetyl-CoA; store energy as body fate, make ATP via CAC
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155
Q

How does Acetyl-CoA stimulte glucose synthesis?

A

Activates pyruvate carboxylase

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156
Q

What protein activates transcription in response to glucose?

A

ChREBP

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157
Q

What protein activates transcription in response to insulin (high blood glucose)?

A

FOX01

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158
Q

Where is glycogen mainly stored?

A

Liver and muscle.

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159
Q

What removes glucose residues from glycogen?

A

Glycogen phosphorylase

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160
Q

What does it mean for glycogen to have many nonreducing ends?

A

One glycogen can end up as many glucose molecules.

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161
Q

What is the function of debranching enzyme?

A
  1. Tranfers 3 residues to the non-reducing end of the chain
  2. cleaves the remaining linked glucose
    We need to squeeze all the glucose out of a glycogen
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162
Q

How is G-1-P metabolized?

A

Has to be isomerized to G6P first

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163
Q

How is G6P transported out of the liver?

A

First it is dephosphorylated to Glucose and then transported out via GLUT2 transporter.

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164
Q

What enzyme makes glycogen?

A

Glycogen synthase

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165
Q

What is the function of UDP in glycogen synthesis?

A

We use Uracil rather than Adenosine in order to keep ATP separate. UDP acts as a good leaving group so we can attach glucose in a chain.

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166
Q

What is the substrate for glycogen synthase?

A

UDP-glucose

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167
Q

What enzyme is responsible for synthesis of branches in glycogen?

A

Glycogen-branching enzyme

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168
Q

What molecule starts a new glycogen chain?

A

Glycogenin (OH-Tyr-Glycogenin)

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169
Q

How many glucose residues are in a glycogen chain?

A

12-14

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170
Q

What starts the signaling pathway for glycogen breakdown?

A

Glucogon or epinephrine

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171
Q

What is the 2nd messenger in the glycogen breakdown pathway and what does it activate?

A

cAMP activates PKA, which activates phosphoralase b kinase, which activates glycogen phosphorylase b to a

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172
Q

What type of cells does epinephrine signal for glycogen breakdown?

A

Myocytes

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173
Q

What type of cells does glucagon signal for glycogen breakdown?

A

Hepatocytes

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174
Q

What initiates signaling for glycogen sythesis?

A

Insulin

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175
Q

What effect does the active hexokinase have in glycogen synthesis?

A

Activates glucose

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176
Q

What is the other control enzyme for glycogen synthesis besides hexokinase?

A

Glycogen synthase.

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177
Q

What activates glycogen synthase?

A

dePhosphorylation - glycogen synthase b is phosphorylated and inactive, glygocgen synthase a loses the Ps via PP1 and becomes active.

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178
Q

What stimulates PP1

A
  1. Insulin
  2. G6P
  3. Glucose
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179
Q

What down regulates PP1

A
  1. Glucagon
  2. Epinephrine
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180
Q

What organ is mostly affected by glycogen storage diseases?

A

Liver

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181
Q

What molecules is nitrogen found in within the body?

A
  1. Nucleic acids and proteins
  2. Cofactors (NAD, FAD, Biotin)
  3. Small hormones (epinephrine)
  4. Neurotransmitters (Serotonin)
  5. Defense mechanisms (amanitin)
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182
Q

What is the most important step in the synthesis of heme?

A

1st step: 8 x delta-aminolevulinate to 4 x porphobilinogen

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183
Q

How does the production of heme affect it’s synthesis?

A

It feedsback to inhibit synthesis by blocking PLP

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184
Q

What is needed to work around the feedback from heme in heme synthesis?

A

Glycine is requested by the feedback inhibition because if the concentration of glycine is too low, the feedback from heme blocks PLP so we need more glycine to get around this.
Uses PLP to make succinyl-CoA, then the majority of d-ALA is committed to making heme.

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185
Q

What usually causes defects in heme biosynthesis?

A

Mutations or misregulation of enzymes.

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186
Q

What do defects in heme synthesis lead to?

A

Porphyria:
Precursors accumulate in RBCs, body fluids and liver
Homozygous individuals suffer intermittent neuro impairment, abdominal pain

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187
Q

What are signs of buildup of heme molecules

A

Pink to dark purple urine
Teeth may look red under UV light
Skin is sensitive to UV light
Craving for heme
(Vampire myths come from here)

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188
Q

When there is a defect in heme biosynthesis, what can spontaneously form?

A

Uroporphyrinogen III

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189
Q

What is the source of bile pigments?

A

Heme

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190
Q

What are the steps of heme degradation to bilirubin?

A
  1. Heme oxygenase linearizes heme to create biliverdin (green compound)
  2. Biliverdin reductase converts biliverdin to bilirubin (yellow). Bilirubin binds ot serum albumin in the bloodstream.
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191
Q

Describe the full pathway of heme breakdown.

A

Heme is broken down to biliverdin (green)
Biliverdin is broken down to bilirubin
Bilirubin enters the bloodstream or stays in liver.

In LIVER:
Further broken down to Bilirubin diglucuronide which is transported to small intestine where it is changed back to bilirubin in bile.
In BLOOD:
Transported as a complex with serum album to small intestine.
Bilirubin broked down to Urobilinogen
Urobilinogen transported to kidney and broken down to Urobilin

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192
Q

What causes jaundice?

A

Bilirubin accumulation

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193
Q

What causes bilirubin accumulation?

A
  1. Impaired liver
  2. Blocked bile secretion (gallstones, cancer)
  3. Insufficient glucouronyl bilirubin transferase to process bilirubin (infants). This is treated with UV which causes photochemical breakdown of bilirubin.
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194
Q

What molecules are synthsized from glycine and argenine?

A

Creatine and phosphocreatine

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195
Q

What is phosphocreatine used for?

A

Hydrolized for energy in muscle.

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196
Q

What is the cofactor used after Gly and Arg combine for phosphocreatine synthesis?

A

Methyl group from Adomet (Adomet from methionine)

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197
Q

What is Glutathione (GSH)?

A

Reducing agent/antioxidant

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198
Q

What amino acids is Glutathione derived from?

A

Glutamate, Cysteine and Glycine

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199
Q

What do racemases use as a cofactor?

A

PLP (used to tranfer nitrogen around in bacteria)

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200
Q

What do aromatic a.a.’s act as precursors for in mammals?

A

Hormones

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201
Q

What does decarboxylation of tryptophan give us?

A

serotonin

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202
Q

What does decarboxylation of tyrosine give?

A

Dopa, Dopamine, Norepinephrine and Epinephrine

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203
Q

What does carboxylation of glutamate yield?

A

GABA

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204
Q

What does carboxylation of histidine yield?

A

Histamine

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205
Q

What aa is the precursor for NO?

A

Arginine

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206
Q

What is the cofactor for the production of NO from Arg

A

NADPH

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207
Q

What can be used to synthesize nucleotides?

A
  1. Amino acids
  2. Ribose-5-phosphate
  3. CO2
  4. NH3
  5. Salvaged nucleobases
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208
Q

How do parasites get the components for nucleotides and how does this impact anti-parasitic drugs?

A

Salvage, therefore compounds that inhibit salvage pathways are promising anti-parasitic drugs.

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209
Q

What is the precursor for purines?

A

Glycine

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210
Q

What is the precursor for pyrimidines?

A

Aspartate

211
Q

What provides most of the amino groups in nucleotide synthesis?

A

Glutamine

212
Q

What regulates the 1st step in biosynthesis of purines?

A

PRPP

213
Q

Describe regulation of ribonucleotide reductase

A

Most forms of the enzyme have 1 specificity site and 1 primary regulation site on each of the a subunits.
Specificity site influenced by ATP, dATP, dGTP, dTTP
Regulation site influenced by ATP, dATP

214
Q

What activates and inhibits the activity regulatory site of ribonucleotide reductase?

A

ATP activates
dATP inhibits

215
Q

What activates and inhibits the specificity site on ribonucleotide reductase?

A

High ATP or dATP give less specificity to adenine and more specificity to UDP, CDP

216
Q

What does folic acid deficiency lead to?

A

Reduced thymidylate sythesis, which causes Uracil to be incorporated into DNA. Repair mechanisms create strand breaks that affect structure and function of DNA.
Leads to cancer, heart disease, neuro impairment.

217
Q

Where does uric acid come from?

A

Breakdown of purines

218
Q

What causes gout?

A

Build up of xanthine from purine breakdown

219
Q

What does the break down of pyrimidines lead to?

A

Ammonia, then urea
Can produce intermediates of CAC

220
Q

What organ is dependent on salvage pathways?

A

Brain

221
Q

How does fructose contribute to gout?

A

Fructose is too quickly phosphorylated by fructokinase, this uses up too much ATP and creates a build up of ADP.
Excess ADP is broken down to AMP and ATP .sAMP goes through purine degradation to urate.
The excess of ADP means an excess of urate, which gives us too much N
N goes crazy and causes inflamation.

222
Q

State the steps in heme synthesis

A

1.8 succinyl-CoA combine with 8 glycine to make d-aminolevulinate
2. 2xd-aminolevulinate condense with water to form 1xporphobilinogen
3. porphobilinogen goes through 4 other steps to become protoporhyrin
4. Fe ion is inserted into the protoporphyrin to create the final heme molecule

223
Q

What are creatine and phosphocreatine used for?

A

Anaerobic energy needs in muscle tissue

224
Q

How does synthesis of purines begin?

A

Reaction of PRPP with Glu, then 3 carbons from Gly.
Intermediate (IMP) is then modified via AMP or GMP to make adenylate or guanylate.
IMP + GTP = AMP
IMP + ATP = GMP

225
Q

What molecule plays a large role in the inhibition of purine biosynthesis?

A

AMP

226
Q

How is pyrimidine synthesis different from purine sythesis?

A

The pyrimidine ring is made first and then it gets attached to the ribose 5-phosphate.

227
Q

What is the first commitment step in the biosynthesis of pyrimidines?

A

Asp and N-carbamyolphosphate are catalyzed by aspartate transcarbamoylase (ATCase)

228
Q

How does ATCase work?

A

Channels substrates from one site to another

229
Q

How is pyrimidine biosynthesis regulated?

A

ATCase is inhibited by CTP and accelerated by ATP

230
Q

What are the precursors for deoxyribonucleotides?

A

Ribonucleotides

231
Q

How are ribonucleotides modified to become deoxyribonucleotides?

A

Redox reaction removes oxygen.
Catalyzed by ribonucleotide reductase.
2 H atome are donated by NADPH

232
Q

Describe the catabolism of purines

A

Dephosphorylation via 5’-nucleotidase
Adenosine yields hypoxanthine
Guanosine yields xanthine
These are oxidized into uric acid

233
Q

What does a buildup of xanthine cause?

A

Gout

234
Q

Describe the catabolism of pyrimidines.

A

Leads to NH4+ then urea.
Can produce intermediates of the CAC

235
Q

What is used to treat gout?

A

Xanthine oxidase inhibitor, allopurinol

236
Q

How is ammonia incorporated into biomolecules?

A

With Glu and Gln

237
Q

How is glutamine made by Glu?

A

Glu + ATP = phosphorylated Glu which creates a good leaving group, the leaving group is replaced by ammonia.

238
Q

How is glutamine synthetase regulated?

A

Allosteric inhibitors AMP, CTP, Trp, His, Gly, Ala, Glucosamine 6-phosphate, carbamoyl phosphate.
All are products of glutamine except Gly and Ala.

239
Q

How does adenylylation inhibit Gln synthetase?

A

Increases sensitivity to inhibitors.

240
Q

What is the result when Gln is high?

A

Gln synthetase is less active.
Nees less NH4+ conversion to Gln

241
Q

What is the result when Gln is low?

A

If a-ketoglutarate and ATP are available, Gln synthetase is more active.
Converts more NH4+ to Gln

242
Q

What is PLP

A

Active form of vit B6

243
Q

What enzymes hydrolyze a.a. and where do they function?

A
  1. Pepsin hydrolyzes peptides (<15 a.a.) in the stomach
  2. Trypsin and chymotrypsin cut larger proteins into smaller peptides in the small intestine.
  3. Aminopeptidase and carbosypeptidases A&B degrade peptides in the small intestine.
244
Q

Describe the general overview of a.a. catabolism.

A

1.Proteins are broken down to a.a.
2. A.a. broken down to release NH4+ and Carbon skeletons.

NH4+ goes to building new a.a, nucleotides, amines as well as carbamoyl phosphate which enters the urea cycle.

CARBON SKELETONS become a-keo acids which enter the CAC to form ATP and eventually glucose.

Urea cycle and CAC communicate via Aspartate-arginino-succitate shunt.

245
Q

What is the importance of vit B6

A

It is PLP which is the cofactor for moving nitrogen.

246
Q

How is ammonia safely transported in the bloodstream?

A

Glutamine

247
Q

What regulates a.a. synthesis?

A

Many layers of regulation.
1. Feedback inhibition
2. Allosteric regluation
3. Isozymes

248
Q

What are the 3 types of reactions involved in a.a. biosynthesis?

A
  1. Transamination and rearrangements using PLP
  2. Transfer of 1-C groups via tetrahydrofolate or adoMet (both can act as carbon donors)
  3. Transfer of amino groups from Glu
249
Q

What is the catabolic pathway for amino acids in the liver?

A
  1. a-ketogluterate takes the amino group off the a.a. and becomes glutamate. Glutamate cycles and gives up the NH4+ to be transported out of the liver as ammonia, urea or uric acid. The glutamate is now a-ketoglutarate again. Cycle repeats.
  2. the a-keto acid (a.a. w/out amino group) gets together with a-ketoglutarate and alanine (from the muscles) to make pyruvate. Donates the amino group from alanine to the glutamate cycle in step 1. Now we have pyruvate.
  3. Glutamine from muscle and other tissues gives up its Nitrogen in the R group which gets transported right out of the liver and becomes the glutamate, which then donates its amino group as in step 1.
250
Q

How does the a-ketoglutarate pick up the amino group and become glutamate?

A

PLP is the cofactor catalyzed by amino-transferase.

251
Q

a-Melanocyte-stimulating hormone (a-MSH)

A

Anorexigenic hormone
Release is stimulated by leptin

252
Q

ACP

A

Acyl carrier protein is the shuttle that holds the system of FA synthase together. It is thought to tether the growing acyl chain to the surface of FA synthase and carry the reaction intermediates to the next active site.

253
Q

Adipokines

A

Carry information about fuel stores to the brain.
Include Leptin and Adiponectin

254
Q

Are higher order structures well understood?

A

No

255
Q

Bacterial genomes

A

Double stranded circles (plasmids)

256
Q

Changes in LK

A

If LK decreases = (-) change = negative supercoil

257
Q

Chylomicron

A

Molecules made up of triacylglycerols, cholesterol, apolipoproteins

258
Q

Cruciform DNA

A

Rarely occur in relaxed DNA
Facilitates formation of stretches of left handed Z-form
Allows for sequence to be read
Results from underwinding
Means there is an important sequence nearby

259
Q

Describe fuel use over four hours of normal metabolism

A

Immediately after meal glucose increases.
Insulin stimulates glycolysis and glycogen synthesis.
2 hours post meal blood glucose starts to drop, glucagon is secreted and liver glycogen releases glucose.
4 hours post meal more glucagon is secreted, triacylglycerides are hydrolyzed to FAs which become fuel for liver and mm.

260
Q

Describe leading and lagging strand synthesis with Poly III

A

One poly with many clamps.
Folding occurs so that DNA is still made in the correct direction.
Clamp has to let go because extra tension is created.
A new clamp brings in another piece of lagging strand.

261
Q

Describe nucleosome packaging

A

Compacts DNA seven-fold.
Occurs in regions where sequence specific non-histone proteins bind.
Solenoid and Zigzag models (nucleosome creates yet another helix)

262
Q

Describe the Ames test

A

Used to indicate the mutagenic potential of a compound.
Uses salmonella with a mutation that makes bacterium unable to synthesize His.
Add a compound to the salmonella and see if it grows.
If you get colonies, the compound was able to mutate the salmonella.
More colonies mean the compound was more mutagenic.

263
Q

Discuss mismatch repair

A

Mismatches arise from occassional incorporation of incorrect nucleotides.
In bacteria, Dam methylase methylates the template strand so the daughter strand can be identified and ther repair made accurately based on the template.
Mut complex forms - looping the DNA
MutH cleaves non-methylated strand on the 5’ side.
DNA unwinds and is degraded 3’-5’ (Helicase and exonuclease)
Sequence is replaced (Poly III and Ligase)

264
Q

Discuss base excision repair.

A

Caused by Uracil, Hypoxanthine, Alkylated bases, Dimers
Cytosine spontaneously deaminates to Uracil.

Glycosylases recognize specific lesions and cleave N-glycosyl bond between sugar and base.
CREATES AP SITE
AP endonucleases cut the backbone aroudn the AP site and remove DNA
Poly I synthesizes new DNA.
Ligase seals the nick.

265
Q

Discuss direct repair

A

Pyrimidine dimers repaired by DNA photolyases which use light energy to repair dimers. Not found in humans and placental mammals.

Methylguanine repaired by Methylguanine-DNA methyltransferase.

1-Methylguanine & 3-methylcytosine repaired by AlkB protein which demethylates the guanine and cytosine.

266
Q

Discuss DNA poly III

A

Complex structure with 10 types of subunits.
2 core domains linked by the clamp-loader complex.
Core domains interact with a dimer of B subunits that increase processivity.
The sliding clamp prevents dissociation giving Poly III high processivity.

267
Q

Discuss elongation in DNA replication

A

LEADING STRAND
Primase makes primer: DnaG primase interacts with helicase but primase moves in opposite direction of helicase.
Poly III is linked to helicase which is tethered to the opposite DNA strand.

LAGGING STRAND
Primase makes primer and Poly III adds nucleotides but the SAME DNA POLY III works on both strands because the DNA of the lagging strand loops around.

Both strands being elongated at the same time requires interesting folding and the use of the clamp complex.

268
Q

Discuss how high [cholesterol] in membrane regulates cholesterol synthesis.

A

When cholesterol levels are high there is more cholesterol in the membrane which causes a folding change so that INSIG interacts with it, causing proteolytic degradation.

When cholesterol levels are low the SREBP-SCAP does not interact with the INSIG. This causes a vesicle to undergo endocytosis. Once in the cell the regulatory factor is cleaved off of SREBP it enters the nucleus and upregulates HMG-Co A reductase.

269
Q

Discuss how low cholesterol in ER causes upregulation of transcription.

A

Low cholesterol in membrane - INSIG prtoein does not interact.
SREBP is then sorted to GA
Cleavage in GA releases SREBP response element which enters nucleus, interacts with RNA poly.
mRNA codes for HMG-Co A redcutase.
HMG-Co A reductase sythesizes mevalonate.

270
Q

Discuss insulin release from the pancreas.

A
  1. Glucose enters pancreas via GLUT2 transporters.
  2. Hexokinase IV coverts glucose to G6P
  3. G6P enters glycolysis cycle increasing [ATP] in cell.
  4. Increased [ATP] closes K+ channels.
  5. Depolarization d/t closed K+ channels leads to increased [Ca2+] in cell.
  6. Increased [Ca2+] leads to exocytosis of insulin to blood stream.
271
Q

Discuss methylation in DNA replication regulation.

A

After replication oriC is hemimethylated by Dam methylase.
Hemimethylated oriC sequences interact with plasma memberane via SeqA.
SeqA dissociates, oriC sequences are released from membrane.
Dam methylase fully methylates DNA to allow DNaA to bind.

Daughter strand is fully methylated at the end of the process and can now be a new parent strand.
Methylation becomes important for repair.

272
Q

Discuss Nucleotide-excision repair.

A

DNA lesions cause large structural changes like pyrimidine dimers and other mutations due to UV light or cigarette smoke.

Bacteria:
ABC exonuclease cleaves backbone in 2 places, removes 12-13 nucleotides.
Poly I replaces DNA
Ligase seals.

Eukaryotes:
Removes 27-29 nucleotides

273
Q

Discuss the different subunits of polymerase.

A

Active site to add base.
Active site to take off base if it is wrong.

274
Q

Discuss the locations of Triacylglycerol metabolism.

A

Digestive system:
Ingestion of fats.
Fats are emulsified in the small intestine by bile salts.
Emulsified fats are degraded by lipases, transported across mucosa to blood stream, and taken to liver.
Glycerols are transported to liver.

Liver:
FAs are used to make Acetyl-Co A whcih is then used to make ketone bodies.
Glycerol is used for gluconeogenesis.

Ketone Bodies:
Transported to muscle or brain and converted back to Acetyl-Co A for CAC

Glucose:
Transported to brain.

275
Q

Discuss the role of cerulenin as an antibiotic as it pertains to tumor growth.

A

Fatty acid synthase binds irreversibly to cerulenin which would then stop FA synthesis resulting in no Malonyl-Co A.
B-oxidation would continue until all the FA were used up and no more energy was available for the microorganism.
This only works in mice, not humans.
FA synthase inhibition slows tumor growth in mice.
Extrahepatic cells only use FA synthase when they are dividing.

276
Q

Discuss the rold of glucokinase (hexokinase IV) in hepatocytes.

A

Has higher Km than other hexokinases.
Not inhibited by G6P so G6P can be made continually in hepatocytes.
But G6P isn’t made when glucose is low in hepatocytes.

277
Q

Discuss the Termination stage of replication.

A

Replication forks meet at the Ter region.
Replication forks cannot leave Ter region.
Ter is binding site for Tus (Termination Utilization Sequence) which causes replication fork to stop.

There are multiple Ters in case one gets missed. This ensures proper termination.

278
Q

Discuss TLS polymerases in mammals.

A

Recognize specific types of damage.
Limited to short regions of DNA, minimizing mutagenic potential.
Very well controlled and low processivity to minimize chaos it create.

279
Q

DNA supercoiling

A

Is one level of organization of DNA.
Allows for packaging of large DNA molecules.
Supercoil forms up or down.
Changes gaps between the strands so there is access for proteins to read DNA sequence.
Has a great influence on transcription and replication of DNA.
Can be highly regulated.

280
Q

E. coli DNA polymerase:
1. How many?
2. Which has largest processivity?
3. Which cleans up and makes Okazaki fragments have no gaps?
4. Which are involved in DNA repair?

A
  1. At least 5
  2. Poly III
  3. Poly I
  4. Poly II, IV, V
281
Q

Endonucleases

A

Cleave bonds within a DNA sequence.

282
Q

Error-prone TLS process and benefits

A

Part of SOS response.
SOS proteins include UvrA, UvrB, UmuC and UmyD.
These proteins bind with RecA to create DNA Poly V.
Poly V works without a template and randomly adds nucleotides.

Benefits: May kill some cells, mutate DNA in others….BUT some cells still survive.

283
Q

Exonuclease

A

Cleaves bonds remove nucleotides form the ends of DNA.

284
Q

Explain why defective ABD transports lead to disease.

A

If ABC1 transporters cannot move sterols to membrane surface, HDL cannot pick it up and take back to the liver.
Then macrophages become foam cells and undergo apoptosis, releasing contents into the blood and surrounding areas.
Defective ABCC2 transporters lead to build up of bile and decreased excretion of many drugs.

285
Q

List the fates of a.a. in the liver

A
  1. Protein synthesis
  2. Blood stream to other organs for protein synthesis
  3. Nucleotides, hormones and other nitrogenous compounds
  4. Transamination or deamination for pyruvate; Pyruvate to glycogen, glucose or Acetyl-Co A
  5. Ammonia to urea
286
Q

Fates of lipids in the liver

A
  1. Liver lipids
  2. FAs are oxidated to Acetyl-Co A; Acetyl-Co A to CAC, ETC, ketone bodies, cholesterol
  3. FAs to phospholipids and TAGs
  4. FAs to hear and mm for fuel via oxidation
287
Q

Fatty Acid Synthase

A

A single multifunctional polypeptide chain with 7 active sites for different reactions in FA synthesis.

288
Q

Function of PPARs

A

LIke isozymes these do similar things - modularity
All types are present in the liver
One for fat, one for heart and mm, one for mm

In mice is a key regulator of fat metabolism.

289
Q

Functions of leptin

A

Stimulates production of anorexigenic hormones.
Stimulates SNS.
Triggers cascade that regulates gene expression.

290
Q

Gene

A

Segments of DNA that code for peptides and RNA
Different from regulatory sequences
One gene - different products

291
Q

Ghrelin

A

Short-term orexigenic peptide
Secreted in stomach
Receptors are in brain, heart and adipose.
Works via GPCR to increase sensation of hunger.
Prader-Willi syndrom

292
Q

How are bacterial genes named? Proteins?

A

Genes: 3 lowercase italicized letters, usually reflects function. Capital letters added to reflect order of discovery.

Proteins: Often named after their genes.

293
Q

How are bile acids recycled?

A

Secreted in biliary ducts to intestine.
Reuptake in instestine w/Na+.
Excreted from intestinal cells to get carred back to liver.
Liver reuptake with 2 different transporters.
Secreted into biliary duct via ABC transporter.

294
Q

How are human topoisomerases different?

A

We have additional types because we are complicated.

Type I - Topo I & Topo III. Cannot add supercoils, only relax

Type II - Type IIA & Type IIB. Can relax both positive and negative supercoils.

295
Q

How are TAGs carried from the intestinal tract to adipose cells?

A

Chylomicons.

296
Q

How are TAGs carried from the liver to adipose cells?

A

VLDLs

297
Q

How are telomeres associated with cellular aging?

A

The become shorter after each round of replication.
Normal cells can divide about 52 times before losing ability to divide.

298
Q

How are the substrates added to the growing daughter strand in DNA elongation?

A

The nucleophilic OH group at the 3’ end of the growing chain attacks the a-phosphate of the incoming trinucleotide.

299
Q

How can Lk be broken down?

A

Into Twist (Tw) and Writhe (Wr)

300
Q

How do bacteria acquire antibiotic resistance?

A

Plasmid exchange.

301
Q

How do E. coli regulate DNA replication to 1/cell cycle?

A

The kinetics of the step wise reaction is quite long relative to other cellular processes.
Hda binds to B subunits of poly III, this stimulates hydrolysis of DnaA’s ATP.
DnaA complex then dissociates.
ADP dissociates
ATP rebinds to DnaA to stimulate all over again.
Takes 20-40 minutes.

302
Q

How do exonucleases proofread synthesis?

A

3’-5’ direction.
Translocation to next position is inhibited until enzyme can remove the incorrect nucleotide.

303
Q

How do FAs with chains of 12 or less carbons enter the mitochondria?
14 or more?

A

12 of less can pass through the membrane without a transporter.
14 or more must use the Carnitine shuffle (majority enters this way).

304
Q

How do LDL and HDL differ in cholesterol transport?

A

LDL drops it off at extrahepatic capillary beds.
HDL picks it up in the blood stream and takes it back to the liver.

305
Q

How do statins function?

A

Inhibition of HMG-Co A reductase.
This stops the formation of mevalonate so that no more cholesterol is made.

306
Q

How does acetone and acetol affect seizures?

A

Inhibits seizures.
Seizures are caused by PTZ binding to GABA which is inhibitory, blocking its inhibition.
Acetone and acetol interfere with GABA receptors, not 100% effective.

307
Q

How does AMPK activation affect the different body tissues?

A
  1. Heart: increased FA oxidation, increased glucose uptake, increased glycolysis
  2. Skeletal mm: increased mitochondria numbers, increased FA oxidation, increased glucose uptake
  3. Brain: increased feeding behaviour, decreased energy expenditure
  4. Pancreatic B cells: decreased insulin secretion
  5. Liver: decreased FA synthesis, decreased cholesterol synthesis
  6. Adipost tissue: decreased FA synthesis, decreased lypolysis
308
Q

How does DNA ligase seal the gaps?

A

Makes a bond between a 3’ OH and a 5’ PO4.
Phosphate must be activated by AMP.
Then the 3’ OH nucleophile attacks the phosphate, displacing AMP.

309
Q

How does insulin binding regulate hunger?

A

Inhibits release of NPY.
Stimulates a-MSH.
Interacts with hypothalamus via crosstalk with Leptin, but we don’t know how they crosstalk.

310
Q

How does metabolism change during fasting and starvation?

A

Shifts to provide fuel for the brain.

311
Q

How does the liver ensure that there is glucose available for the brain and mm?

A

Hexokinase IV has a high Km for glucose so if there is not enough glucose, it doesn’t get changed into G6P.

312
Q

How does winding around a histone affect the supercoil?

A

Underwinding occurs without a strand break so (+) supercoil forms.
Need a topoisomerase to relax the (+) supercoil.
Winding of DNA around histone core requires removal of 1 helical turn.

313
Q

How is bacterial DNA organized?

A

Nucleoids.
Can occupy much of cell volume.
DNA attaches to plasma membrane.
Transient binding to proteins - HU (acts like a histone)

314
Q

How is brown adipose tissue (BAT) divverent from white adipose tissue (WAT)?

A

Smaller polygonal cell shape.
Store TAGs in several small droplets.
More mitochondria.
More capillaries and innervation.
UCP1 gene upregulated for thermogenesis

315
Q

How is cholesterol modified to create steroids?

A
  1. “Side chain” of C17 of D ring is modified or cleaved.
  2. The 2 adjacent carbons are hydroxylated. The process uses mixed-function oxidases, NADPH and Cytochrome P450.
  3. Further processing for the specific steroid occurs at the activated hydroxyl groups.
316
Q

How is cholesterol transported from the liver to other cells in the body?

A

As plasma lipoproteins with apolipoprotein.

317
Q

How is muscle broken down for fuel?

A

Liver deaminates or transaminates the a.a.s converting amino groups to urea. Carbon skeletons are converted to pryruvate then glucose via gluconeogenesis.

FAs are oxidized to Acetyl-Co A but oxaloacetate is depleted so forms ketone bodies rather than glucose that are exported to other tissues.

318
Q

How is the C-C stability overcome in triacylglyceride oxidation?

A

The carboxyl group at C1 is activated by coenzyme A attachment.

319
Q

How is the transition between Okazaki fragments handled?

A

Core subunits of Poly III dissociate from on the B-clamps and bind to a new one.
RNA primer is removed.
DNA Poly I fills in the gap.
DNA ligase seals the nick.

320
Q

How many genes in the human body?

A

25,000

321
Q

How was a unique origin of replication proven?

A

Denatured DNA at A-T rich regions - bubbles.
Mapped these bubbles.
Showed that loops always initiate at a unique origin.

322
Q

How was bidirectional replication proven?

A

H3 label on DNA.
Showed circular DNA w/extra loop.
2 replication forks showing bidirectional replication.

323
Q

Information flow as per central dogma and what is the exception?

A

DNA to RNA to protein.
Exception is viruses which can use RNA as template in reverse transcription.

324
Q

Introns in bacterial genomes.

A

Do not interrupt protein coding sequences, mainly interrupt tRNA sequences.
Interons in phage genomes within bacteria interrupt protein coding sequences.
Many bacterial introns code catalytic RNA sequences that can insert and reverse transcribe into DNA.

325
Q

Is there any connection between genome size and organism complexity?

A

No. Amphibians have much more DNA than humans. Most eukaryotic DNA is non-coding.

326
Q

Klenow fragment

A

A distinct domain within Poly I that can be separated by protease treatment.
Is a nick where translation and Poly I actively take place.

327
Q

Leptin

A

Peptide hormone released from adipose tissue that reduces appetite.

328
Q

Lesion

A

DNA damage

329
Q

Linking number (LK)

A

Describes supercoiling
Changes in Lk is an indication the organism is trying to do something and make the genome more accessible.

330
Q

Lipid burden hypothesis

A

Adipocytes become packed and can’t take on anymore TAGs.
This leads to increased FAs in the blood.
Excess FAs enter mm and liver, create TAG lipid droplets and cause these organs to lose sensitivity to insulin (excess fat interferes with peroxisome receptors and changes gene regulation so we don’t repsond to high glucose bc fat interes with transport of glut receptors.).
Lipid filled cells release proteins that attract inflammatory macrophages.

331
Q

List the simplified steps of the carnitine shuttle.

A
  1. Acyl-Co A synthetase adds a Co-A to the triglyceride *activating it.
  2. CPT1 replaces the Co-A with a carnitine and in the process moves the FA across the outer membrane of the mitochondria.
  3. Acyl-carnitine/carnitine transporter allows the Acyl-carnitine to pass into the matrix where the carnitne group is replaced with a Co-A group creating an Acyl-Co A.
332
Q

List the steps of cholesterol synthesis.

A
  1. 3 acetate condense to form mevalonate.
  2. Mevalonate converts to phosphorylated 5 carbon isoprene.
  3. 6 isoprenes polymerize to form a 30 carbon linear sequence.
  4. Squalene cylclizes to form the 4 rings which get modified to cholesterol.
333
Q

List the steps within FA Synthase

A
  1. Condensation with acetate {b-ketoacyl-ACP synthase (KS)}
  2. Reduction fo carbonyl to hydroxyl (KR)
  3. Dehydration of alcohole to alkene (DH)
  4. Reduction of alkene to alkane (ER)
  5. Chain transfer/charging (Malonyl/acetyl-Co A ACP transferase)
334
Q

Liver G6P fates

A
  1. Dephosphorylated to glucose which enters blood stream.
  2. Glycolyis
  3. Glycogen stored in liver.
  4. Glycogen used in pyruvate dehydrogenase goes to Acetyl-Co A for CAC
  5. Acetyl-Co A to FAs to TAGs and cholesterol
  6. Pentose phosphate pathway for NADPH
335
Q

Metabolic Syndrome

A

Cluster of symptoms along with insulin resistance:
Abdominal obesity
High TAGs
Low HDL
High blood pressure
Elevated blood glucose (may not be full blown diabetic)
Often other signs of inflammation

336
Q

Mutation

A

DNA damage that is unrepaired.

337
Q

Name one way bacteria acquire antibiotic resistance.

A

Plasmid exchange.

338
Q

Neuropeptide Y (NPY)

A

Orexigenic (appetite stimulating) hormone.
Sends signal to eat.
Levels rise in starvation.
Inhibited by leptin and insulin.

339
Q

Nick translation

A

A strand break moves along with DNA Poly I

340
Q

Peroxisome proliferator-activated receptors (PPARs)

A

Alter expression of genes for fat and carb metabolism.
Were discovered in peroxisomes.
Bind to FAs and derivitives
Then bind to RXR and become powerful transcription factors.

341
Q

Primer

A

Short strand complementary to the template.
Contains a 3’ OH to begin the first DNA Poly catalzyed reaction.
Can be DNA or RNA because it gets degraded later.

342
Q

Processivity

A

The # of nucleotides that a DNA polymerase can add before dissociation.
Kind of like how long can the polymerase hang on. Different polymerases have different processivity. We use this to distinguish between them.

343
Q

PYY3-36

A

Appetite suppressing hormone.
Secreted in response to food entering stomach.
Tranported to hypothalamus.

344
Q

Replisome

A

Set of over 20 enzymes and proteins required for DNA replication.
Includes; Helicases, Topoisomerases, DNA binding proteins to stabilize strands, Primases, Ligases.

345
Q

Silent Mutation

A

Has no effect on gene function.

346
Q

SMC proteins

A

Hav 5 domains.
N & C domains form ATP-binding site.
Cohesions - help link sister chromatids.
Condensins - help chromosome to condense, create (+) supercoil.

347
Q

SSRs

A

Highly repetitive DNA.
Sort sequences 10bp or less.
Repeated millions of times.
AKA satellite DNA.
Associated with centromeres and telomeres.

348
Q

Superhelical density (sigma)

A

AKA specific linking difference
Shows change in Lk in a quantity independent of DNA length.
Most cellular DNAs have (-) supercoils.

Sigma = change in Lk/original Lk

349
Q

Telomeres

A

Sequences that cap the ends of eukaryotic chromosomes.
Many form special loop to keep DNA ends from unravelling by preventing nucleases attaching.
Added by enzyme telomerase.
G rich (more strenth in G-C bond)

350
Q

Through was process to steroid hormones alter gene expression?

A

Nuclear receptors.

351
Q

Topoisomerases

A

Enzymes that change Lk.
Required for unwinding and rewinding DNA.

352
Q

Topoisomers

A

DNAs that differ in linking number only (slightly different shape).
Have same # of bp, same sequence but different degree of coiling.
Conversion between topoisomers requiers a DNA strand break.

353
Q

Transposons.

A

Sequences that can move within the genome.
Ends contain terminal repeats.
Repeats hybridize with complementary regions of target DNA during insertion.
Account for 50% of human genome.
Activity slows as we age.
May have connection with neural plasticity

354
Q

Treatment for type 2 diabetes.

A
  1. Weight loss - reduces lipid burden
  2. Exercise - aids weight loss
  3. Sulfonylureas - Stimulate insulin secretion from pancreas
  4. Biguanides (metformin) - increases glucose uptake by mm, decreases glucose production in liver.
355
Q

Twist (Tw)

A

The number of twists or turns of the helix.

356
Q

Types of DNA damage repair

A

Mismatch/methylation
Base-excision
Nucleotide-excision
Direct repair

357
Q

Viral genomes

A

Many are only RNA, use host genes.
RNA genomes are small and single stranded.
Can change from circular to linear in their lifetime.

358
Q

What accounts for the high fidelity of DNA synthesis?

A

Geometry of base pairing.
Polymerase tries to match the H-bonds, but other patterns are possible. Polymerase must detect mismatches and fix them so they don’t need exonuclease activity.

359
Q

What are low fasting levels of blood glucose for men and women and what can it mean?

A

Men: 50mg/100ml
Women: 40mg/100ml

Warning signs of hypoglycemic conditions.

360
Q

What are some intermediates in cholesterol synthesis?

A

Vit A, Vit E, Vit D, quinone e-carriers, plant hormones, rubber, phytol chain of chlorophyl.

361
Q

What are the 2 types of diabetes mellitus?

A

Type I - B cells in pancrease don’t produce insulin. Usually because of autoimmune. Develops early in life. Fat breakdown is accelerated which leads to high production of ketone bodies.

Type II - Insulin resistant. Develops later in life, usually associated with obesity. Cells do not respond properly to insulin.

In both forms blood glucose levels are elevated. Body tries to dilute by excessive thirst which leads to excessive urination.

362
Q

What are the 2 types of topoisomerases?

A

Type I - Topo I & Topo II. Make a transient cut in one DNA strand. Removes negative supercoil.

Type II - Topo II (DNA gyrase). Introduces supercoils. Uses ATP and double strand breaks.

363
Q

What are the 3 stages of complete oxidation of FAs to CO2 and H2O?

A
  1. Oxidation of long-chain FA to 2 carbon fragments.
  2. Oxidation of acetyl-Co A to CO2 in the CAC
  3. Transfer of e from carriers to mitochondrial respiratory chain.
364
Q

What are the 5 types of homone/receptor induced intracellular consequences?

A
  1. 2nd messenger acts as allosteric regulator of 1 or more enzymes.
  2. Receptor Tyrosine Kinase is activated by the hormone.
  3. Change in membrane potential opens or closes a hormone gated channel.
  4. Adhesion receptor conveys info to cytoskeleton.
  5. Steroid or steroid like molecules cause a change in the level of gene expression.
365
Q

What are the effects of fructose?

A

Liver is shocked by fructose because it can process all other sugars to glucose except fructose. Fructose becomes a burden on liver.

Gut flora should help prevent the liver from becoming shocked and we see connection between gut microbe and fructose in obesity.

366
Q

What are the effects of prolonged fasting?

A

Muscle breaks down and is used for fuel.

367
Q

What are the eukaryotic polymerases?

A

Poly alpha - similar to Poly I - has primase but no 3’-5’ activity.
Poly sigma - similar to Poly III - largest processivity and can proofread 3’-5’
Poly epsilon - used in DNA repair.

368
Q

What are the fates of G6P in the liver?

A
  1. Dephosphorylate to yield glucose for other tissue.
  2. Made into liver glycogen
  3. Glycolysis - Acetyl-Co A - ATP for hepatocytes themselves.
  4. Glycolysis - Acetyl-Co A - FAs - Triacylglycerides.
  5. Pentose phosphate pathway to yield NADPH and Ribose-5-phosphate
369
Q

What are the fates of the 3 ketone bodies?

A
  1. Acetone is produced in smaller quantities and is exhaled.
  2. Acetoacetate and D-B-hydroxybutyrate are transported to tissues, except the liver, converted to Acetyl-Co A and oxidized in the CAC.
370
Q

What are the features of DNA polymerase?

A

Has a pocket with 2 regions:
Insertion site where incoming nucleotide binds
Post insertion site where newly made base pair resides when the polymerase moves forward.

Can add nucleotides or dissociate.

Have widely varying processivity rates.

371
Q

What are the long term effects of high blood glucose?

A
  1. Proteins can be glycosylated.
  2. Hemoglobin becomes glycosylated - Hemoglobin is abundant, has many exposed amino groups and entry of glucose into erythrocytes is not regulated. This compromises O2 delivery, expecially in the extremities.
  3. Increases risk of CVD, renal failure and damage to small blood vessels and nerves due to glycosylated lipids.
  4. Macrophage receptors and scavenger receptors will take up things that are glycosylated, including hemoglobin.
372
Q

What are the main effects of glucagon and how are they regulated?

A
373
Q

What are the main effects of glucagon and how are they regulated?

A

Stimulates glucose release and synthesis in liver.
Mobilized FAs from adipose tissue.

Mediated by cAMP dependent protein phosphorylation

374
Q

What are the specific regulators for cholesterol synthesis?

A
  1. Decrease [ATP] inhibits formation of mevalonate.
  2. Glucagon inhibits formation of mevalonate.
  3. Oxysterol (intermediate of cholesterol) feedsback to inhibit formation of mevalonate and inhibits receptor mediated endocytosis of LDL-cholesterol needed to make cholesteryl esters.
  4. Insulin promotes formation of mevalonate.
  5. Cholesterol feeds forward to promote formation of cholesteryl esters.
375
Q

What are the potential biological signifaces of non-coding DNA sequences?

A
  1. Some regions directly participate in the regulation of gene expression.
  2. Some DNA encodes for regulatory RNA
  3. Some DNA are “junk” - pieces of unwanted genes, remnants of viral infections.
376
Q

What are the steps in the formation of ketone bodies?

A
  1. 2 x acetyl-Co A [thiolase] condense to acetoacetyl-Co A
  2. Acetoacetyl-Co A condenses with acetyl-Co A to B-hydroxy-Bmethyglutaryl-Co A (HMG-Co A)
  3. HMG-Co A is cleaved to acetoacetate and acetyl-Co A
  4. Acetoacetate [D-B hydroxybutyrate dehydrogenase] to D-B-hydroxybutyrate
377
Q

What are the steps of the Carnitine shuttle?

A
  1. Acyl-Co A synthetases catalyze FA + CoA + ATP = fatty acyl-CoA + AMP + PP
    (Fatty acyl-Co A can be transported to mitochon to make ATP or used in cytosol to make membrane lipids)
  2. In the outer membrane Carnitine acyltransferase I catalyzes Fatty acyl-Co A to attach to OH group of carnitine to form fatty acyl-carnitine
  3. Fatty acyl-carnitine enters the matrix via Acyl-carnitine/carnitine transporters of the inner membrane.
  4. Carnitine acyltransferase II transfers the fatty acyl group from carnitine to intramitochondrial Coenzyme-A
  5. Carnitine leaves the matrix back through the acylcarnitine/carnitine transporter.
378
Q

What are the substrates in strand synthesis?

A

Nucleoside triphosphates.

379
Q

What are the therapeutic ways to lower LDL?

A
  1. Inhibit cholesterol synthesis
  2. Inhibit cholesterol uptake (transporters)
  3. Inhibit bile acid reuptake so that more cholestrol is used to make new bile acid
  4. LDL apheresis
380
Q

What are the 3 fundamental rules of DNA replication?

A
  1. Semiconservative
  2. Begins at origin and proceeds bidirectionally
  3. Occurs in the 5’-3’ direction and is semidiscontinuous
381
Q

What are the 3 types of ketone bodies?

A

Acetate
Acetoacetate
D-B-hydroxybutyrate

382
Q

What are the 2 modes of cholesterol uptake into macrophages?

A
  1. LDL receptors - regulated by negative feedback.
  2. Scavenger receptor - meant to pick up foreign LDL but will pick our own if it is modified by amine, acetylation, carbonylation, or glucosylation
383
Q

What are topoisomerase inhibitors used as?

A

Chemotherapy agents.
Rapidly growing cells express topoisomerases.
Lots of side effects though, some are the only option for particular cancers.

384
Q

What are topoisomerases therapeutic targets for?

A
  1. Antibiotics: Coumarins inhibit bacterial Type II from binding ATP, Quinolones inhibit the last step of resealing DNA strand breaks, wide spectrum.

Can get weird side effects from these drugs, only used in extreme cases like anthrax.

385
Q

What are we supposed to know about cholesterol?

A

We can make our own.
It has other uses besides membrane fluidity.

386
Q

What can happen if there is a low level of bile acids?

A

Precipitation of cholesterol; crystals form and block the process of bile formation.

387
Q

What carries cholesterol to extrahepatic cells?

A

LDL

388
Q

What contributes to the variety of proteins from one gene?

A

Post transcriptional processing, introns exicised.

389
Q

What determines the biological function of a protein?

A

The sequence.

390
Q

What do higher level DNA structures depend on?

A

Chromosomal scaffolding - includes Topo II and SMC proteins.
SMC proteins = structural maintenance of chromosomes.

391
Q

What does histone binding depend on?

A

DNA sequence.
Histone binding is not random. It occurs more often at A-T rich segments.

392
Q

What emulsifies fatty acids?

A

Bile salts.

393
Q

What enzyme is frequently seen in cholesterol modification to steroid hormones?

A

Cytochrome P-450

394
Q

What enzyme synthesizes DNA?

A

DNA polymerase

395
Q

What enzymes degrade DNA?

A

Nucleases

396
Q

What gene encodes for the leptin receptors and where is it expressed?

A

DB gene expressed from hypothalamus.

397
Q

What happens in the liver when carbohydrate ingestion increases?

A

GLUT2 transporters and hexokinase IV are upregulated.
Glucose is phosphorylated to G6P.

398
Q

What happens to Acetyl-Co A when oxaloacetate is depleted?

A

It is converted to ketone bodies which free the Coenzyme A to be used in B-oxidation.

399
Q

What happens to the excess FAs obtained through diet?

A

Liver converts to triacylglycerols which are packaged with specific apolipoproteins into VLDLs.
VLDLs are then transported via blood to adipose tissues where triacylglycerols are removed and stored in lipid droplets in adipocytes.

400
Q

What happens when there is no undamaged DNA to use a template for repair?

A

Recombination - using another chromosome as a template.
Error-Prone Translesion Synthesis (TLS)

401
Q

What induces supercoil?

A

Strain due to fewer helical turns (underwinding)
Underwinding makes later separation of strands easier.

402
Q

What is a glucose level sign for diabetes?

A

High fasting blood glucose level (126mg/100ml)

403
Q

What is B-oxidation?

A

The repetitive 4 step process that converts FAs into Acetyl-Co A.

404
Q

What is cholesterol used to make?

A

Steroid hormones
Bile acids
Vit. D.

405
Q

What is DNA metabolism?

A

A set of tightly regulated processes that achieve:
High fidelity of DNA synthesis before cell division
Error checking and repair
Rearrangement of segments within a chromosome or between two DNA molecules, giving offspring a novel DNA

406
Q

What is important about the 3’ end of the growing chain?

A

The 3’ OH is required.
Mg2+ ions nearby make the 3’ OH a more powerful nucleophile.
The pyrophosphate (2 remaining phosphates of a nucleoside) is a good leaving group.
Mg2+ stabilizes phosphate group, Asp (-) charges and other (-) charges.

407
Q

What is malonyl-Co A formed from?

A

Acetyl-Co A and bicarbonate.

408
Q

What is needed for Acetyl-Co A to enter the CAC?

A

Oxaloacetate

409
Q

What is required for initiation of DNA replication?

A

At least 10 different proteins:
DnaA opens duplex at specific sites in origin
Helicase
DnaC allows helicase to bind
HU stimulates initiation
FIS stimulates initiation
Primase synthesizes RNA primers
SSB stabilizes single strands
Topoisomerase
Dam methylase methylates 5’ sequences at oriC

410
Q

What is the benefit of the slower DNA replication as seen in eukaryotes?

A

Avoid mutations.
Slow but multiple origins which help keep things moving.

411
Q

What is the difference in replication cycle regulation in eukaryotes?

A

Regulation is due to cyclin proteins and CDKs.
Cyclins are ubiquinated for proteolytic destruction at the end of the M phase
Multiple origin sites; ARS (autonomously replicating sequences)

Not as dependent on timing because we have external control but more proteins involved.

412
Q

What is the difference in the energy derived from WAT and BAT?

A

WAT electrons enter the ETC and the protons are used to create energy via ATP synthase.

BAT electrons enter the ETC, get carried by NADH & FADH2, but thermogenin facilitates the proton transfer. No ATP made. Energy is disipated as heat.

413
Q

What is the fate of chylomicrons after delivering FAs to the cells?

A

Transported back to liver where any remaining TAGs are either oxidized for energy or used in the synthesis of ketone bodies.

414
Q

What is the function of ABC transporters?

A

To transport large lipid structures across the membrane (sterols)

415
Q

What is the function of Cholesterol ester transfer protein (CETP)?

A

Raises the ratio of HDL:LDL

416
Q

What is the function of topoisomerases in regards to histones?

A

Help with the tension cuased by wrapping around the histone.
Relaxes the (+) supercoil, keeps the Lk down.

417
Q

What is the general process of lipid metabolism?

A
  1. Lipids are emulsified by bile salts into micelles
  2. Lipases breakdown lipids into FAs
  3. FAs are taken up by intestinal mucosa and converted to TAGs
  4. TAGs are incorporated with cholesterol and apolipoproteins into chylomicrons
  5. Chylomicrons move through lymphatic system and blood stream to tissues
  6. Lipoprotein lipase activated by apoC-II in the capillary, converts TAGs to FAs and glycerol
  7. FAs enter cell
  8. FAs are oxidized as fuel or reesterified for storage
418
Q

What is the main form of cholesterol regulation?

A

Feedback inhibition

419
Q

What is the most common therapeutic for preventing plaque formation?

A

Statins.

420
Q

What is the primary fuel for the liver?

A

FAs

421
Q

What is the product of Fatty acid synthase?

A

16 chain palmitate, no intermediates are released.

422
Q

What is the state of chromosome structure in G0 and interphase?

A

Chromatin in randomly dispersed.

423
Q

What is the state of chromosome structure in prophase?

A

Condensed and sister chromatids form.

424
Q

What is unique about DNA metabolism?

A

DNA encodes it’s own metabolism.

425
Q

What isotope was used to prove semi-conservative replication?

A

N15

426
Q

What maintains the condensed chromosome structure?

A

SMC proteins.

427
Q

What molecule (intermediate) is required for biosynthesis of FAs, that is not required for the breakdown of FAs?

A

Malonyl-Co A

428
Q

What molecule can be used to absorb bile acids?

A

Cholestyramine

429
Q

What molecules make DNA dynamic?

A

Transposons

430
Q

What protein therapy shows the best promise for diabetes therapy?

A

GLPs (Glucagon Like Proteins)

431
Q

What regulates B-oxidation?

A

Malonyl-Co A from CAC: stops the carnitine transfer to Fatty Acyl-Co A

432
Q

What regulates FA synthesis?

A

Citrate from CAC promotes Acetyl-Co A carboxylase to change Acetyl-Co A to Malonyl-Co A.
Palmitoyl-Co A feedsback to inhibit formation of Malonyl-Co A.
Glucagon, epinephrine trigger phosphorylation which inhibits formation of Malonyl-Co A.

433
Q

What techniques are used to detect and quantify hormones?

A

Radioimmunoassay
ELISA

434
Q

What tissues release adipokines?

A

Adipose

435
Q

What triggers AMPK?

A

Low [ATP] and increasing [AMP].
Increasing [adiponectin].

436
Q

What type of reaction does a reactase indicate and what is needed?

A

Redox reaction - needs cofactor NADH, FAD, or NADPH

437
Q

What types of LDL modifications are significant in vivo?

A

Carbamylation - promoted by urea, kidney disease and smoking.
Glucosylation - promoted by high blood glucose.
Partial proteolysis - proteases released from macrophages.
Oxidation - ROS released from macrophages, if out of control lipids become oxidated.

438
Q

What were the problems with Avandia and Actos (Thiazolidinediones)?

A

Were supposed to target the receptors that lead to activation of adiponectin gene transcription but:
Avandia causes heart disease
Actos can be carcinogenic

439
Q

When are blood glucose levels usually determined?

A

After several hours of fasting

440
Q

When do we find ketone bodies in the blood?

A

Starvation state.

441
Q

Where are dietary fats absorbed?

A

Through small intestine walls after they are converted to micelles and then broken down by lipases to FAs

442
Q

Where do the carbons for FA synthesis come from?

A

C15 & C16 come from methyl and carboxyl carbons if the Acetyl-Co A used to prime the system.
The rest come from Acetyl-Co A via Malonyl-Co A.

443
Q

Where does cholesterol modification to steroids occur?

A

Mitochondria

444
Q

Where does intiation of replication in E. coli begin?

A

oriC which is 245 bp, highly conserved sequence elements.

445
Q

Where does oxidation of FAs occur in animals?

A

Mitochondrial matrix

446
Q

Where does the body get energy from during starvation?

A

MM degradation provides glucogenic a.a. which either end up as urea or enter CAC.
In CAC oxaloacetate is diverted to gluconeogenesis.
FAs are imported from adipose tissue and converted to Acetyl-Co A but no oxaloacetate to bring Acetyl-Co A into CAC so it builds up.
Acetyl-Co A favours ketone body synthesis, ketones enter blood stream and are used for fuel.
Excess keton bodies are excreted in urine.

447
Q

Where does transcriptional regulation of cholesterol synthesis begin?

A

Endoplasmic recticulum

448
Q

Which current drug for diabetes acts on the AMPK pathway?

A

Metformin

449
Q

Which DNA polymerase has extra functions the others don’t?
What are they?

A

Poly I
5’-3’ exonuclease activity as well as 3’-5’
Moves ahead fo the enzyme and hydrolyzes things in it’s path.
NICK translation.
Klenow fragement.

450
Q

Which group of indigenous people were key in understanding diet influences on diabetes?

A

Pima people

451
Q

Which hormones alter gene expression via nuclear receptors?

A

Steroids.
Vit. D.
Retinoid.
Thyroid hormones.

452
Q

Which ketone builds up the most and fastest in starvation?

A

D-B-hydroxybutyrate.
Yes it can help with epileptic seizures but we don’t want it around any other time.

453
Q

Which organ produces ketone bodies but does not utilize them?

A

Liver.

454
Q

Which type of sugar is highly indicated in obesity?

A

Fructose.

455
Q

Which types of hormones act through GPR & 2nd messengers?

A

Peptide hormones.
Catecholamine hormones.
Eicosanoid hormones.

456
Q

Why do we need proteins to help unwind DNA?

A

Ends cannot act freely, this will change the structure of the strands.
Proteins help unwind without rotation.

457
Q

Why do we need the carnitine shuttle?

A

Because FAs are like detergents and could cause damage to the cell/mitochondrial membranes.
Transport systems ensure there is a uniform headgroup.

458
Q

Why does defect in LDL receptor lead to disease?

A

LDL receptors mediate cholesterol uptake into the cell.
If there is a defect in the LDL receptor, LDL concentrations build up in the blood stream and once concentrations get high enough, causes plaque build up, blood concentration/viscosity.

459
Q

Why is HDL cardioprotective?

A

Macrophages pick up cholesteryl ester droplets and eventually turn into foam cells if they pick up too much.
Foam cell undergoes apoptosis as they continue to gather cholesterol.
Free cholesterol aggregates on the walls of blood vessels causing plaque buildup.
HDL picks up excess cholesterol in the blood stream and on membrane surfaces and takes it back to the liver.

460
Q

Writhe (Wr)

A

Number of coils

461
Q

DNA recombination

A

Segments of DNA can rearrange their location:
Within a chromosome
From one chromosome to another

462
Q

What is DNA recombination used for?

A

Repair of DNA.
Segregation of chromosomes during meisosis.
Enhancement of genetic diversity.

**Recombination and mutations are the 2 driving forces of evolution in sexual organisms.

463
Q

How does recombination affect viruses?

A

Recombination of co-infecting viral genomes may enhance virulence and provide resistance to antivirals.

464
Q

What are the 3 classes of recombination?

A

Homologous/general: exchange between 2 DNAs that share and extended region of similar sequence.

Site-Specific: exchange only at a particular sequence.

DNA transposition: “jumping genes”, short DNAs that can move from one chromosome to another.

465
Q

Describe homologous recombination in bacteria.

A

Replication fork encounters damage in template strand and collapses due to creation of a double strand break.
5’ ending strand is degraded.
3’ strand invades the other replication creating a branched structure with 3 strands.
Branch moves to create Holliday Junction.
Nuclease and Ligase restore the structure of the replication fork.

466
Q

What is important to remember about homologous recombination in meiosis?

A

The x forms that needs to be broken by nucleases and ligated back together.
Used to trace ancestry.

467
Q

How is homologous recombination used in gene mapping?

A

Frequency of homologous recombination between 2 points on a chromosome is proportional to the distance.

468
Q

Potential outcomes of site-specific recombination

A

Inversion or deletion
Intermolecular recombination
Insertion

Remember this only affects certain areas.
Effects can be varied.

469
Q

What can recombinational repair of circular DNA yield?

A

Dimeric genome.

470
Q

What is the role of transposons in bacteria?

A

Recombination:
Direct/simple = Cut & paste
Replicative = Copy & paste

471
Q

What is the most practical application of recombination in humans?

A

Immune response:
Immunoglobulin genes assemble by recombination to produce different antibodies.

472
Q

How does recombination result in such a high number of possible IgG molecules?

A

Both the light chains and heavy chains can undergo recombination.

473
Q

What are the functions of RNA?

A

mRNA
tRNA
rRNA
microRNA play a role in gene regulation
Genomic material in viruses
Ribozymes

474
Q

How are RNAs synthesized?

A

DNA is the template for transcription.
Transcription is tightly regulated to control concentration of each protein.
Processed after synthesis; introns/exons, poly A tail, 5’ cap

475
Q

Describe RNA transcription in E. coli.

A

RNA poly binds to PROMOTER sequence (no primer required).
Nucleoside triphosphate added to the 3’ end of growing RNA strand (like in DNA replication).
Temporarily base pairs with template DNA.
RNA poly generates (+) supercoils ahead which are later relieved by topoisomerases.

476
Q

Discuss RNA polymerase

A

Large enzyme.
No proofreading capability.
Holoenzyme with 5 core subunits and a 6th sigma subunit.
No 3’-5’ exonuclease so has high error rate.

477
Q

Discuss the FOOTPRINTING technique.

A

A way to find a DNA-binding site.

Isolate DNA fragment that you think has a binding site.
Radiolabel the DNA.
Bind a protein that should interact with promoter region to DNA in one tube, keep another as a control.
Treat both samples with agent to cleave DNA.
Separate fragments by gel electrophoresis.
DNA segments with bound protein at promotor sequence won’t be cleaved.

478
Q

How is RNA replication regulated?

A

Mainly through transcription because it is energy intensive.
Regulate affinity of RNA poly for a promoter by:
Promoter sequence
Activator proteins
Repressor proteins

479
Q

What are the 2 types of termination of RNA replication in E. coli?

A

Rho-independent: regions in transcript form a hairpin that stops the RNA poly.

Rho-dependent: needs Rho-protein to stop RNA poly.

480
Q

What are the general classes of enzymes needed for RNA poly to work?

A

Helicase
Kinase

481
Q

Describe the processing of mRNA

A

Many proteins coordinate with each other and proteins involved in RNA transport to ribosome.
Processing includes:
Intron/exons
5’ cap
3’-poly A tail
Degradation

482
Q

What 2 features are unique to mRNA?

A

5’ cap
3’ -poly A tail

483
Q

Discuss the mRNA 5’ cap.

A

Methylguanosine
Protects from nucleases
Forms binding site for ribosome

484
Q

What are the 4 classes of introns?

A

Group I & Group II: self-splicing
Splieosomal: need splicesomes
tRNA introns: cleaved by endonuclease, exons joined by ATP-dependent ligase.

485
Q

Which OH groups are responsible for Group II intron function?

A

Nucleophile = 2’ OH of intron
3’ OH of the 5’ exon acts as the 2nd nucleophile.

486
Q

Discuss spliceosome function

A

Spliceosome made up of snRNPs
snRNP RNA is called snRNA - helps spliceosome get into position.
GU at 5’ and AU at 3’ usually mark sites of splicing.

487
Q

Discuss polyadenylate polymerase.

A

Specific poly that adds A regardless of what it binds to.
Endonuclease breaks RNA at a point so that Poly A can add A tail.
If no poly A tail, no protein because the mRNA will be degraded quickly.

488
Q

Post transcriptional processing of mRNA

A

Bases can be removed/added
Cleave/polyadenylation patterns can vary
IgG heavy chain gene: Many different outcomes
A tail can be modified as well.

489
Q

MicroRNA function

A

Gene regulation:
Bind to specific regions of mRNA to alter translation by cleaving mRNAs or blocking them from translation.

490
Q

Function of reverse transctiptase

A

Makes DNA from RNA
Then degrades the RNA from the DNA-RNA hybrid and replaces it with more DNA.
DNA is then incorporated into host DNA

491
Q

Structure of retroviruses.

A

3 genes plus a long repeat.
gag encodes for six smaller proteins that make up viral core.
pol encodes; protease that cleaves the long peptide made by gag, reverse transcriptase, and integrase.
env encodes viral envelope.
LTR facilitates integration of viral genome into host DNA

492
Q

What 3 reactions does reverse transcriptase catalyze?

A
  1. RNA-dependent DNA synthesis
  2. RNA degradation
  3. DNA-dependent DNA synthesis
493
Q

Why do viruses have a high rate of mutation/evolution?

A

Lack 3’-5’ proofreading

494
Q

How do some retroviruses cause cancer?

A

Some retroviruses contain an oncogene

495
Q

Discuss HIV retrovirus

A

Has genes for killing host (T-lymphocytes), results in suppression of immune system.
Because HIV-encoded reverse transcriptase is error prone it complicates a vaccine.

496
Q

Discuss antiretroviral drugs

A

Reverse transcriptase inhibitors
Protease inhibitors - more effective

497
Q

Discuss retrotransposons in eukaryotes.

A

Mobile genetic elements in eukaryotes.
Encode an enzyme with homology to reverse transcriptase but no env gene so no viral particles.
Move between positions and use enzyme to make DNA from RNA.

498
Q

Discuss Telomeres

A

They are DNA at the ends of eukaryotic chromosomes.
Tandem repeats of TG.
TG strand is longer than it’s complement, extending the end of linear chromosomes.
Not easily replicated via DNA polys becuase there is not template for RNA primer.
They use RNA as a template.

499
Q

Describe the mechanism of telomerase

A

RNA repeat serves as template for synthesis of TG strand of telomere.
Binds to 3’ end of chromosome and hangs off so the RNA template extends.
Telomerase extends teh 3’ end using RNA of enzyme as primer.
Gap is filled by DNA polys.

500
Q

What is the relationship between DNA/RNA/ telomerase

A

DNA is main stroage of info but how long it lasts depends on RNA that dictate the amount of telomerase.

501
Q

Describe SELEX

A

Random RNA/DNA sequences are added to ATP coupled resin.
Sequences that do not bind ATP are discarded.
Sequences that bind ATP are sorted from resin and amplified.
Repeat to get a pool of specific RNA sequences.

502
Q

Which a.a. only have one codon?

A

Met
Trp

503
Q

gRNA

A

guide RNAs that temporarily hybridize with mRNA and act as templates for editing.

504
Q

5 stages of protein synthesis

A
  1. Activation of a.a. - tRNA is aminoacylated, needs activation factors
  2. Initiation of translation - mRNA and aminoacylated tRNA bind to ribosome, needs translation factors.
  3. Elongation - until stop codon, needs elongation factors.
  4. Termination and ribosome recycling - mRNA and protein dissociate.
  5. Folding and post-translational processing - needs variety of enzymes.
505
Q

What are the characteristic features of tRNA?

A

Cloverleaf shape.
Amino acid arm - has a.a. esterified via carboxyl group
Anticodon arm - has anticodon
D arm - contributes to folding
TC arm - contains pseudouridine, helps in folding.

506
Q

Aminoacyl-tRNA synthetases

A

Each one binds a specific amino acid and matching tRNA.

507
Q

Why would some tRNA synthestases have a proof reading function and others not?

A

Proof reading needed if a.a. is similar to another (eg, aliphatic a.a.’s are all similar but histidine is pretty unique).

508
Q

Discuss the second genetic code.

A

a.a-tRNA synthetases must be specific for both a.a. and tRNA.
Matching of the two can be viewed as 2nd genetic code.
Sequence of tRNA helps specify which a.a is going to be attached.

509
Q

How do we know a tRNA is going to attach Ala?

A

G-U at position 70

510
Q

What is the first a.a. in a bacterial peptide?

A

fMet

511
Q

What is the first a.a. in a eukaryotic peptide?

A

Met

512
Q

What else does tRNA tell us about a.a.

A
  1. What a.a should it be acylated with.
  2. If that a.a should be modified.
513
Q

Why is GTP used for making proteins instead of ATP?

A

ATP is used for cellular function. Proteins will end up using ATP later, so we don’t want cross talk between making proteins and using ATP for their function.

514
Q

Discuss the first 3 steps of initiation.

A

1.Small subunit binds intiation factors 1, 2 & 3 and mRNA.
AUG codon is guided to correct position by Shine-Dalgarno sequence.

2&3. fMet binds to P site along with AUG, this causes the large subunit to combine with small subunit forminig the intiation complex.

515
Q

Discuss elongation

A

a.a tRNA binds to elongation factor Tu that carries GTP.
This new complex binds to A site and GTP hydrolysis occurs releasing elongation factor and GDP from ribosome.
a.a from P site is transferred to A site.
Ribosome moves one codon toward the 3’ end of the mRNA, leaving A site open for new a.a. tRNA

516
Q

What is the role of ribose in tRNA?

A

Recognizes the active site.

517
Q

Discuss termination

A

Signalled by stop codon UAA, UAG, UGA.
Stop codon triggers release factors 1, 2 & 3.
RFs hydrolyze terminal peptide tRNA bond, release peptide and tRNA, cause subunites to dissociate.

Need: Stop codon, release factors, termination factors.

518
Q

Describe the function of Puromycin

A

Similar structure to 3’ end of a.a. tRNA
Binds to A site of ribosome (because of sugar) and forms bond with growing peptide.
Can’t participate in translocation and dissociation, so it terminates protein synthesis.
Stops protein from being made and/or stops further elongation. Bacteria has spent energy trying to make pr and keeps trying so no proteins made and all bacterial energy used up.

519
Q

Describe the role of signal recognition particles.

A

Proteins move from site of synthesis to exit cell, become part of membrane or enter subcellular compartment.
Most have signal sequence which gets bound to signal recognition protein (SRP).
SRP/ribosome/RNA complex delivered to ER lumen.
Transport vesicles take pr to GA.
Pr destined for mitochondria/chloroplast bind to chaperone proteins which help deliver.

520
Q

Discuss how proteins are targeted for and imported into the nucleus.

A

Proteins for nucleus have nuclear localization sequence (NLS)
NLS binds to importin and Ran.
This complex docks at a pore and is imported.

521
Q

Where, in a protein, is the NLS located?

A

Middle

522
Q

Where, in a protein, is a signal sequence located?

A

N-terminus.

523
Q

Discuss protein degradation

A

In E. coli, Lon hydrolyzes defective or short-term peptides.

Eukaryotes:
Proteins are linked to ubiquitin (kiss of death) via:
activating enzyme E1
conjugating enzyme E2
ligating enzyme E3
Ubiquinated proteins are cleaved by a 26 proteasome complex.

BioChem (2 decks)

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