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SPM (ARSH) > Weeks 1-4 > Flashcards

Weeks 1-4 Flashcards

1
Q

What are the three phases of polymerization for cytoskeleton?

What is dynamic instability?

How do kinesin and dynein play a role?

Name a disease associated with cytoskeleton.

A
  • 3 phases of polymerization
    • Nucleation: assembly of monomers
    • Elongation: rapid growth at (+) end
    • Steady-state: equal rate of polymerization and de-polymerization
  • Dynamic instability: rapid de-polymerization to cause separation of mitotic spindle.
  • Polymerization and de-polymerization occurs at (+) end and nucleation occurs at (-) end
    • Kinesin moves things to (+) end {cell surface is +}
    • Dynesin walks things back to (-) end {centrosome is -}
  • Disease: Hereditary Spherocytosis
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2
Q

Where do clathrin coats, COP I coats, and COP II coats transport to and from?

A

Clathrin

  • Transport: PM to early endosomes and Golgi to lysosomes

COP I

  • Transport: Golgi to PM and Golgi to ER

COP II:

  • Transport: From ER to Golgi
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3
Q

What is the assembly process of clathrin coats?

A
  • Arf-GEF recruits Arf-ADP → Arf-ATP → inserts into membrane → fatty acid tail exposure → clathrin recruitment → dynamin pinches off vesicle using accessory proteins and PIP2
  • Phorsphorylation of PIPs to PIP2s are also involved in recruitment
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4
Q

What is the disassembly process of clathrin coats?

A
  • Heat shock protein (Hsp70) is an ATPase stimulated by Auxilin → ATP hydrolyzes into ADP → Hsp70 uses energy from ATP hydrolysis to peel off coat
  • PIP2s are dephosphorylated to PIPs weakening coat-membrane interactions
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5
Q

What is the COP I assembly process?

A
  • Arf-GEF recruits Arf-ADP → Arf-ATP → inserts into membrane → fatty acid tail exposure → COPI recruitment → dynamin pinches off vesicle using accessory proteins and PIP2
  • Phorsphorylation of PIPs to PIP2s are also involved in recruitment
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6
Q

What is the COP I disassembly process?

A
  • Heat shock protein (Hsp70) is an ATPase stimulated by Auxilin → ATP hydrolyzes into ADP → Hsp70 uses energy from ATP hydrolysis to peel off coat
  • PIP2s are dephosphorylated to PIPs weakening coat-membrane interactions
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7
Q

What is the COP II assembly process?

A
  • Sar1-GEF recruits Sar1-GDP → Sar1-GTP → inserts into membrane → fatty acid tail exposure → COPII recruitment → dynamin pinches off vesicle using accessory proteins and PIP2
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8
Q

What is the COP II dissassebly process?

A
  • Heat shock protein (Hsp70) is an ATPase stimulated by Auxilin →ATP hydrolyzes into ADP →Hsp70 uses energy from ATP hydrolysis to peel off coat
  • PIP2s are dephosphorylated to PIPs weakening coat-membrane interactions
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9
Q

What is the function, structure of SNARE proteins, and the fusion process?

A
  • Function: acts as tethers to bring membranes together for fusion; this is a Ca++ dependent process
  • Structure
    • V-SNARE (transport vesicle made up of one polypeptide chain)
    • T-SNARE (target membrane made up of three polypeptide chains)
  • Fusion Process
    • T-SNARE traps V-SNARE
    • Energy from four helix bundle drives membrane fusion
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10
Q

What is the disassembly process of SNAREs?

A
  • NSF (i.e. NEM sensitive factor) and accessory proteins react with two cysteine residue to block activity
    • Hydrolyzes ATP to destabilize four-helix bundle
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11
Q

What is the process of RAB GTPases?

A
  • Rab-GEF (could be a SNARE or tether) recruits Rab-GDP on donor membrane → Rab-GTP → Rab-GTP inserts into donor membrane → transport vesicle/budding forms/occurs → Rab effector binds Rab-GTP → fusion → Rab-GDP
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12
Q

What is the transport mechanism for lysosomal hydrolase?

A
  • Acid hydrolases are only active at low pH
    • Vacuole ATPase pumps H+ against gradient into lysosome
  • M6P is used to tag lysosomal hydrolase precursors from ER in the Golgi
  • M6P binds to M6P receptor in Golgi → early endosome → lysosome through Clathrin
  • Addition of GlcNAc-P to M6P in the early endosome to release hydrolase precursor
  • M6P receptor is recycled back to Golgi
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13
Q

What are the properties of amino acids and what are the amino acids under each property?

A

Non-Polar AAs

  • GAVLIMP WF – “GAVin LIMPed with Warm Fingers”
    • Glycine, Alanine, Valine, Leucine, Isoleucine, Methionine, Proline, Tryptophan, Phenylalanine

Polar

  • STCYNQ – “SomeTimes Cats Yell Not Quietly”
    • Serine, Threonine, Cysteine, Tyrosine, Asparagine, Glutamine

Charged

  • DEKRH – “Dumb Evil Kings Rule Hell”
    • Aspartate, Glutamate, Lysine, Arginine, Histidine
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14
Q

What effect do increases and decreases in pH, DPG, and temperature have on oxygen binding curves?

A
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15
Q

What is a competitive inhibitor and how does the lineweaver-burk plot look like?

A
  • Competitive
    • Competes with substrate at active site to bind enzyme
    • Inhibitors have structures similar to the substrate or product
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16
Q

What is non-competitive inhibition and what is the lineweaver burk plot for it?

A
  • Inhibitors bind to free E and ES at same affinity
  • Can also be called a “mixed” inhibitor as it is both a competitive and non-competitive inhibitor
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17
Q

What is uncompetitive inhibition and what is the lineweaver burk plot for it?

A
  • Uncompetitive
    • Inhibitors bind only to the ES complex and block product formation
    • Increase substrate affinity
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22
Q

Describe how amyloid fibrils form in protein folding diseases. What are the two types that were discussed?

A
  • The amyloid itself is toxic where ever it accumulates.
  • In AL, the many different light chains of an AB are misfolded and aggregate together to form amyloid fibrils.
  • Familial transthyretin amyloidosis is caused by misfolded transthyretin monomers that denature and aggregate into amyloid.
  • Mechanistically, the growth of the amyloid fibril can break cell membranes and kill cells due to its rigid “cross-bridge structure”.
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23
Q

What is the preganglionic receptor and its transmitter in the sympathetic nervous system?

What are the agonists and antagonists?

A
  • Nicotinic (ACh) [NN]
  • Agonist: nicotine
  • Antagonist: curare
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24
Q

What is the agonist and antagonist to muscarinic receptors?

A
  • Agonist: muscarine
  • Antagonist: atropine
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25
Q

What are the agonists and antagonists to adernergic receptors?

A
  • Agonists: NE, EPI
  • Antagonists: Proponolol (B1/B2 nonspecific blocker)
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26
Q

What are the 3 types of Phase I biotransformation reactions and what do they do?

A
  • Oxidation: CYP P450 are important oxidative enzymes occurring in the ER of liver cells; susceptible to induction and inhibition
    • RH (active drug) + O2 + NADPH + H+ → ROH (polar drug metabolite) + H2O + NADP+
  • Reduction: favors certain chemical groups (ex: nitro group); carried out by CYP enzymes
  • Hydrolysis: uses water to break the parent drug into smaller pieces; carried out by CYP enzymes (ex: esterases)
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27
Q

What are the two main types of Phase II reactions and how do they work? What are the other four kinds of reactions possible?

A
  • Glucuronidation: many side-groups (i.e. hydroxyl group) can be glucuronidated by UDPGA (uridine diphosphate glucuronic acid) to become more polar
  • Glutathione Conjugation: glutathione readies drugs for excretion by binding to an intermediate (when glutathione is used up, necrosis of liver occurs)
  • Sulfation
  • Acetylation
  • Methylation
  • Glycine conjugation
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28
Q

What are the factors (6) that impact hepatic clearance and the significance of those factors on drug elimination.

A
  • First pass effect: only fraction of drug reaches bloodstream after oral intake (bioavailability)
  • Hepatic blood flow: increased blood flow increases clearance
  • Free drug: binding of drug to plasma proteins (ex: albumin) → less free drug to be excreted
  • Enzyme inhibitors/inducers: P450 inducers can increase excretion
  • Enterohepatic Recirculation: estrogen is often glucuronidated in liver → bile duct → sugar is cleaved by gut bacteria in GI → estrogen is re-circulated in body
  • Extraction Ratio: value close to 1 suggests efficient clearance by an organ; value close to 0 suggests inefficient clearance
    • E = (Ca – Cv) / Ca
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29
Q

What is

  • glomerular filtration
  • tubular secretion
  • tubular reabsorption

and how do they impact renal elimination of drugs?

A
  • Glomerular filtration: free drug passively diffused into renal tube
    • Limited by size
    • Creatinine is used as measure of renal function (not reabsorbed or secreted)
  • Tubular reabsorption: lipid-soluble drugs renter bloodstream (can be passive/active)
    • Acidifying urine (aka: vitamin C) causes acidic drugs to be reabsorbed and vice-versa for basic drugs
  • Tubular secretion: active transport (or secretion) from blood to tubules after glomerulus with saturation kinetics
    • Para-aminohippuric acid (PAH) is used as measure since it is completely filtered and secreted
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30
Q

What is the difference in Area Under the Curve (AUC) between PO and IV in the context of bioavailability.

A

PO has less AUC compared to IV because IV is injected directly into blood, therefore having less bioavailability

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31
Q

Apply pharmacokinetic principles to make predictions about:

  • how dose affects duration of action
  • how changes to clearance
  • or volume of distribution

affect half-life, etc.

A
  • Lower dose → lower drug concentration → low duration of action
  • Increasing Vd → increases half-life because greater [drug] in body requires elimination (50% of present drug is eliminated each half-life)
  • Increasing Clearance → lowers half-life because less [drug] in body requiring elimination (50% of present drug is eliminated each half-life)
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32
Q

Apply knowledge from ADME lectures to describe elements that can alter a drug’s pharmacokinetic properties.

ADME: Absorption, Distribution, Metabolism, Elimination

A
  • Absorption
    • Increased absorption → increased Vd → increased half-life
  • Distribution
    • Increased tagging → increased reservoirs → decreased [drug plasma] → increased Vd → increased half-life
  • Metabolism (biotransformation)
    • Increased hepatic blood flow → increased biotransformation → Increased polarity → increased plasma solubility → increased elimination
  • Elimination (clearance)
    • Increased renal blood flow → increased secretion → increased elimination
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33
Q

Define/describe potency.

A
  • A comparative term to compare drugs that work through the same mechanism (same maximal effect, shape of curve, and slope)
    • A more potent drug has lower KD
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34
Q

Define/describe tachyphylaxis.

A

Unexpected physiological response due to desensitization (in presence of agonists).

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35
Q

Describe pharmacodynamic changes that occur with aging.

A
  • Changes in
    • [Drug at receptor]
    • Receptor numbers
    • Receptor affinity
    • Post-receptor alterations
  • Increased “sensitivity” to drugs (especially anti-cholinergics and CNS drugs)
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36
Q

What are the different lines/bands of the sarcomere?

A
  • Z-line – anchor of actin
    • Separate sarcomeres in series
  • A-band – length of myosin and includes overlap of actin
    • Does not change length
  • I-band – actin only
    • Shrinks during contraction
  • H-band – area where myosin filaments are not overlapped with actin filaments
    • Shrinks during contraction
  • M-line – anchor of myosin
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37
Q

Define the steps in excitation-contraction coupling in skeletal muscle.

A
  1. Action Potential Travels into T-tubules
  2. L-Type Ca++ Channels Open
  3. Direct Coupling Between L-Type Channel and RyR causes Ca++ release from SR
  4. Ca++ stimulates contraction – most of the Ca++ that actually stimulates contraction is from the SR (as opposed to the Ca++ coming in through the L-Type Ca++ channels)
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38
Q

How is calcium-induced calcium release different than mechanical-induced calcium release?

A
  • Calcium Induced Calcium Release – in cardiac myocytes, RyRs are ligand-gated, requiring calcium to bind in order to release calcium
  • Mechanical Induced Calcium Release – in skeletal muscle, RyRs are voltage-gated, sensing conformational change in L-type calcium channel due to depolarization, releasing calcium
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39
Q

What are the steps in the myosin ATPase cycle?

A

ATP binds → myosin head detaches from actin → ATP hydrolyzes on myosin head into ADP + Pi → myosin head goes back to cocked position (“recovery stroke”) → myosin cross-bridges with actin → phosphate group is released → power stroke (“working stroke”) causes filaments to slide past each other → ADP released (rate-limiting step) → ATP binds

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40
Q

How are intracellular calcium levels maintained by the SERCA pump and plasma membrane pumps?

A

SERCA pump uses ATP hydrolysis on SR and NCX/NKX (sodium-calcium/sodium-potassium exchange) system on sarcolemma compete for Ca++ reuptake

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41
Q

How does calcium activate the actin thin filament with the three different toponin molecules and tropomyosin in skeletal muscle?

A
  • Troponin C – binds calcium, causing conformational change allowing actin to bind to myosin
  • Troponin I – covers the myosin binding site
  • Troponin T – binds tropomyosin and TnC
  • Tropomyosin – string-like protein that binds actin molecules
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42
Q

Define the structural, enzymatic, and functional features of the three major categories (fast-glycolytic, fast-oxidative-glycolytic, and slow-oxidative fiber types) of skeletal muscle fiber types.

A
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44
Q

What are the steps in muscle repair?

A
  1. Degeneration Phase: Injured fibers undergo rapid necrosis and degeneration – due to influx of Ca++ and activation of proteolysis
  2. Inflammatory Phase: Necrotic fibers activate an inflammatory response – invasion by inflammatory cell populations
  3. Regeneration Phase: Satellite cell (muscle stem cell) activation allows for regeneration of fibers – controversial how they are activated to differentiate into a muscle cell
    1. Can be altered by sarcopenia – muscle atrophy due to aging
  4. Remodeling/Repair Phase: is characterized by a maturation of the regenerated fibers, remodeling of the extracellular matrix, recovery of functional performance of injured muscle.
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45
Q

What are the steps of action in gap junction in cardiac myocytes?

A
  1. AP electrically stimulates the first cell – Na+ ions flow into the cell to depolarize
  2. Na+ also flows into the adjacent cell – they are attracted by the more negative ions in the adjacent cell as well as the low concentration of Na+ in the adjacent cell (down concentration gradient)
  3. The extracellular current is the capacitive current – the positive ions from inside repel the positive ions near the extracellular surface of the cardiac muscle cell – the positive extracellular ions move back toward the original cell (cell A)
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46
Q

What are the two phases of contraction.

A
  • Phase 1: Tension Development – build up of passive elastic forces not yet high enough to move the afterload
  • Phase 2: Muscle Shortening – when tension can overcome afterload → muscle shortens
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48
Q

Describe the differences in actomyosin regulation of smooth and skeletal muscle and indicate the structural similarities in their respective contractile units.

A
  • Activity in skeletal muscle is regulated by troponin C uncovering myosin binding sites on actin, whereas smooth muscle regulates MLCK and
  • Slow tension development – the kinase activity is slower than diffusion of Ca++ to troponin/tropomyosin in skeletal muscle
  • The smooth muscle system allows for a graded control of muscle tension – the percentage of myosin crossbridges activated is directly proportional to muscle tension
  • The response is more graded and not all-or-none like skeletal muscle, different amounts of Ca++ produce different levels of muscle tension
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49
Q

What is the equation of bioavailability?

A
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50
Q

What are the equations for loading dose?

A
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51
Q

What are the maintenance dose equations?

A
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52
Q

What are the equations for Ke and half life?

A
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53
Q

What is the clearance equation in terms of Vd and half life?

A
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54
Q

What is the Ct equation in terms of C0?

A
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55
Q

What are the equilibrium concentrations of Na+, Ca2+, Cl-, K+?

A
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56
Q

Diagram the two intracellular pathways that control contraction and relaxation in smooth muscle.

A
  • Contraction using Myosin Light Chain Kinase (MLCK)
    • 4 Ca++ ions bind Calmodulin → activates MLCK → MLCK phosphorylates myosin regulatory light chain (RLC) → activating myosin
    • Is stretch-induced contraction and is not dependent on nerve stimulation
  • Relaxation via Latch Bridge Mechanism
    • The latch bridge occurs when there is an intermediate level of phosphorylation (and calcium) of the smooth muscle myosin regulatory light chain. Relaxation will occur when all of the RLC becomes dephosphorylated which will occur when the calcium levels drop to near baseline.
    • Reducing [Ca++] → inactivates MLCK
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57
Q

Distinguish between electromechanical coupling and pharmacomechanical coupling.

A
  • Electromechanical Coupling
    • Voltage-gated L-type calcium channel can activate RyR by calcium-induced calcium release
  • Pharmacomechanical Coupling
    • GCPR can activate IP3, allowing IP3 to bind to SR receptor to release Ca++ from SR without depolarization
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58
Q

Hereditary Spherocytosis

A
  • Description: Disease of the cytoskeleton. Type of hemolytic anemia.
  • Mechanism: Defects in spectrin → loss of membrane stability.
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59
Q

Hutchinson Gilford Progeria Syndrome

A
  • Description: Disease of the nucleus.
  • Mech: Accelerated aging due to lack of synthesis of Lamina A (DNA/RNA synthesis)
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60
Q

Lysosomal Storage Disease (Tay-Sachs, Krabbe, Gaucher)

A
  • Description: Seizures, developmental delay, movement disorders
  • Mech: lack function of one or more lysosomal hydrolase → undigested material accumulates causing swelling → major impact on neuronal cells
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61
Q

Lufts Disease

A
  • Description: weakness, excessive perspiration, increased basal metabolic rate, high caloric intake without increase in body weight
  • Mechanism: Caused by defect in mitochondrial oxygen utilization → uncoupling of oxidative phosphorylation
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62
Q

Age Related Degenerative Diseases (Parkinson and Alzheimer)

A
  • Description: Disease of the mitochondria.
  • Mech: formation of free radicals (superoxides) that cause DNA damage
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63
Q

Zellweger Syndrome Spectrum

A
  • Description: Disease of the peroxisome.
  • Mech: Mutated PEX gene → inability to import proteins → impaired B-oxidation → increase in FAs
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64
Q

Dyskinesia (Kartagener’s Syndrome)

A
  • Description: Disease of the cilia/flagella.
  • Mech: Defect in motility of cilia → infections in mucus lining
  • Note: May cause infertility in male. Think sperm.
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65
Q

Tay-Sachs

A
  • Description: effects mostly nerve cells in the brain and spinal cord.
  • Mech: The lysosomal hydrolase not present is hexosaminidase A and therefore GM2 ganglioside does not get broken down. GM2 ganglioside is important in nerve cells.
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66
Q

Neiman Pick

A
  • Description: This disease mostly impacts neuronal cells but also causes enlargement of liver and spleen.
  • Mech: effects sphingomyelin forming cells, accumulation of sphingomyelin because of lack of sphingomyelinase. The sphingomyelin accumulates in lysosomes and results in cell death.
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67
Q

Gaucher

A
  • Description: most prevalent LSD. Not just nerve cells altered (liver, spleen, white blood cells, kidney, bone marrow).
  • Mech: A deficiency in glucocerebrosidase which results in the accumulation of sphingolipids
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68
Q

I-Cell Disease

A
  • Description: Very severe because all lysosomal hydrolases are not localized to the lysosome and instead are secreted outside the cell. Many cell types altered.
  • Mech: problem with the targeting of lysosomal hydrolases to the lysosome. Tagging with mannose-6-phosphate is disrupted.
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69
Q

Von Gierck’s Disease

A

Description: Severe hypoglycemia and weakness

Mechanism: deficiency in glucose-6-phosphatase (type 1a) or G6P transporter (type 1b) so glucose cannot be mobilized from liver

Treatment: Manageable through diet

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70
Q

Malignant Hyperthermia

A

Description: Increased temperature due to increased metabolic activity.

Mech: Mutated RyR is sensitive to anesthetic, causing extended opening of RyR, leading to increased hydrolysis of ATP

Treatment: RyR blocker

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71
Q

Pompe’s Disease

A

Description: heart enlargement leading to cardiac arrest by age 2; autosomal inherited

Mechanism: lose alpha(1-4) glucosidase activity in lysosomes leading to increased levels of glycogen accumulation in many tissues

Treatment: no treatment

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72
Q

Cori’s Disease

A

Description: hypoglycemia weakness

Mechanism: deficiency in debranching enzyme leads to short outer branches with non-reducing ends

Treatment: glucose infusion

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73
Q

Andersen’s Disease

A

Description: liver failure and death

Mechanism: deficiency in branching enzyme leading to long

Treatment: no treatment just death

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74
Q

McArdle’s Disease

A

Description: painful cramps because muscle can not utilize glucose

Mechanism: muscle phosphorylase deficiency → cannot degrade glycogen

Treatment: liver is unaffected so mild disease

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75
Q

Her’s Disease

A

Description: nothing notable

Mechanism: mild liver phosphorylase deficiency → cannot degrade glycogen

Treatment: complete liver phosphorylase deficiency is lethal

76
Q

Refsum’s Disease

A
  • Description: build up of long branched FAs which accumulate in the blood and disrupt function of neurons – attack myelin
  • Mechanism: lack peroxisomal hydroxylating enzyme and leads to the accumulation of phytanic acid
  • Treatment: change diet
77
Q

Deficiencies in Acyl -CoA dehydrogenases

A
  • Description: lethargy, edema, cardiac failure. Deficiencies in these enzymes can be fatal. Different enzymes for different length FAs. (VLCAD, LCAD, MCAD, SCAD). Can lead to SIDS when babies sleep at night because cannot metabolize FAs.
  • Mechanism: lack of the enzyme means those affected can’t metabolize FAs
  • Treatment: screening for MCAD for neonates
78
Q

How are sugars digested and absorbed? What molecule do they need to be catabolized to?

A
  • All sugars are reduced to monosaccharides
  • This allows for transport across a membrane (dissaccharides cannot be transported)
79
Q

How does the SGLT1 channel function? Where is it located?

A
  • The Na+-glucose symporter (SGLT1) functions exclusively in the intestinal epithelial cells to draw glucose in from the gut lumen and pass it into the blood
    • Uses the concentration gradient of sodium to provide energy
81
Q

What are the irreversible steps in glycolysis?

A
  • Glucose → Glucose-6-Phopshate
  • Fructose-6-Phosphate → Fructose 1,6 bisphosphate
  • Phosphoenolpyruvate → pyruvate

All of these have steep -ΔG values.

82
Q

Compare and contrast hexokinase and glucokinase.

A

Hexokinase

  • Used in all tissues (including liver)
  • Nonspecific (can reduce any molecules)
  • Low Km (if satrurated, reaction cannot continue)
  • Inhibited by product (G6P

Glucokinase

  • Liver only
  • Only works on glucose
  • High Km (everything is phosphorylated as soon as glucose enters)
  • No inhibition
83
Q

At what step in gluconeogenesis is the pathway regulated?

A
  • Fructose 1,6-bisphosphate converted to fructose 6-phosphate by fructose 1,6-bisphosphatase (FBPase-1)
    • Inhibited by: AMP, F26BP
      • PFK-2/FBPase-2 complex creates F26BP
      • F26BP ensures that PFK-1 and FBPase-1 are not active at the same time.
84
Q

How does the Cori Cycle maintian glucose availability in the blood?

How might it be related to muscle cramps?

A
  • Glucose in muscle cells is used for energy and metabolized into lactate
  • Lactate is transferred by a transporter via bloodstream to the liver and converted back into glucose through gluconeogenesis
  • Lactate builds up to quickly in the muscle cells → decrease in pH → muscle cramps
85
Q

How is glycogen degraded in the body?

A
  • Glycogen phosphorylase cleaves an alpha 1,4 linkages creating one glucose molecule (G1P)
    • G1P to G6P by phosphoglucomutase
  • Debranching Enzyme
    • Transferase activity: transfers last 3 alpha 1,4 linked molecules from one branch to another
    • Glucosidase activity: cleaves an alpha 1,6 linkages creating one glucose molecule
86
Q

How is the TCA cycle regulated?

A
  • Inhibiton: ATP and NADH
  • Activation: Ca++, AMP, ADP
87
Q

How is glycogen synthesized?

A
  • Formation of UDP-glucose catalyzed by UDP-glucose pyrophosphorylase
  • Addition of a glucose residue to glycogen catalyzed by glycogen synthase
89
Q

Where does insulin originate from and what is its chemical nature?

A
  • Beta-cells of the pancreatic islets
  • Chemical Nature
    • Pre-prohormone synthesized on rough ER
    • “Pre” domain directs molecule into the ER – it is cleaved from pro-insulin
    • “Pro” domain (C peptide) organizes disulfide bonds
    • “Pro” domain is cleaved in trans-Golgi, yielding insulin
    • “Pro” domain is packaged in same vescile for exocytosis
90
Q

Where does glucagon originate from and what is its chemical nature?

A
  • Alpha-cells of the pancreatic islets
  • Chemical Nature
    • Synthesized as pro-glucagon
    • “Pro” domains have functional properties in GI tract and brain
    • In intestinal cells, several exons of the glucagon gene are incretins (cause release of insulin)
91
Q

Where does somatostatin originate from and what is its chemical nature?

A
  • Delta-cells of the pancreatic islets
  • Somatostatin and prosomatostatin are active
92
Q

Where does amylin originate from and what is its chemical nature?

A
  • Beta-cells of the pancreatic islets
  • Synthesized as a small precursor
93
Q

Function of somatostatin?

A

Somatostatin slows everything and inhibits glucagon and insulin release

94
Q

Function of amylin?

A

Amylin complements insulin by sensitizing cells to insulin

95
Q

What is the process that takes place in Complex I of the Electron Transport Chain?

  • What is Complex I called?
  • How many H+ pass into the intermembrane space?
A

Complex I – NADH Dehydrogenase

  • NADH + H+ → NAD+
  • A hydride ion (H-) is donated from NADH to FMN where 2 electrons pass onto a series of Fe-S centers
  • The preceding 2 electrons at the FMN pushes the electron at each Fe-S center separately via “tunneling” (wave function of quantum mechanics)
  • The last Fe-S center pushes an electron to the ironsulfur protein N-2
  • Electron transfer from N-2 to ubiquinone (Q) forms (QH2) along with 2 H+
  • 4H+ pass to intermembrane space (per NADH)
96
Q

What is the process that takes place in Complex II of the Electron Transport Chain?

  • What is Complex II called?
  • How many H+ pass into the intermembrane space?
A

Complex II – Succinate Dehydrogenase

  • FADH2 → FAD + 2e- + 2H+
  • FADH2 is oxidized to FAD, donating 2e- and 2H+ to Fe-S complexes, pushing the electron at each Fe-S center separately via “tunneling” (wave function of quantum mechanics)
  • Electron transfer from last Fe-S center to ubiquinone (Q) forms (QH2)
  • FAD has less negative reduction potential than NAD+, therefore FAD’s electrons have lower energy potential
97
Q

Where does Ubiquinol transfer from and to in the electron transport chain? Why does this occur?

A

Ubiquinol Transfer from Complex I and II to Complex III

  • Hydrophobic molecule, so it moves through plasma membrane by planar diffusion to complex III
98
Q

What is the process that takes place in Complex III of the Electron Transport Chain?

  • What is Complex III called?
  • How many H+ pass into the intermembrane space?
A

Complex III – Cytochrome Reductase

  • 2 QH2 molecules donates 2 electrons each to complex III
    • One electron → Heme(b) → Heme(b) → Free Q at QN or QP → free radical Q
      • The free radical Q is reduced back to QH2 with second electron following QN or QP path (and is used again)
    • One electron → Fe-S center (Rieske Fe-S Protein) → Heme(c) → Heme(c) on Cyt C → Cyt C
      • The second electron following this path forms second Cyt C (which is why we need 2 NADH to form the 4 Cyt C to be used in complex IV)
  • 4H+ are pumped into intermembrane (per NADH)
99
Q

What is the process that takes place in Complex IV of the Electron Transport Chain?

  • What is Complex IV called?
  • How many H+ pass into the intermembrane space?
A

Complex IV – Cytochrome C Oxidase

  • This complex requires 2NADH molecules to get the 4e- required to reduce O2
  • Four cytochrome c molecules each bring an electron to complex IV
  • Electron flows to CuA → Fe-Cu Center (aka Heme a) → Heme a3-CuB → O2 → 2H2O
  • 3 protein subunits critical to electron flow
  • 2H+ are pumped into intermembrane space per NADH (4 to complete process)
100
Q

What is the transport process for fatty acids from the cytosol into the matrix of the mitochondria?

A
  1. Acyl-CoA Synthetase – an outer mitochondrial membrane enzyme – converts FAs into fatty acyl-CoA using ATP
  2. Carnitine acyl transferase I (CPTI) transfers the FA via carnitine, forming acylcarnitine (removes CoA)
  3. Acylcarnitine is transferred across inner membrane with the translocase enzyme on the inner mitochondrial membrane
  4. Carnitine acyl transferase II (CPTII) transfers the FA back to fatty acyl-CoA and carnitine is restored to the intermembrane space
101
Q

What are key inhibitors in the four electron transport chain complexes?

A

Complex I (one)

  • Rotenone – causes an increase [NADH]

Complex II

  • Carboxin – causes an increase [QH2]

Complex III

  • Antimycin A – cause a block in electron flow from heme b to Q, binds at QN (An-3-mycin)
  • Myxothiazol – cause a block in electron flow from QH2 to the Rieske iron-sulfur protein, binds at QP

Complex IV (CO/CN - 4 letters)

  • Cyanide – binds to heme A3 preventing transfer of electrons to O2
  • Carbon Monoxide – binds to heme A3 preventing transfer of electrons to O2
102
Q

How are the main fatty acids absorbed by the intestine and then transported to the adipocyte?

A
  1. Fats ingested
  2. Bile salts emulsify fats, forming micelles
  3. Intestinal lipases degrade triacylglycerols into glycerol and free FAs
  4. Free FAs taken up by mucosa and converted back into triacylglycerols in intestinal epithelial cells
  5. Triacylglycerols, cholesterol, and apolipoproteins form chylomicrons
  6. Chylomicrons move through lymphatic system and bloodstream to tissues
  7. Lipoprotein lipases is activated by apoC-II in capillaries releases FAs and glycerol
  8. FAs enter cells
  9. FAs are oxidized as fuel or converted back to triglycerides for storage
104
Q

What is the general reaction sequence of beta oxidation?

  • How many ATP are generated?
A

Reaction Sequence

  1. Oxidation that creates FADH2
  2. Hydration
  3. Oxidation that creates NADH
  4. Thiolysis → results in FA with 2 less carbons

ATP Generated – 2.5 ATP per NADH and 1.5 per FADH2 are created in each step

105
Q

What is the basic mechanism for synthesis of fatty acids?

A
  1. Acetyl-CoA goes to Malonyl-CoA via acetyl-CoA carboxylase (key regulation prior to fatty acid synthase)
  2. Malonyl-CoA goes to Palmitate via Fatty Acid Synthase (adds two carbons at a time via NADPH reactions)
106
Q

What are the control points in fatty acid synthesis?

A

Control Points by Acting on Acetyl-CoA Carboxylase

  • FA synthesis turned on/degradation turned off by:
    • Citrate, insulin, thyroid hormone, high carbohydrate diet, prolonged increased insulin levels
107
Q

What are the control points for fatty acid degradation?

A

Control Points by Acting on Acetyl-CoA Carboxylase

  • FA degradation turned on/synthesis turned off by:
    • Epinephrine, glucagon, palmitoyl-CoA, fasting, high fat diet
108
Q

What is the rate limiting step for cholesterol synthesis?

A

HMG-CoA Reductase Is Rate-Limiting Step of Cholesterol Synthesis

109
Q

How is HMGCoA reductase regulated?

Inhibition of enzyme?

Stimulation?

A
  • Inhibited by: high cholesterol, phosphorylation of AMP dependent-kinase (senses high [AMP], glucagon, epinephrine, statin
  • Stimulated by: insulin
110
Q

What are the other products of intermediates (isopreniod precursors) of the cholesterol pathway? (4)

A
  • coenzyme Q – used in ubiquinone synthesis (ETC) – can lead to muscle soreness
  • Isoprenyl – used in tRNA synthesis
  • Farnesyl
  • Geranyl
111
Q

What are 3 products of synthesis pathways involving cyt. P450s and cholesterol?

A

Vitamin D

BIle Acids

Steriod hormones

112
Q

What is LCAT in relation to HDL?

A

Catalyzes esterification of 2/3 of plasma cholesterol

  • Nascent HDL → Mature HDL
113
Q

Fuction of ApoE and on what lipoproteins?

A

Function: Mediates remnant uptake.

(Everything Except LDL)

LP: Chylomicron, Chlyomicron remnants, VLDL, IDL, HDL

114
Q

Fuction of ApoA-1 and on what lipoproteins?

What would a mutation to this cause?

A

Function: ApoA-1 Activates LCAT

LP: Chylomicron, HDL

Mutation: Poor HDL function

ApoA1 R173C mutation: patients have reduced HDL levels, however, patients are protected from heart attacks. HDL increase their rate of clearance due to low numbers.

115
Q

Fuction of ApoC-II and on what lipoproteins?

A

Function: Lipoprteins lipase (Cofactor that Catayzes Cleavage)

LP: Chylomicron, VLDL, HDL

116
Q

Fuction of ApoB-48 and on what lipoproteins?

A

Function: Mediates chylomicron secretion into lymphatics

LP: Chylomicron,Chylomicron remnants

117
Q

Fuction of ApoB-100 and on what lipoproteins?

A

Function: Binds LDL receptor

LP: VLDL, IDL, LDL

118
Q

Identify the source of the fatty acid precursor for eicosanoid synthesis

A

Most eicosanoids are synthesized from arachidonic acid, which has 20 carbons

119
Q

Describe the role of cyclooxygenase in the synthesis of prostaglandins

A

Two separate reactions on same enzyme.

First cyclooxygenase reaction to make PGG2, then peroxidase reaction to make PGH2, which is substrate for further reactions

PGH2 is the precursor to all the prostaglandins in the body

120
Q

How do inhibitors of COX1 and COX2 work?

A
  • Inhibitors of COX1&2: aspirin and NSAIDs (most pain drugs like ibuprofen)
    • Aspirin: Acetylation of the serine results in the irreversible inactivation of PGH synthase.
  • NSAIDs inhibit PGH synthase by interacting with the hydrophobic active site thereby blocking its reaction with substrate.
  • Tylenol (acetaminophen) not an NSAID. Blocks COX enzymes but not inflammation. Acts in CNS.
121
Q

Describe leukotriene chemistry and pharmacology

A
  • Leukotrienes are characterized by the presence of 3 conjugated double bonds.
  • Longer half-life than other eicosanoids.
  • Cause contraction of vascular, respiratory, and intestinal smooth muscle.
  • Leukotrienes can activate CysLT1 receptors on airway smooth muscle cells (SMC) and postcapillary venule endothelial cells to cause bronchoconstriction and edema.
    • Singulair and Accolate block this binding step.
122
Q

Describe the maintenance of the pools of amino acids required for protein synthesis. (in terms of KM)

A
  • KM of aminoacyltransferases is low and therefore prefers to charge tRNA to attract AAs
    • Degradation has high KM, or low affinity
    • tRNA formation has low KM, or high affinity, favoring protein synthesis
123
Q

Describe why some AAs are essential while others are nonessential.

A
  • Essential AAs cannot be synthesized or the body cannot make them in sufficient quantities
    • R MLK had HIV WTF
  • Nonessential are synthesized in appropriate quantities by the body
124
Q

What is the relationship of most nonessential AAs to common intermediary metabolites.

A
  • The carbon skeletons of the nonessential amino acids are largely related to common intermediates of metabolism [consider alanine and pyruvate. The reason that the essential amino acids are essential is that we cannot make their carbon skeletons]
125
Q

What is the general equation for creating different metabolites from AAs?

What is the cofactor?

Name some specific examples?

A
  • General: AA1 + alpha-keto acid2 = alpha-keto acid1 + AA2 (PLP or vitamin B6 as cofactor)
    • The Keq of reactions using aminotransferases is ~1, meaning the reaction is dependent on concentrations
  • Alpha-ketoglutarate + aspartate = glutamate + oxaloacetate (using aspartate aminotransferase and PLP as cofactor)
  • Alpha-ketoglutarate + alanine = glutamate + pyruvate (using alanine aminotransferase and PLP as cofactor)
126
Q

How is PLP affected by certian TB treatments?

A

Isoniazid – used to treat TB – competitively binds to PLP, inducing a B6 deficiency

127
Q

Describe Kwashiorkor?

A
  • Inadequate protein intake
  • “the disease of the deposed baby when the next baby is born” so no nutrients through breast milk
  • Characterized by retention of water in the stomach, failure to thrive, composition of gut bacteria
128
Q

Describe Marasmus?

A
  • Inadequate energy intake
  • Characterized by failure to thrive and delayed mental development
129
Q

Describe Marasmic Kwashiorkor?

A

Inadequate energy and protein intake

130
Q

What is the urea cycle?

Explian the cycle. (Intermedates and major enzymes)

A
132
Q

Describe the glucose-alanine cycle and its roles.

A
133
Q

Describe the role of glutamine in movement of nitrogen.

A
  • Glutamate + NH3 + ATP = Glutamine + ADP+ Pi via Glutamine Synthetase in periphery
  • Glutamine + H2O → glutamate + NH3 via Glutaminase in liver and kidney tissue
  • Therefore, glutamate acts as a shuttle carrier for NH3
135
Q

Describe the degradation and use of AAs as energy sources.

A
  • Glucogenic: pyruvate or oxaloacetate create a net gain of glucose
  • Ketogenic: acetyl-CoA and acetoacetyl-CoA enter into citric acid cycle with no net gain of glucose
136
Q

What is the source of NO and pathway?

A

Source: arginine

Arginine + O2 + NADPH → citrulline + nitric oxide + NADP+

137
Q

What are the five metabolites that trypotphan breaks down into?

A
  1. seretonin
  2. melatonin
  3. xanthuenote
  4. NAD+
  5. acetoacetyl CoA
138
Q

What is the importance of Vitamin K?

What does deficiency lead to?

A
  • Vitamin K is a cofactor for post-translational modification of glutamate to Gla
    • Vitamin is oxidized, and in order to be used as a cofactor again, it must be reduced through 2 enzymatic steps
    • Gla is used in clotting and in osteocalcin (Ca++ binding protein in bone)
  • VKDB (Vitamin K Deficiency Bleeding): internal bleeding due to lack of blood clotting (can be mistaken for child abuse)
139
Q

What are Vitamin K inhibitors?

A

Dicumerol

Warfarin

141
Q

How tryptophan broken down?

A
  • Tryptophan is broken down into alanine (glucogenic) and acetoacetyl CoA (ketogenic)
    • Degradation:
      • Urine color via xanthurenate
      • Feces odor
      • Halitosis (bad breath)
142
Q

How does Sumatriptan work?

A

5-HT1 agonist. Treatment for migraines.

143
Q

What is the pathway of catecholamines?

A
  • Tyrosine → L-Dopa → Dopamine → Norepinephrine → Epinephrine
  • 1st Step: tyrosine hydroxylase uses BH4 as cofactor
    • Negative feedback by all catecholamines
  • 3rd Step: vitamin C is a cofactor
  • 4th Step: SAM methylates norepinephrine
  • Lack of dopamine causes Parkinson’s, which can be treated with L-Dopa because it can cross the blood brain barrier
144
Q

How does Prozac work?

A

serotonin specific reuptake inhibitor

145
Q

Describe the relationship of phenylalanine and tyrosine?

A
  • Phenylalanine (essential) synthesizes tyrosine (non-essential as long as there is enough F)
    • F → Y via phenylalanine hydroxylase and BH4 oxidation
    • BH2 must be reduced back to BH4 in order to act as a cofactor in future reactions
146
Q

PKU causes?

A
  • Phenylketonuria
    • Malignant: mutation in the dihydrobiopterine reductase (BH2 to BH4)
    • Mutation in phenylalanine hydroxylase, so there is an accumulation of its alpha-ketoacid, phenylpyruvate
148
Q

Pathway for melanin?

A

Tyrosine → → → Melanin using tyrosinase by adding 2O2

149
Q

How are thryroid hormones created?

A
  • Derived from post-translationally modified tyrosines
  • Thyroglobulin degrades into T4
150
Q

Describe the symptoms and basis of oculocutaneous albinism.

A
  • Deficiency in tyrosinase
  • Symptoms
    • Sensitivity to sunlight
    • Decreased visual acuity
151
Q

Describe the synthesis of pyrimidine bases and nucleotides

A
152
Q

Describe the synthesis of purine nucleotides

A
153
Q

How are catecholamines inactivated?

A
  • Monoamine oxidase inhibitors (MAOIs)
    • Catecholamines must be degraded to become inactive
    • MAO and COMT AND COMT and MAO act together to inactivate these compounds
    • MAOIs are used to treat depression
      • May interfere with metabolism of monoamines
154
Q

Describe thymidine (as TMP) synthesis

A
155
Q

Describe how tetrahydrofolate (THF) carries C1 units at (3) different oxidation levels.

A
  • C1 level at methanol
    • C1 unit is passed from N5-methyl-THF to another cofactor, S-adenosylmethionine (SAM)
    • B12 deficiency creates a “folate trap” that prevents 5-methyl-THF from making dTMP and methionine
  • C1 level at formaldehyde
    • Glycine/serine interconversion
  • C1 level at formate
    • Two reactions in purine biosynthesis
156
Q

Describe why sulfanilamide inhibits bacterial folic acid synthesis
.

A
  • Bacteria treated with sulfanilamide mis-incorporate this compound in place of PABA during synthesis of folic acid
  • Humans do not have this enzyme to synthesize folic acid, so unaffected
157
Q

Describe the critical role of vitamin B12.

A
  • Used as a cofactor in only two reactions in the body
    • Homocysteine methionine (for DNA synthesis)
    • L-methylmalonyl-CoA → succinyl-CoA (oxidation of some AAs or beta-oxidation of odd-numbered fatty acids)
      • B12 deficiency leads to build up of methylmalonyl-CoA, which can go on to degrade myelin sheaths
160
Q

Formation of deoxyribonucleotides by ribonucleotide reductase

A
  • Ribonucleotide reductase converts NDPs (ribose) to dNDPs (deoxyribose)
    • 3 different classes of RNRs
    • Reaction proceeds via free radical mechanism of action
161
Q

How are purines catabolized in the body?

A
163
Q

Describe the salvage pathway for purines.

A
164
Q

Describe the salvage pathway for pyrimidines.

A
165
Q

How does Trimethoprim work

and

what does in inhibit?

A
  • Trimethoprim
    • Antibiotic
    • Binds to bacterial DHF reductase strongly, inhibiting it in bacteria
    • Binds weakly to human version
    • Selectively inhibits bacterial growth
166
Q

How does Hydroxyurea work

and

what does in inhibit?

A
  • Hydroxyurea
    • Free radical scavenger
    • Inhibits ribonucleotide reductase → decreasing dNTP pool (especially in proliferating cells)
167
Q

How does Methotrexate work

and

what does in inhibit?

A
  • Methotrexate
    • DHF reductase inhibitor
      • Competes with DHF for binding DHF reductase
        • Can’t convert to THF
    • Recovery and reversal by giving high levels of nucleosides and folate
    • Anti-cancer (inhibits DNA synthesis, stopping cell division)
168
Q

How does 5-fluorouracil work

and

what does in inhibit?

A
  • 5-fluorouracil
    • FdUMP a derivative of 5-fluorouracil
    • “suicide inhibitor” for thymidylate synthase (UMP → TMP)
169
Q

How does 5-azacytidine work

and

what does in inhibit?

A
  • 5-azacytidine
    • Prodrug
    • Pyrimidine biosynthesis inhibitor
170
Q

How does 6-mercaptopurine work

and

what does in inhibit?

A
  • 6-mercaptopurine
    • Inhibits purine synthesis at multiple steps
    • Cells starve of purines and die​
172
Q

Factors effecting presentation of gout?

epidemology?

A
  • Presentation
    • Present at physiological pH as sodium urate
    • Alcohol consumption – beer has yeast, which produces high levels of purines
    • Dehydration
    • High purine diet (meat, seafood, asparagus, spinach)
    • “Tophi” – monosodium urate tissue aggregates that eat through bone
    • Sodium urate precipitate in joints and kidney stones
    • Epidemology
      • Men > 30
      • Postmenapuasal women
175
Q

Treatments for chronic gout?

A

Chronic Gout

  • Xanthine oxidase inhibitor – inhibits purine degradation
    • Allopurinol
    • Febuxostat
  • Uricosuric agent – increase excretion of uric acid in urine
    • Pegloticase
176
Q

Treatments for acute gout?

A

Acute Gout

  • NSAIDs – COX1 & COX2 inhibitor – reduce pain and inflammation
    • Indomethacin
  • Colchicine – Reduces gout symptoms
  • Intra-articular Corticosteroids – Reduce inflammation
177
Q

What is Azanthioprine (AZA)?

Whats the mechanism?

and effect?

How is it affected by Xanthione oxidase inhibitors?

A

Azathioprine (AZA)

  • Prodrug
  • Immunosuppressant
  • Cyclosporin is often used in conjunction with AZA
    • Decreases uric acid excretion, leading to higher prevalence of gout in transplant recipients
  • Xanthine oxidase inhibitors (allopurinol) are used then to decrease uric acid production
    • Can lead to AZA toxicity because some AZA metabolites use xanthine oxidase
178
Q

What is Cytosine Arabinoside (AraC) and Alanine Arabinose (AraA)?

Whats the mechanism?

and effect?

A

Cytosine Arabinoside (AraC) and Alanine Arabinose (AraA)

  • Arabinose is substituted in place of ribose
  • Results in cell death in leukemia tumors
  • Must be phosphorylated to nucleoside triphosphates to be incorporated into DNA
179
Q

What is 2-cholorodeoxyadenosine?

Whats the mechanism?

and effect?

A

2-cholorodeoxyadenosine

  • Used in treatment of hairy cell leukemia
  • Cytotoxic, especially in inhibition of DNA repair of double-strand breaks
  • As resists breakdown by adenosine deaminase as a chemotherapeutic drug
180
Q

What is 5-Iodouridine?

Whats the mechanism?

and effect?

A

5-Iodouridine

  • Functional analogue of thymidine (not uridine!) that must be metabolized to a dNTP before it is incorporated into DNA
  • Pairs with G instead of A due to aberrant hydrogen bonding properties
    • Mispairs in DNA and RNA
  • Treats herpesvirus infections
181
Q

What is Acyclovir?

Whats the mechanism?

and effect?

A

Acyclovir

  • Analogue of guanosine that lacks most of ribose ring
  • Missing 3’-OH group causes chain termination of DNA strand once incorporated
  • Treats herpesvirus infections
    • Must be in monophosphorylated form
    • Only virally-encoded thymidine kinase phosphorylates acyclovir (human thymidine kinase does not)
182
Q

What is Azidothymidine (AZT)?

Whats the mechanism?

and effect?

A

Azidothymidine (AZT)

  • Analogue of thymidine and has no 3’-OH group on ribose ring
  • DNA elongation is terminated
  • Treats HIV
    • Anti-viral because the HIV DNA reverse transcriptase has 100x increase in affinity for AZT triphosphate than normal DNA polymerases
183
Q

What is Hydroxyurea?

Whats the mechanism?

and effect?

A

Hydroxyurea

  • Inhibits ribonucleotide reductase, decreases dNTP pool, especially in proliferating cells
  • Helps drugs like AZT, which competes with endogenous TTP supply
184
Q

Connect elevated uric acid levels to Lesch-Nyhan Syndrome.

A

HGPRT deficiency → increased [hypoxanthine] → increased [uric acid]

185
Q

What is receptor-mediated endocytosis and give the process using LDL particles?

A
  • Clathrin mediated
  • Example: LDL particles
    • LDL receptors on ECM of PM recognize LDL particle
    • LDL receptor binds adaptor protein and clathrin coat assembles
    • Transported to early endosomes then lysosomes
    • LDL receptor dissociates from LDL particle in early endosome and receptor is recycled back to PM
    • Free cholesterol enters cytoplasm
    • Promotes homeostasis by inhibiting LDL receptors and shutting down cholesterol synthesis when [LDL]cell is high
186
Q

What is transcytosis used for and provide an example of where it would be used?

A
  • Used in polarized epithelial cells to transfer macromolecules from one extracellular space to another (apical to basolateral)
    • Example: transferring of ABs from mother’s blood to baby’s blood
187
Q

Number of half-lifes or clearance?

effect of doubling dose ?

A

5

double dose only increase time in body by one half-life

188
Q

Vd Numbers?

A
  • 5L - plasma
  • 15L plasma + insterstitual fluid
  • 40L plasma + interstitual fluid + intracellular fluid
189
Q

similarities between cardiac and smooth

A

autonomic

gap junctions

mecahnical coupling? stretch induced contraction?

structure: intercalated disks & desosomes similar to dense bodies

types of smooth muscle cont.

phasic: GI
tonic: blood vessels

SPM (ARSH) (5 decks)

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