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Biochemistry > Biochem 2 M2 > Flashcards

Biochem 2 M2 Flashcards

1
Q

Triad of Thrombosis

A
  • Increased coagulability of the blood
  • Abnormality in blood vessel wall structure
  • Change in Circulation
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2
Q

What is FIIa

A

Thrombin

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3
Q

Steps of Hemostasis

A

1) Primary Hemostasis
2) Blood coagulation
3) Clot maturation

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4
Q

Primary Hemostasis

A
  • Platelet binds to damaged surface
  • Platelet aggregation
  • Vasoconstriction
  • Not that stable
  • Fast, seconds
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5
Q

Blood Coagulation

A
  • Formation of Fibrin
  • More stable
  • Takes minutes
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6
Q

Clot Maturation

A
  • Covalent crosslinks
  • Very stable
  • Clot retraction
  • Hours / Days
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7
Q

NETosis

A

Neutrophil release of extracellular traps (NETs) that binds infectious agents

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8
Q

Thrombin

A
  • Serine Protease
  • Cleaves next to Arg (+Lys)
  • Regulated by Protein Cofactors
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9
Q

How is Fibrin formed

A
  • Activation of Fibrinogen by Thrombin
  • Thrombin cleaves 4 peptide bonds
  • Arg-Gly bond at FpA & FpB at N-term.
  • New GRP formed at N-term.
    (Gly-Pro-Arg)
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10
Q

Fibrinogen Structure

A
  • 6 Polypeptide chains
  • 2 Alpha, 2 Beta, 2 Gamma
  • Covalently linked (26 disulfide)
  • All N-term. at center / E-region
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11
Q

Fibrinogen Charges

A
  • Highly Negative (-25)
  • Mostly at FpA & FpB in E-region
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12
Q

Formation of Fibrin Protofibrils

A
  • FpA cleavage shows HOLE
  • FpB cleavage shows KNOB
  • HOLE fits into KNOB
  • C-term. of a-chain form bridges bw protofibers (lateral dimension)
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13
Q

Formation of Fibrin Dimers

A

1) C-term. of y-chain interact with Ca+
2) Neutralization of Regions
3) H-Bonds formed b.w Tyrosine-Arginine & Arginine-Serine

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14
Q

Fibrinogen y’

A

Due to the alternative splicing of mRNA coding for y-chain
- 20 a.a longer
- Can lead to arterial Thrombosis

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15
Q

Polymerization due to FpA & FpB

A
  • FpA: Linear Polymerization
  • FpB: Perpendicular Polymerization
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16
Q

FXIII Structure

A
  • Tetramer
  • 2A (Megak, Monocy) + 2B (Liver) subunits
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17
Q

FXIII Active site

A

Active site contains Cysteine (Sulfur)

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18
Q

FXIII Lifespan

A
  • Very short
  • Eliminated by Ultrafiltration in Kidney
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19
Q

Activation of FXIII

A

1) Thrombin cleaves activation proteins = FXIII’
2) Ca2+ initiates cleavage of B from the A’ subunit = FXIIIa

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20
Q

FXIIIa Catalyzed reaction

A
  • Forms Iso-peptide bonds bw 2 y or a-chains
  • Initiates Cross-Linkage
  • Bw Lysine-Glutamine side chains
  • NH3 released (Ammonia)
  • Increases clot mech. stability
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21
Q

Rotational Thromboelastometry (ROTEM)

A
  • Info on overall efficiency of Blood Coagulation system
  • Based on detecting mech. strength of blood clots
  • Quick results, but no reason given
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22
Q

FXa

A
  • For Conversion of Prothrombin to Thrombin in 2 step process
  • 2 Hydrolytic steps
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23
Q

Conversion of Prothrombin to Thrombin

A

1) FXa cleaves peptide bond next to Arg forming Meizothrombin
2) FXa catalyzes another hydrolytic step and forms Thrombin
3) Positive feedback of Thrombin can cleave second bond to form Th from MT

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24
Q

Prothrombin Structure

A
  • Catalytic Domain
  • Fragments 1 & 2
  • F1 & F2 serve as attachment to Phospholipids
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25
Q

Prothrombinase Complex makeup

A
  • Phospholipid Membrane
  • FXa - protease
  • FVa - cofactor
  • FII - inactive prothrombin
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26
Q

Prothrombinase Function

A
  • Conversion of Prothrombin to Thrombin
  • FVa is used as a Cofactor that Enhances the reaction of FXa
  • Increases rate by 300,000 fold
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27
Q

Tissue Factor

A
  • Transmembrane Protein
  • Found in cells not normally exposed to blood
  • Binds to FVIIa
  • Acts on FX —> FXa
  • Extrinsic Xase complex
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28
Q

TFPI

A

(Tissue Factor Pathway Inh.)
- Produced by Endothelial cells in Liver
- Made up of K1, K2, K3
- Cofactor S

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29
Q

TFPI Process

A

1) K2 binds FXa
2) K1 binds FVIIa
3) K3 binds Protein S cofactor for stability

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30
Q

TFPI Isoforms

A
  • a: All 3 domains
  • B: No K3 domain (hemophilia)
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31
Q

Hemophilia Treatments

A
  • TFPI Blockers
  • FVIII infusion
  • FVIIa infusion
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32
Q

Antithrombin

A
  • Protease inhibitor (SERPIN)
  • Prevents spread of Thrombin from point of its formation by inactivation
  • 3400 nm
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33
Q

Heparin

A
  • Polysaccharide
  • Highly negative (COO-, SO3-)
  • Accelerates inhibition of Thrombin
  • Allosteric activator of Antithrombin
  • Exposes reactive loop by HBS
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34
Q

Heparan Sulfate

A
  • Same function as Heparin
  • Produced by body
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35
Q

Does Heparin work alone?

A

No
Antithrombin is necessary for its function

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36
Q

a2-Macroglobulin

A
  • Thrombin Inhibitor
  • Creates trap for Thrombin
  • Tetrameric Structure
  • Attracts thrombin to cleave peptide bonds
  • Produced by Liver
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37
Q

Protein C system effect

A

Destroys Prothrombinase complex

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38
Q

How is Protein C ativated

A
  • Cleavage done by Thrombin
  • Mediated by Thrombomodulin binding to Th instead of fibrin
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39
Q

Protein C system Steps

A

1) Thrombin binds Thrombomodulin
2) Thrombomodulin activates Protein C
3) APC + Protein S inhibits FV & FVIIIa
(Less clotting)

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40
Q

Thrombin Exosite 1 binds Fibrin

A
  • Keeps making Fibrin from Fibrinogen
  • Activates FXIII for cross-linkage of fibrin
  • Strengthened clot
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41
Q

Thrombin Exosite 1 binds Thrombomodulin

A
  • Activates Thrombomodulin
  • Protein C activation
  • Protein C System
  • Inhibited Clotting factors FV & FVIII
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42
Q

Where is Highest amount of TM found?

A

Capillaries

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43
Q

Does Meizothrombin have any effect on Protein C system?

A

Yes (93%)
Meizothrombin can activate Thrombomodulin to activate Protein C leading to clotting inhibition

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44
Q

Gla Domains

A
  • Found in Vitamin-K dependent proteins
  • Keeps factors attached to phospholipid membrane
    (y-carboxyglutamate domain)
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45
Q

Gla domain funtion

A

1) Gla binding sites bind Ca2+
2) Hydrophobic group inserted into phospholipid layer
3) Anchors the Factors to the plasma membrane for efficient function

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46
Q

Vitamin K dependent Proteins

A
  • II (Prothrombin)
  • VII
  • IX
  • X
  • Protein C & S
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47
Q

How is Gla domain formed

A
  • Postranslational Modification of Glutamic Acid
  • Carboxylase in E.R of Liver adds carboxylic group to glutamic acid
48
Q

How Vitamin K forms Gla

A

1) Vitamin K Hydroquinone needed as a cofactor + CO2 + O2
2) y-Carboxylase turns Glu to Gla
3) VK epoxide is formed (unusable)
4) VKOR (oxidoreductase) used to form VK hydroquinone and repeat

49
Q

What blocks VKOR?

A
  • Coumarins
    (Warfarin)
50
Q

Indirect Anticoagulant Drugs

A

Do not bind the active site of Thrombin
- Heparin (LMWH)
- Vitamin-K antagonists
- Fondapurinux

51
Q

Direct Oral Anticoagulant Drugs

A

Inhibit Thrombin and FXa sites
- Dabigatran
- Rivaroxaban
- Apixaban

52
Q

How are DOAC drugs safe?

A

They do not affect FVIIa which still allows clot formation do to Extrinsic pathway by Tissue Factor

53
Q

Plasminogen Structure

A
  • Carboxy Terminal
  • Kirngle Domains
    (Produced by liver)
54
Q

What can cause Plasminogen C-term. activation

A

Plasmin through Positive-Feedback

55
Q

Plasminogen Kringle domain

A

Binds the plasminogen to Lysine residues on the Fibrin

56
Q

Plasminogen Activation

A
  • Activated to tPA or uPA
  • tPA + Plasminogen = Plasmin
  • Fibrin Cofactor
57
Q

What a.a form Plasminogen Active site

A
  • Serine
  • Histidine
  • Aspartate
    (Serine Protease)
58
Q

tPA Inhibitor

A

Tissue Type Plasmin Activator
- PAI-1
(release by endothelial cells)

59
Q

Plasmin Inhibitor

A

a2-Antiplasmin

60
Q

Plasminogen Activation by uPA

A

Urokinase
- Inflamation
- Produced by Monocytes, Neutrophils, Tumor cells, Endothelial cells.
- uPA-R

61
Q

What stimulates activation of uPA by uPA-R?

A
  • Plasmin
  • Kallikrein
    Convert single chain (inactive) pro-uPA to Double chain (active) uPA
62
Q

Endogenous Plasminogen Activators

A
  • tPA
  • uPA
  • FXIIa
63
Q

What anchors Plasminogen & tPA to PM?

A
  • Annexin a2
  • p11 (Ca2+)
64
Q

Exogenous Plasminogen Activators

A

Proteins that bind either Plasminogen or Plasmin to break down Fibrin
- Streprokinase (Plasminogen)
- Staphylokinase (Plasmin)

65
Q

Streptodornase

A

DNAase enzyme released by bacteria to break down NETs from Neutrophils

66
Q

How is integrity of clot broken down?

A

Plasmin must cleave 3 peptide bonds in the same cross sectional plane of Fibrin

67
Q

If Plasmin acts on Fibrinogen

A
  • E Fragments
  • D Fragments
68
Q

If Plasmin acts on Fibrin

A
  • D-Dimers (iso-peptide bond)
  • E Fragments
69
Q

Antifibrinolytic Agents

A
  • Lysine (free)
  • e-amino caproic acid
  • Tranexamic acid
70
Q

PAP Complex

A
  • When Plasmin binds a2-antiplasmin
  • Irreversible (covalent)
  • Most aggressive Plasmin inhibitor
71
Q

Role of FXIIIa in a2-antiplasmin

A
  • Cross-links a2-antiplasmin in fibrin mesh
  • Embeds a2-antiplasmin into clot to inhibit plasmin action
72
Q

Forms of a2-antiplasmin

A
  • Meth (native) / 30% / Reduced stroke
  • Asp / 70%
    More methionine formed by Polymorphism where Arg swapped for Trp
73
Q

TAFI

A

Thrombin Activable Fibrinolysis Inh.
- Carboxypeptidase
- Inactive precursor
- Produced in Liver, Monocytes, Megakaryocytes
- Removes Lys binding sites of tPA from Fibrin
- Removes Plasminogen from fibrin

74
Q

TAFI activation

A
  • Once cleaved by Thrombin
  • Becomes Carboxypeptidase
  • Specificity towards Lys & Arg residues
75
Q

Steps of Platelet function

A

1) Injury
2) Adhesion
3) Activation
4) Secretion and Aggregation

76
Q

Adhesion Stage Platelets

A

1) Platelets recognize collagen (type-4)
2) Either bind directly or by specific receptors (GP-VI or VWF)

77
Q

Activation Stage Platelets

A

Ca2+ released in platelet cytosol

78
Q

Secretion & Aggregation Stage Platelets

A

1) Due to Ca2+ signal, Vesicle secretion
2) Exposure of cell surface receptor to mediate aggregation of platelets
3) Activated by Thromboxane-A & ADP

79
Q

What Adhesion happens in Arteries

A

1) GP1ba binds VWF
2) Bridge between Collagen and Platelets (Catch Bond)
3) Strength of binding increases with more flow & shear stress

80
Q

Von Willebrand Factor

A
  • Produced in endothelium of Venules
  • Polymer of monomers (disulfide bridges)
  • The longer, the more adhesive
  • Catch Bond GPIba
  • Increases FVIII lifespan
81
Q

What controls VWF length

A

ADAMTS13
- Cleaves VWF monomer to smaller pieces
- >40 can attract platelets without damage

82
Q

ADAMTS13 deficiency leads to

A

Thrombotic Thrombocytopenic purpura

83
Q

GPIIbIIIa activation

A

1) ADP (TXA) provokes Ca2+ signal
2) PKC phosph. GDP to GTP
3) GTP attracts Talin and Kindlin
4) Receptor activates and binds Fibrinogen
5) Fibrinogen forms bridges bw 2 platelets = Aggregation

84
Q

Vesicles released by activated Platelets

A
  • Dense Body: ADP, Serotonin, Ca2+, Poly(Pi)
  • a-Granule: Proteins that support blood clotting (P-selectin, binding site for neut. NETosis)
85
Q

PAR

A

Protease Activated Receptors
- Thrombin activated
- Irreversible
- Platelet aggregation

86
Q

Prostacyclin (PGI2) in Platelets

A

Potent antiplatelet agent
- Higher cAMP
- PKA act.
- inh. aggregation

87
Q

Why is Scramblase activated when Platelets activate?

A

It sends Negative PL to the outer PM layer, which allows for better attachment of clotting factors
(Phosphatidylserine/inositol)

88
Q

How does Aspirin work?

A

Inhibits COX, so no TxA formed.
- COX-1: Platelets
- COX-1/2: Endothelial cells

89
Q

Effects of Clopidogrel

A
  • Purinergic Receptor Antagonist
  • Blocks Platelet activation & aggregation by ADP
90
Q

ectoADPase

A
  • Hydrolyzes ADP
  • Opposes the platelet aggregating effect
91
Q

Effects of NO on Platelets

A

1) NO from eNOS
2) sGC turns GTP to cGMP
3) cGMP activates PKG
4) PKG activates MLCP
5) Vasodilation
(Anticoagulant)

92
Q

cGMP / PDE3 effects

A
  • cGMP inhibits PDE3
  • Inh. causes Increased cAMP
  • More cAMP means less Ca2+
  • Less platelet aggregation
93
Q

S-Nitrosylation

A

NO attaches to S group on FXIII
- Inh. of FXIII

94
Q

Primary Cilium Mechanosensors

A

1) PC1 detects mechanical signal
2) PC2 causes Ca2+ influx as a result
3) Signal transduction and TFs
(STAT6 & P100)
4) Can cause activation of eNOS

95
Q

Ach-R

A

Pentamer
2a, 1B, 1y, 1d

96
Q

Hydropathy plot

A

Allows the prediction of a Protein’s TM topology

97
Q

Open probability

A

The time an ion channel spends in the open state within a chose time period
= total open time / total obs. time

98
Q

Single Channel rate constants

A

Determine how many times the channel opens before inactivation

99
Q

What happens to channels at Physiological ion concentrations

A

They reach theoretical limits of Throughput rates
(since they are diffusion limited)

100
Q

Can ion channels tell between same charged Ions

A

Yes
Only the specific ion can go through due to Carbonyl Oxygens that mimics hydration shells of specific ions

101
Q

Can a specific ion channel let another ion in in absence of its usual ion

A

No
Na channel for Na+ only
K channel for K+ only

102
Q

VG-K channel

A

Tetramer
with 6 TM domains and conserved P loop
Extracellular selectivity filter (GYG)

103
Q

Passage of K+ through its channel pore

A

Only 2 K+ found in pore at a time either in 1,3 or 2,4 conf.
Separated by water in bw.

104
Q

VG-Na channel

A

Monomer
made up of 4 domains
Asp. and Glu on P-loop

105
Q

VG-Ca channel

A

Monomer
made up of 4 domains
4 Glu on P-loop

106
Q

What determines the selectivity of VG channels?

A

The conserved P-loop

107
Q

X-ray crystallography

A

To determine 3D structure of Proteins
(hard on ion channels since they are hydrophobic)

108
Q

What provides the Gating charge in VG K+ channels?

A

Arg-Lys residues on Subunit 4

109
Q

What treatment can stop inactivation of VG K+ channels?
(+ Name)

A

Trypsin
Cuts N-terminal peptide providing the “Ball & Chain” mechanism
Called N-type inactivation

110
Q

What do mutations in the VG K+ channels lead to?

A

Increased excitability
e.g prolonged ventricular AP

111
Q

Explain Inward rectification in ATP sensitive K+ channels

A

Large cations (e.g Mg2+) found in cytosol
Plug outward K+ channels
So more inward K+

112
Q

Where do ATP and ADP bind on ATP sensitive K+ channel?

A
  • ATP: KIR subunit (P-loop)
  • ADP: SUR subunit
113
Q

VG-Cl channel

A

Homodimer
in Skeletal Muscle to stabilize Em
Mutations cause Myotonia (inability to relax)

114
Q

CFTR Cl channel

A

Monomer
ABC protein family
Activated by PKA (cAMP) that phosphorylates 10 serines in regulatory domain

115
Q

What did CFTR evolve from

A

Degradation of the inner gate of an active transporter

116
Q

nACH-R

A

Pentamer
Activated by 2 ligands binding
Can be desensitized
Mutations lead to Myasthenia/weakness

Biochemistry (3 decks)

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