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Biochemistry > Semester 3: Midterm 2 > Flashcards

Semester 3: Midterm 2 Flashcards

1
Q

Definition of biotransformation

A

It is a normally occurring metabolism of foreign substances via either conversion or inactivation

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2
Q

What is a xenobiotic?

A

A chemical found in an organsim but not normally produced or expected to be present in it.

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3
Q

Specificity of the enzymes of biotransformation?

A

They have broad and overlapping substrate specificity (aspecific)

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4
Q

Phases of biontransformation (4)

A
  • Uptake
  • Oxygenation -> liberate/form functional group
  • Conversion via enzymes
  • Transport via transporter
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5
Q

What is the function of phase 1 enzymes?

A

Converting active exogenous/endogenous drugs into inactive oxygenated signal molecules and oxygenated drugs

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6
Q

In what organ does most biotransformation take place?

A

Liver
(xenobiotics transported out via:
1: Blood (->kidney->urine)
2: Bile (->intestine->feces))

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7
Q

What is the function of CYP enzymes?

A

Catalyzing the oxidation of organic substances

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8
Q

Substrates of CYP enzymes

A
  • Metabolic intermediates (lipids, steroid hormones)

- Xenobiotic substances (drugs)

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9
Q

In what organs are CYP1-4 expressed?

A

Mainly in the liver, but also in the lungs, intestine, skin and in the kidney

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10
Q

What induces CYP1 formation and what are its substrates?

A

Inducers: Methylcholanthrene, dioxin derivatives, cigarette smoke
Substrates: PAH, teophyllin, caffeine, phenacetin

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11
Q

What induces CYP2 formation and what are its substrates?

A

Inducers: Phenobarbital, ethanol, acetone, diazepam derivatives
Substrates:
2A: steroids, testosterone
2B: progesterone, vitamin D3, antiepileptics
2C: mephenytoin - antiepileptics
2D: antidepressants, beta blockers, antihypertensive agents
2E: ethanol, acetone

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12
Q

What is the intracellular receptor/TF responsible for induction of CYP1?

A

Ah (only hydrocarbon receptor)

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13
Q

What is the intracellular receptor/TF responsible for induction of CYP2?

A

CAR

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14
Q

What is the intracellular receptor/TF responsible for induction of CYP4?

A

PPAR

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15
Q

What induces CYP3 formation and what are its substrates?

A

Inducers: steroids, oral contraceptives, PCN (pregnenolon carbonitril)
Substrates: antibiotics, nifedipine, cyclosporine

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16
Q

What induces CYP4 formation and what are its substrates?

A

Inducers: chlofibrate
Substrate: fatty acids, eicosanoids

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17
Q

What’s the end product after phase 1?

A

Either a nucleophile or an electrophile. Usually inactivated and reactive intermediate

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18
Q

List the ways of conjugation

A

Glucorunidation, sulfation, glutathione conjugation, acetylation, amino acid conjugation, methylation

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19
Q

What’s the reagent and enzymes for glucuronidation?

A

UDP-glucuronate

UDP-glucuronosyltransferases (UGTs)

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20
Q

What’s the reagent and enzymes for sulfation?

A

Reagent: PAPS
Enzymes: sulfotransferases (STs)

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21
Q

What’s the reagent and enzymes for glutathione conjugation?

A

Glutathione (GSH) and glutathione S-transferases

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22
Q

What’s the reagent and enzymes for aminoacid cinjugation?

A

Glycine and taurine are the reagents, while the enzymes are acetyltransferases (ATs)

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23
Q

What’s the reagent and enzymes for methylation?

A

The reagent is SAM while the enzymes are methyltransferases (MTs)

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24
Q

What diseases can be caused by unconjugated hyperbilirubinemias?

A

Gilbert’s disease (SNPs in promotor region of UGT genes)
Treatment: phenobarbital

Crigler-Najjar syndrome (early stop codon in UGT genes)

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25
Q

What diseases can be caused by conjugated hyperbilirubinemias?

A

Dublin Johnson syndrome and Rotor syndrome

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26
Q

Where is the enzymes of conjugation located?

A

UGTs are located in the ER, while the rest of the enzymes are located in the cytosol

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27
Q

Can lipophilic signal molecules enter the cell? What about hydrophilic signal molecules?

A

Lipophilic binds to nuclear receptors, while hydrophilic molecules bind to plasma membrane receptors

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28
Q

Which response is faster? The response of hydrophobic or hydrophilic hormones?

A

The response of hydrophilic molecules: seconds to minutes

Hydrophobic molecules: hours to days

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29
Q

What structural domains does an intracellular receptor have?

A
  • DBD (DNA binding domain)- contains 2 zink fingers that can bind DNA at its HRE
  • LBD (ligand-binding domain)- high affinity, selective, stereo specific and reversible
  • NH2 terminal - binds activators + transcription proteins
  • C terminal- binds proteins such as HSP and transactivators
  • D- translocation
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30
Q

When steroid/non steroid receptors bind to their respective response elements they do it as homodimers or heterodimers?

A

Steroid receptors bind their response elements as homodimers, non-steroid receptors as heterodimers

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31
Q

What is the function of HSP in steroid receptors and when is it released?

A

It’s an inhibitory molecule (heat shock protein) that is released when a ligand binds to the receptor

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32
Q

What domain is shorter in non-steroid receptors than in steroid receptors?

A

A/B domain

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33
Q

List the processes regulating the effects of nuclear receptors

A
  1. Posttranslational modifications (phosphorylation, acetylation, sumoylation, ubiquitation, methylation)
  2. Chromatin remodeling
  3. Chromatin-based mechanisms
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34
Q

What is HDAC and what is its function?

A

HDACs are histone deacetylases and they cleave the acetyl moiety from histone tails allowing the histones to wrap DNA more tightly -> decreased transcription

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35
Q

What is tamoxifen and what is it used for?

A

Its an antiestrogen used to treat/prevent certain types of breast cancer

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36
Q

How is the structure of HIF-1 and what are its domains?

A
  • It is a heteromeric protein consisting of two subunits, HIF-1alpha (O2 sensitive) and HIP-1beta (O2 insensitive)
  • It has three domains:
    1. bHLH domain: DNA binding dimerization
    2. PAS domain: Substrate binding, dimerization, transactivation
    3. ODD domain: O2 dependent degredation
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37
Q

What does HIF-1 stand for and what is its function?

A

Hypoxia inducible factor 1 is an intracellular TF that functions as an oxygen sensor

38
Q

Which TF family does AHR belong to? What do these receptor bind?

A

The Aryl hydrocarbon receptor belongs to the bHLH transcription factor family, and it binds PAH or HPAH

39
Q

What is TCDD?

A

TCDD (dioxin) is an herbicide and a carcinogen. It acts via the AHR receptor.

40
Q

What are 6 characteristics of PAHs?

A

Polyaromatic hydrocarbons:

  1. Hydrocarbon molecules made up of multiple benzene rings
  2. Products of incomplete combustion
  3. Co-planar
  4. Lipophilic
  5. Unreactive
  6. Readily metabolized by P450 enzymes
41
Q

List the 4 major stages of hemostasis

A
  1. Vasoconstriction at the location of the injury
  2. Platelet activation and aggregation
    (1+2 takes seconds, primary hemostasis)
  3. Formation of a network of fibrin fibers (takes minutes, secondary hemostasis)
    -> clot maturation (hours to days)
  4. Fibrinolysis
42
Q

Blood clots are mainly composed of ………. in arteries, and …………. in veins.

A

platelets in arteries, fibrin in veins

43
Q

What makes the coagulation factors zymogens?

A

They are mostly released from the liver in inactive form, and needs to be activated by interactions with other molecules

44
Q

What kind of proteins are FI, FIII, FV and FVIII?

A

Glycoproteins

45
Q

What kind of protein is FXIII?

A

A transglutaminase

46
Q

What factors are involved in the intrinsic pathway?

A

HMWK, prekallikrein + factor XII

47
Q

What are the steps of the intrinsic pathway? (What activates what)

A
  1. Prekallikrein -> kallikrein and HMWK is activated when they bind to negative surfaces (collagen, platelets)
  2. These activate factor XII
  3. Factor XIIa activates factor XI
  4. Factor XIa activates factor IX
  5. Factor IXa makes complex with VIIIa, Ca2+ and phospholipids (=tenase complex) and activates factor X
48
Q

What causes Hemophilia A and B?

A

Hemophilia A:
- FVIII def.
Hemophilia B:
- FIX def.

49
Q

Factor VII can be activated by these 5:

A

1) Thrombin
2) Plasmin
3) FXa
4) FXIa
5) FXIIa

50
Q

List the steps of the extrinsic pathway

A
  1. Tissue factor and FVIIa makes complex
  2. These two activates FIX and FX
    (after this it shares a common pathway with the intrinsic pathway)
51
Q
  1. What is TFPI?
  2. What does it do?
  3. How is it carried in the blood?
A
  1. Tissue factor pathway inhibitor is a single chain polypeptide
  2. It reversibly inhibits FXa, can also inhibit FVII+TF complex while bound to FX
  3. Carried from the liver by LDL
52
Q

List the steps of the common pathway after FX is activated

A
  1. FXa, FVa, Ca2+ and phospolipids makes a complex (=Prothrombinase)
  2. Complex cleaves prothrombin into its active form thrombin
  3. Thrombin cleaves fibrinogen into its active form fibrin
  4. Fibrin aggregate and connects via weak bonds into a fibrin polymer (soft clot)
  5. FXIIIa converts these weak bonds into peptide bonds (hard clot)
53
Q

Where is FV stored and what is it a co-factor of?

A

Stored in alpha granules of platelets, its a cofactor of FX

54
Q
  1. Structure of fibrinogen (FI)

2. Where is it synthesized

A
  1. Soluble plasma glycoprotein
    - Symmetrical dimer (6 paired polypeptide chains- alpha, beta, gamma)
    - Chains covalently linked near N-terminal through disulfide bonds
    - Fibrinopeptide A and B on each alpha and betta chain
  2. Synthesized by liver and megakaryocytes
55
Q

What is the function of fibrinopeptides A and B?

A

Prevents fibrinogen from forming polymers with itself.
Contains glutamate + aspartate residues = negative -> makes fibrinogen soluble in blood + the molecules repulse each other

56
Q

What is thrombins (FIIa) function with fibrinogen?

A

It cleaves off 4 arginine-glycine bonds (one on each alpha and beta chain) releasing the fibrinopeptides

57
Q

What is the function of FXIIIa?

A
  1. It’s a transglutaminase that make bonds between lysine and glutamine to remove NH4+ = peptide bonds
  2. Catalyzing the binding of alpha2-plasmin inhibitor to fibrin (preventing plasmin from trying to break down the clot)
58
Q

Thrombin can cleave these 5 molecules:

A
  1. Factor V
  2. Factor VIII
  3. Factor XI
  4. Factor XIII
  5. Fibrinogen
59
Q

How does thrombin have a role in decreasing coagulation?

A

Neg. fb mechanism:

  1. Binds to thrombomodulin
  2. Thrombins affinity to fibrin decreases, affinity to protein C increases
  3. Activates protein C -> (APC)
  4. APC + cofactor protein S inactivates FVa and FVIIIa
60
Q

List 3 SERPIN type of protease inhibitors and their function

A
  1. Antithrombin - Irreversibly inhbits thrombin activity + activities of FIXa, Xa (in vitro), FXIa and XIIa
  2. Heparin cofactor II - Coagulation factor inhibiting FIIa (thrombin)
  3. alpha1-protease inhibitor (alpha1-antitrypsin) - Primarily inhibits elastase but can also inhibit thrombin and plasmin
61
Q

What is the function of heparin/heparin sulfate?

A

Heparin binds to antithrombin to increase its activity -> speeds up inhibition of further clot formation

62
Q

How is hirudin different from heparin?

A
  • Hirudin can be used to stop further clotting even if we have antithrombin def. because hirudin binds straight to thrombin
  • Heparin cannot be given when there’s an antithrombin def. as it only binds to this molecule
63
Q

How does APC cleave FVa?

A
  • Free FVa: R506 -> R306

- In PT complex (+PS cofactor): R306

64
Q

How does FVa work as a pro- and anticoagulant?

A

Procoagulant: FVa as a cofactor of FXa in prothrombin activation
Anticoagulant: Cofactor of APC/PS in factor VIIIa inactivation

65
Q

What is the relationship between diameter of vessels and conc. of thrombomodulin and thrombin?

A
  • Vessel diameter and thrombomodulin concentration is close to inversely proportional
  • Thrombin conc. increases with increasing diameter
66
Q

Where can we find Gla and what is it?

A
  • Gla can be found in prothrombin, proteins C, S and Z, and in factors VII, IX, X
  • Gla is gamma-carboxyglutamic acid (glutamate with an extra carboxyl group)
67
Q

What enzyme is responsible for the synthesis of Gla from Glu?

A

Gamma carboxylase

68
Q

Name some vitamin K antagonists

A

Warfarin, Coumarins

69
Q

How can plasminogen be activated?

A

By tPA, uPA, streptokinase, plasmin

70
Q

What is tPA and what is required for its function?

A

Tissue plasmin activator can activate plasminogen and requires fibrin as a cofactor

71
Q

Where does tPA cleave plasminogen?

A

It cleaves a peptide bond adjacent to Arg561

72
Q

What is uPA short for, and where is it produced?

A

Urokinase plasmin activator is produced by endothelia lining excretory ducts and tumor cells

73
Q

How is uPA activated?

A

1) By kallikrein

2) Pos. fb by already activated plasmin

74
Q

What inhibits both uPA and tPA? And what induces their activity?

A

Inhibitor: PAI1 and 2 (plasminogen activator inhibitor)
Inducer: Plasmin

75
Q

How can plasmin activate plasminogen?

A

Pos. fb: Plasmin cleaves a peptide bond adjacent to Lys77

76
Q

How does plasmin dissolve the clot?

A

By hydrolyzing the peptide bonds of fibrin. The fibrin will be separated into monomers or dimers (D-dimers)

77
Q

What is the most important inhibitor of plasmin?

A

alpha2-plasmin inhibitor

78
Q

Can antiplasmin bind and inhibit plasmin in any form?

A

No, it can’t bind to plasmin that is already incorporated into fibrin

79
Q

Neutrophil granulocytes produces which 3 proteins?

A
  1. Myeloperoxidase
  2. Elastase
  3. Bactericidal/permeability-increasing protein
80
Q

What are platelets fragments of?

A

Megakaryocytes

81
Q

Does platelets have a nucleus and RNA?

A

No nucleus, some RNA

82
Q

What makes platelets change shape?

A

Actin and myosin

83
Q

What can we find inside dense bodies and alpha-granules?

A
  • Dense bodies containing: ADP, 5HT, calcium, poly (Pi)

- Alpha-granules: Fibrinogen, FV, vWF, P-selectin, beta-thromboglobin, substance P and platelet growth factor

84
Q

What can activate platelets?

A
  1. Collagen
  2. Thrombin
  3. Platelet activating factor (PAF)
  4. ADP
  5. TXA2
85
Q

What produces vWF and how does it work?

A

Platelets and endothelial cells.

Functions as a bridge between collagen and platelets

86
Q

How is vWF activated?

A

When it’s cleaved by Furin

87
Q

What is the function of aspirin?

A

It is an anticoagulant; inhibits thromboxane 2 synthesis

88
Q

How does thrombin, PAF and collagen activate platelets?

A

They all have similar receptors on platelets linked to Gq -> activates PLC —-> Calcium increase

89
Q

What protein will transfer phosphatidylethanolamine and phosphatidylserine to the outer membrane?

A

Scramblase (Defect of this protein can give Scott Syndrome)

90
Q

What can inhibit platelet activation?

A

Adenosine and PGI2 (bind to Gs -> cAMP increases)

91
Q

Hormones that induces rise in cytosolic Ca2+

A
  • Ach
  • Vasopressin
  • Thrombin

Biochemistry (9 decks)

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