Heparin-like GAGs

Question 1

Heparin mode of action

Answer 1

Twofold effect:

• conformational change causing increased rate of thrombin inactivation
• physical approximation of thrombin and antithrombin increased (both bind to GAG)

Question 2

3 first reactions to damaged blood vessel

Answer 2

• vasoconstriction (clamp down)
• platelet plug formation (primary hemostasis)
• stable clot formation (secondary hemostasis/coagulation cascade)

Question 3

Plasminogen

Answer 3

converted to plasmin to break down clot

Question 4

Negative feedback of coagulation

Answer 4

• ATIII (stimulated by thrombin) blocks/degrades clotting factors XIIa, XIa, IXa, Xa, IIa
• thrombomodulin-protein C and TM-S blocks/degrades CF VIIIa and Va (IIa-activated)

Question 5

Serpin

Answer 5

serine protease inhibitor
includes antithrombin and antitrypsin

-undergo conformational change when inhibiting target protease making more effective and allowing dynamic control by cofactors (like heparin which makes reactive site more available)

Question 6

Most common disaccharides of heparin and heparin sulfate GAGs

Answer 6

GlcA-GlcNAc
GlcA-GlcNS
IdoA-GlcNS
Isoa(2S)-GlcNS
IdoA-GlcNS(6S)
IdoA(2S)-GlcNS(6S)

Question 7

Heparin: predominant repeating disaccharide structure

Answer 7

hexose/hexouronic acid linked to hexosamine containing nitrogen

Question 8

Proteoglycan

Answer 8

• core protein with serine: made in ER
• specialized linkage region (usually xylose, galactose, galactose from protein to GAG): made in ER
• at least one GAG: made in golgi

Question 9

Where are PG/GAG distributed?

Answer 9

in ECM, on cell surfaces and in intracellular granules

Question 10

Difference between proteoglycan and glycoprotein

Answer 10

proteoglycan has more glycan than protein

glycoprotein has more protein than glycan

Question 11

Chondroitins

Answer 11

GAGs with hexosamine-galactosamine repeats

Most common is Chondroitin sulfate B/dermatan sulfate

Question 12

Unique ATIII binding domain sequence

Answer 12

• a linear pentasaccharide in heparin like GAGs that specifically bind to antithrombin
• middle saccharide has unique 3-O-sulfate marker which is rare but indicates anticoagulant properites
• induced fit model
• acts like catalyst

Question 13

Protein-GAG interactions

Answer 13

non specific (charge) interactions: negative charged

specific: (lectin like) interactions: lectins are sugar binding proteins that have highly specific interaction/bindng with sugar molecules

Question 14

Proteins that bind heparin sulfate

Answer 14

ATIII, FGF, HGF, IL-8, IFN-gamma, VEGF, Wnt/wingless

Question 15

Where is heparin primarily found in body?

Answer 15

mast cells in secretory granuoles. Usually only releaed at sites of tissue injury

Question 16

Where is heparin sulfate primarily found?

Answer 16

(almost) all cells

Question 17

Which heparin like GAG is most involved in hemostasis?

Answer 17

Heparan sulfates on cell surface

Question 18

Heparin as a modulator

Answer 18

proposed that heparin is mainly to modulate availability/activity of histamine in mast cells (since heparin is very negative and histamine is very positive)

Question 19

perlican

Answer 19

heparin sulfate GAG of basement membrane