MW L5 Proteases

Question 1

RA is mediated by

Answer 1

MMP

Question 2

MMP is secreted by

Answer 2

tissue cells - synovial fibroblasts, chondrocytes

Question 3

Inflammatroy cytokines are particularly derived from macrophages e.g. (2)

Answer 3

TNFa

IL1b

Question 4

………….. and ………….cells help maintain cytokine production

Answer 4

T and B lymphocytes

Question 5

2 e.g. of natural proteases

Answer 5

collagenase

elastase

Question 6

Synovial fibroblasts secrete

Answer 6

• cytokines
• Enzymes
• mediators (PGE2)
• Matrix materials

Question 7

Synovial fibroblasts ‘………….’ T-cells and exhibit ‘………….’ phenotype

Answer 7

nurse

malignant

Question 8

Cartilage is made up of …..

Answer 8

cells and extracellular matrix:

• fibrous protein - collagen
• proteoglycan

Question 9

what is proteoglycan

Answer 9

chondroitin sulphate linked to aggrecan core

Question 10

proteoglycans are …….. and bind to water

Answer 10

charged

Question 11

what happens to proteoglycans in raised intra-articular pressure in RA

Answer 11

displaced and lost

Question 12

proteoglycans have a …………….. structure

Answer 12

open - highly accessible thus sensitive to breakdown by several proteinase

Question 13

Collagen or proteoglycans is lost quicker

Answer 13

proteoglycans

Question 14

Native collagen is only susceptible to

Answer 14

collagenases - after initial damage other enzymes can continue degreading

Question 15

4 families of proteolytic enzymes

Answer 15

MMP
Serine proteinases
Cysteine proteinases
Aspartate

Question 16

MMP1,8, and 13 are

Answer 16

collagenases

Question 17

MMP2 is

Answer 17

gelatinase A

Question 18

MMP3 is

Answer 18

stromelysin 1

Question 19

MMP are active at ……….pH and require……..

Answer 19

neutral

Zn

Question 20

MMPs are inhibited by

Answer 20

TIMPa

Question 21

MMPs are activated by the removal of ……… by …………….

Answer 21

propeptide (hence Cys motif) by sereine proteases

Question 22

………. terminus is important in substrate specificity and regulation

Answer 22

C

Question 23

When inactive MMP is

Answer 23

folded up with Cys on Zn catalyst stopping function

Question 24

Serine and Cys proteinases e.g.

Answer 24

Neutrophil elastase
cathepsin G
kallikrein

Question 25

Serine and Cys proteases break down

Answer 25

Elastin
Laminin
Chondroitin sulfate and proteoglycans
(involved in antigen processing)

Question 26

Endogenous inhibitor of Serine and Cys proteinases by ………… which are inactivated by ………..

Answer 26

Serpins

oxidation

Question 27

3 synthetic MMP inhibitors

Answer 27

Peptidomimetics
Non-peptidomimetics
Tetracycline and derivatives

Question 28

Peptidomimetics are

Answer 28

small hydroxamic-acid-based molecules
mimic substrate recognition site
inhibit MMP

Question 29

are Peptidomimetics specific?

Answer 29

no

Question 30

Peptidomimetics e.g.

Answer 30

Batimastat and merimastat

Question 31

Non-peptidomimetics e.g.

Answer 31

tanomastat and prinomastat

Question 32

Non-peptidomimetics are

Answer 32

based on confirmation of the MMP active site

Question 33

Tetracycline works by

Answer 33

inhibiting synthesis and activity of MMP

Question 34

What are MMP inhibitors not used?

Answer 34

lack of specificity
s/e
(ongoing trials for ser and cys protease inhibitors)

Question 35

ROS are produced by

Answer 35

infiltrating leukocytes and tissue resident cells

Question 36

what catalyses the formation of superoxide

Answer 36

NADPH

Question 37

What decomposes to for OH- and HOCl-

Answer 37

H202

Question 38

Reactive nitrogen species formed from …………….

Answer 38

NOS derived NO combining with oxygen species

Question 39

RA undergoes cycles of ………. and ……….

Answer 39

hypoxia and reperfusion - oxidative stress - superoxide is generated

Question 40

Effects of ROS

Answer 40

• DNA damage
• activate inflam gene transcription (NFKB)
• amino acid modifications
• matrix modifications
• cell apoptosis and necrosis

Question 41

What sort of amino acid modifications does ROS make

Answer 41

make host proteins immunogenic

inactivation of serpins