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18 Cards in this Set

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What are the general features of zymogen activation?
1) Involves cleavage of peptide bond in a protein (zymogen). Cleavage-->conformational change-->exposes/forms active site-->active enzyme!
2) Zymogen activation is IRREVERSIBLE.
3) Zymogen activation is common among proteolytic enzymes.
4) Zymogen activation is a key feature of cascades. Allows for AMPLIFICATION of a signal. (one enzyme activated-->then another-->etc.)
5) There are a small number of mechanisms for zymogen activation.
What happens in zymogen activation, from cleavage of the peptide bond to exposure of the active site?
-Proteolytic cleavage generally occurs between hydrophilic area (N-terminus) and hydrophobic area-->hydrophilic is a "buoy, pulling hydrophobic area toward protein surface-->hydrophilic area is cut off ("activation peptide"--may or may not be useful)-->after cleavage, hydrophobic area is free of "buoy" and sinks into molecule-->has exposed N-terminal amino group (+charge--does not want to go inside protein)-->must be stabilized through salt link--> makes salt link with COOH group of Asp or Glu in active site-->Asp or Glu move, exposing active site-->enzyme can start working!
Describe activation of pepsin
Pepsinogen (inactive) released into stomach--> charges of Asp, Glu on pepsinogen change-->undergoes conf. change ("auto-activation")-->active site should be exposed, but N-terminal is blocking it!-->active site cleaves N-terminal-->active site exposed-->active pepsin! -->active pepsin can cleave other molecules of pepsinogen, activation them, too-->"auto-catalysis"
What is auto-activation?
What is auto-catalysis?
Auto-activation--protein acts on itself (pepsinogen upon entering stomach)

Auto-catalysis--protein acts on other proteins (pepsin activates other pepsinogens)
Why is pepsin such an interesting zymogen activation example?
Pepsin is the ONLY enzyme that can activate itself! (auto-activation)**

--ALL of the other zymogen activation reactions use the mechanism described for chymotrypsin.

**He mentioned this several, several times in class!
What is chymotrypsinogen-->chymotrypsin mechanism?
Trypsin hydrolyzes the bond between Arg15 and Ilu16--> arg 15 leaves (activation peptide)--> ilu-16 is "free" of hydrophilic buoy-->ilu-16 wants to sink into protein, but can't because cleavage exposed positive amino group-->needs to form a salt link--> negatively-charged Asp194 will form salt link with the alpha amino group to stabilize it, thus pulling this residue and its associated residues into the protein-->this conformational change will bring the necessary residues in the active site into their proper position for the reaction to proceed (chymotrypsin!)
What are the important residues (post-cleavage)?
Ilu-16--bond b/w this residue and arg 15 has been cleaved-->ilu-16 sinks into proteins, bringing newly formed amino group with it-->needs to form salt link w/negative group

Asp-194--forms the much-needed salt link! rotates to form link, causing residues 192-193 to turn as well

Gly-193--residue rotates so its amide H can make a H bond w/the substrate as part of catalytic mechanism.

Met-192--rotates to remove its side chain, which is no longer binding substrate specificity pocket!
Which chymotrypsin residues are highly conserved?
Which are not?
Universally conserved--Ser195, Cys191, Gly193

Not always--Asp194, Met192
Describe activation of trypsin

-->trypsin activates TONS of enzymes
-->has a REALLY hydrophilic "activation peptide" associated with REALLY hydrophobic associated region. Shows clear example of these two regions.
How is zymogen activation regulated?
Regulated at two places:

1) Starting the reaction:
activator and molecule to be activated are kept apart until reaction can take place-->eliminates premature activation.

(ex: pepsinogen--made in one group of cells-->can't be activated until enters stomach. pancreatic digestive enzymes--made in pancreas-->can't become active until interact w/enteropeptidase, which is made in small intestine!)

2) Ending the reaction
--Most enzymes have an ideal environment in which they operate-->when they leave the environment, become inactive. (ex: pepsin--inactive when it enters small intestine)
--also, in the case of the pancreas, the digestive enzymes are secreted w/"pancreatic trypsin inhibitor", which inhibits trypsin that is activated too early.
What is pancreatic trypsin inhibitor?
-released by pancreas when digestive enzymes are secreted.
-keeps trypsin from becoming active too soon/activating the other digestive enzymes!
-zymogens go to small intestine-->encounter enteropeptidase (remember-this activates trypsin)-->overwhelm inhibitor-->active trypsin!
Describe pancreatitis
-damage to pancreas (booze, trauma) can cause digestive enzymes to become active inside pancreas.
-destroys pancreatic cells.
Describe emphysema
-Lung has tons of elastic tissue made of "elastin".
-elastin can be digested by elastase, which is normally present as inactive zymogen proteoelastase.
-premature elastase activation is prevented by a-antitrypsin--has a methionine residue that fits into elastase and inhibits it.
-tobacco smoke converts methionine-->methonine sulfoxide-->no longer fits substrate pocket-->a-antitrypsin can't act-->elastase is active-->digests elastin of alveoli.
Describe arthiritis
zymogen procollagenase is activated-->active collagenase degrades collagen.
Describe periodontitis
bacteria that causes this disease releases proteolytic enzyme-->cleaves/activates procollagenase-->(like arthiritis)-->collegen degraded-->allowing bacteria food and a place to stay!
How do residues change from chymotrypsinogen-->chymotrypsin?
Chymotrypsinogen (inactive)

1) Ser 195--work w/histidine and asp to constitute charge relay system (from last module)
2) Asp 194--negatively charged COOH makes salt link w/ilu after cleavage
3) Gly 193--Amide H can NOT form H bond w/substrate--makes residue inactive.
4) Met 192--R group of this residue is covering substrate binding site--makes residue inactive.
5) Cys 191--works to stabilize molecule when Asp is flipping around to make salt links w/ilu.

Chymotrypsin (active)

1) ilu-16--where cleavage takes place. bond b/w ilu and arg is cleaved-->making positive amino group.
2) Asp 194--makes salt link w/positive amino group on ilu-16. moves, causing gly 193 and met 192 to move, as well.
3) Gly 193--when asp moves, this residue moves, also. moves amide H, so can make a H bond w/substrate--activates this residue!
4) Met 192--when asp moves, this residue moves, also. moves to remove side chain, substrate binding site now available--activates this residue!
what is the "digestive enzyme pathway"?
enteropeptidase (from duodenum) activates trypsinogen-->trypsin.

trypsin-->activates: chymotrypsin, elastase, carboxypeptidase A and B, phospholipase A2.

so..trypsin can activate tons of stuff, once it's cleaved!
What are important chymotrypsin residues before cleavage?
Ser-->consitute charge relay system (w/his and asp)

Asp--Will form salt link w/ilu

Gly--Amid H is in wrong position for binding

Met--Side chain is covering substrate binding site

Cys--disulfide bond keeps turning force minimal when asp is moving