Fichas
Proteases
Fichas del conjunto (46)
- 1what are proteases?enzymes that hydrolyze proteins
- 24 major classes of Proteases1. serine proteases
2. cysteine proteases
3. aspartic proteases
4. metalloproteases - 3Serine Proteases-trypsin
-chymotrypsin
-elastase
(enzymes in coagulation cascade) - 4cysteine proteases-cathepsin B
-papain
(capsases/apoptosis, Cath B/Alzheimers) - 5Aspartic Proteases-pepsin
-HIV proteases
(digestion, HIV) - 6Metalloproteases-carboxypeptidase
-MMPs
(angiotensin converting enzyme (ACE)/hypertenstion) - 7proteases have bothinactivating and activating activities
- 8coagulationactivation
- 9digestioninactivation
- 10scissile bond is a bondthat breaks
- 11P1=AA on carbonyl side of scissile bond in substrate, N-terminal
- 12P1'=amino acid on side scissile bond in substrate, C=terminal
- 13S1=enzyme pocket for P1
- 14S1'=pocket for p1
- 15the substrate binding pockets of 3 serine proteases involved indigestion or inflammation
- 16Trypsin cutsCT to K, R
- 17Chymotrypsin cutsCT to F,Y, W
- 18elastase has asmall S1 pocket
- 19enzymes discriminate betweenspecific amino acids of substrate
- 20hirudin is a leech deriveddirect inhibitor of thrombin, a serine protease involved in blood coagulation
- 21Lepirudin is arecombinant form of Hirudin with 0.3pM affinity for thrombin
- 22Lepirudin doesn't inhibit bybinding to the active site, but instead along the fibrinogen binding surface, causing an allosteric effect.
- 23Bovine Pancreatic Trypsin inhibitor is a naturaltrypsin inhibitor that binds with very high affinity and blocks the active site.
- 24serpins areirreversible serine protease inhibitors
- 25reactive site loop of serpin inserts intoactive site of ser protease and reacts with catalytic serine
-cant deacylate because H20 can't get in - 26serpin mechanism1. binding to a reactive center loop
2. irreversible covalent coupling to reactive site Ser
3. huge conformational change that destabilizes thrombin so it gets cleaved - 27TPCK is anirreversible inhibitor of chymotrypsin
-reacts with active site His and Ser 50:50 - 28Types of aspartic proteases-pepsin
-cathepsin D
-renin
-HIV-1 protease - 29all aspartic proteases involve-two asp residues at the active site
- 30two asps work together asgeneral acid-base catalysts
- 31most aspartic proteases have atertiary structure consisting of two lobes (N-terminal and C-terminal) with approximate two fold symmetry
- 32HIV-1 protease is ahomodimer
- 33pKa values of Asp resides arecrucial
- 34One Asp have a relativelylow pKa (normal) other has a high pKa.
- 35deprotonated Asp acts as a general baseaccepting a proton from HOH, forming OH- in the TS.
- 36Other protected Asp (general acid)donates a proton, facilitating formation of tetrahedral intermediate
- 37HIV protease cleavestwo polyproteins into functional proteins during viral maturation
- 38Protease inhibitors asAIDS drugs
- 39If HIV-1 protease can be selectively inhibited, then newHIV particles cannot form
- 40Several novel protease inhibitors are currently marketed asAIDS drugs
- 41A successful drug must be able to inhibit thevirus in the human subject without blocking other essential proteases in the body.
- 42the first HIV protease inhibitors weresubstrate mimetics.
-contain bulky groups that bind active site
-Have the geometry of the tetrahedral TS. but not cleavable. - 43RT has poorfidelity and makes a lot of mistakes
- 44Resistance-Rapidly requires mutations under selective pressure from drugs
-stops binding inhibitor
-maintains the ability to bind substrate - 45Thiol proteases are most similar toserine proteases
- 46Metal proteases are most similar toaspartic proteases
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- Pharm D Biochemistry Fichas sobre Proteases, creado por Ariana Rhoten el 13/04/2016.
- Creado por
- Ariana Rhoten
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