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Natural Sciences Bath Final Year > Enzymes Essays > Flashcards

Enzymes Essays Flashcards

1
Q

What are the modules of interest in cellulases

A

Catalytic modules, cellulose binding modules, linkers, cohesins and dockerin modules

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2
Q

What the are modules of interest in aminoacyl tRNA synthetases?

A

Direct catalytic modules, extra indirect catalytic modules, modules for extra amino acids conversion, tRNA recognition, editing domains, MSC and extra functions.

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3
Q

What are the benefits to SBDD?

A

Save money, use homologs, able to choose target

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4
Q

What are the limits of SBDD?

A

Must know structure, doesn’t predict effect on system, doesn’t identify which ligands to take forward. And must know which structure you want to target.

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5
Q

What are the topics of the SP and ACE essay?

A

Mechanism of action, optimisation for substrates, inhibition, accessibility, convergent and divergent evolution.

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6
Q

What do cellulases do?

A

Hydrolyse the 1,4-beta-D-glycosidic linkages in cellulose

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7
Q

What are the different catalytic modules of cellulases?

A

Cellobiohydrolase (CBH I and II), Endoglucanase, Beta-glucosidase

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8
Q

What does CBH I do?

A

Hydrolyse the reducing end of cellulose

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9
Q

What do endoglucanases do?

A

Cleave in less ordered regions to expose more ends

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10
Q

What do beta-glucosidases do?

A

Cleave free beta-glucosidases

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11
Q

What is the properties of cellulose?

A

Highly ordered crystalline repeats of beta-glucose, with intermittent regions with less order.

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12
Q

What is the benefit to many catalytic modules?

A

Can target complex substrate from more angles = more yield.

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13
Q

How does the catalytic binding module of cellulases bind?

A

Binds with loose, transient bonds using exposed aromatics spread one glucose module apart.

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14
Q

Why are catalytic binding modules of cellulase helpful?

A

Insoluble substrate less likely to collide with correct orientation (thread through CBH I correctly)

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15
Q

How does catalytic binding module of cellulase help?

A

Disrupts crystalline structure and brings CMs closer

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16
Q

What is the linker of cellulases used for?

A

Flexibly joins CM to other modules, aiding positioning

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17
Q

Give an example of a cellulase linker

A

Fibronectin type III

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18
Q

What is the structure of cohesins and dockerins?

A

Highly conserved and species specific

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19
Q

What is the role of cohesins and dockerins?

A

Tether modules together, increasing proximity and activity, allows inclusion of non-cellulases. SYNEGRY

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20
Q

What does cellulases bind to with their dockerin modules?

A

Scaffoldins, which can bind to other scaffoldins.

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21
Q

What is the class I for direct aminoacylation domain?

A

2’ carbon, which moves by transesterification. Conserved Rossman fold, with HIGH and KMSKS motifs.

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22
Q

What is the class II for direct aminoacylation domain?

A

3’ carbon. Less conserved, unrelated beta-sheets.

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23
Q

Why are there many catalytic domains of aaRSs

A

Because amino acids structure varies.

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24
Q

What is indirect charging of tRNA?

A

Charging incorrect AA to tRNA, which is then transamidated by amidotransferase to give the correct AA.

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25
Q

When is indirect charging of tRNA needed?

A

Aspartic and Glutamic acid are converted to Asparagine and Glutamine.

26
Q

Why have some organisms got more domains for charging?

A

Expand from the naturally occurring AAs: formyl-methionine, selenocysteine and pyrrolysine. Converts from methionine, serine and lysine.

27
Q

Which domains recognise tRNA?

A

Acceptor stem binding domain and Anti codon binding domain.

28
Q

Why is tRNA recognition important?

A

Differentiate between the 64 codons, and anticodon binding domain provides stability for transport.

29
Q

What do the editing domains do?

A

Kinetic proof reading, pre or post acylation (in solution or selective release).

30
Q

When are editing domains needed?

A

Only for amino acids which regularly get mischarged: Ile, Leu and Val. They are a defence mechanism.

31
Q

What is the purpose of a multisynthetase complex?

A

Promotes activity, channelling product to ribosomes. Localise, stabilise and act as a reservoir to regulate non-canonical activities.

32
Q

What extra functions are aaRS responsible for?

A

Metabolism, angiogenesis, and Immune functions.

33
Q

What example of SBDD is used for saving money?

A

Cellulase not same as AChE (active site and gorge)

34
Q

What example of SBDD is used for needing to know the structure?

A

Lysozyme easy to crystallise

ACE not easy

35
Q

Why is ACE not easy to crystallise?

A

Glycosylated and membrane bound

36
Q

What example of SBDD is used for use of homologs?

A

ACE and carboxypeptidase A, because both metalloproteases. But ACE turned out to be more similar to neurolysin.

37
Q

What assumption of ACE active site was made?

A

Zn, H bonding region, and positive residue.

38
Q

Using homologs allowed what to be developed?

A

Captopril, Elanapril, and Lisinopril.

39
Q

What was good and bad about using homologs for ACE inhibitors.

A

Allowed life saving drugs to be developed cheaply. But had side effects like dry cough and sore throat.

40
Q

What example of SBDD is used for knowing which drug to screen?

A

LBDD: Hirudin from leeches to Bivalirudin, and Brazillian snake venom to captopril.

41
Q

Why is knowing which drug to screen a problem is SBDD?

A

Knowing pharmacophores doesnt mean you know which potential inhibitors will be a good picture.

42
Q

What is Bivalirudin?

A

A thrombin inhibitor, doesnt target other serine proteases. Binds reversibly to free and clot-bound thrombin.

43
Q

What example of SBDD is used for “predicting the effect on the system”?

A

Glycosylation by golgi alpha-mannosidase

44
Q

How can glycosylation pathways be imbalanced?

A

Too much alpha-mannosidase activity, too many complex sugars = cancer.
Too little, too many hybrid = lupus-like autoimmunity.

45
Q

Why is having to choose the correct structure a limitation to SBDD?

A

Many proteins are present in systems, choosing the right one is hard.

46
Q

Why is having to choose the correct target a benefit to SBDD?

A

Unlike LBDD, you can target domains specific to certain isoforms

47
Q

Give two examples of choosing the right target in SBDD.

A

COX enzymes and ACE enzymes.

48
Q

Why is COX enzyme an example of SBDD “choosing the right target”?

A

COX turn arachidonic acid to prostanoids (for inflammation and pain). COX1 low levels in GI, NSAIDS. COX2, extra domain, only in cellular stress, Vioxx and celecoxib.

49
Q

Why is ACE enzyme an example of SBDD “choosing the right target”?

A

Somatic (2 domain) and Germinal (C domain).
C = cleaves angio, bp control. No increase in bradykinin causing an angioedema.
N = Cleave AcSDKP and haemoregulatory hormone.

50
Q

Why are Serine Proteases comparable to AChE?

A

Same catalytic triad (Ser, His, Carboxy acid - Glu) for hydrolysis.

51
Q

What is the mechanism for SP/AChE cleavage?

A

G+H low barrier H bond, raise pKa and basicity, attacks S
S O- attacks substrate = tetrahedral oxyanion.
H proton attacked, form acyl intermediate, release product.
Repeat with H2O, release second product.

52
Q

How have SPs optimised for their substrates?

A

Binding pocket for n-1 residue
Trypsin = positive residue
Elastase = small neutral residue

53
Q

Give an example of SP specificity

A

Thrombin cleaves proteins such as fibrinogen for blood coagulation.

54
Q

How is inhibition of SP regulated? Why?

A

Serpins, prevent protease activity in unwanted areas.

55
Q

How do serpins work?

A

A prime hydrolysis target, the reactive centre loop, has tension. Moves to relaxed state once acyl-intermediate is formed, preventing its release.

56
Q

Why is AChE active site not easily accessible?

A

Its at the bottom of a 20A gorge; lined with 14 aromatic amino acids.

57
Q

How is AChEs lack of accessibility overcome?

A

Proposed back door mechanism, releasing products. Kineticist say it isn’t needed.

58
Q

How is type of evolution assessed?

A

Sequence identity

59
Q

What examples of convergent evolution are there?

A

AChE with gorge against chymotrypsin-like SPs against subtilisin-like SPs

60
Q

What is the difference in serine proteases structure?

A 
Chymotrypsin-like = 2 beta-barrels
Subtilisin-like = large beta-sheet with several alpha-helices
61
Q

What examples of divergent evolution?

A

Amongst chymotrypsin-like serine proteases, a high sequence identity. Difference in the binding pocket.

Also cysteine proteases may have diverged.

Natural Sciences Bath Final Year (5 decks)

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