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My ESA1 > MGD S3 - Protein Regulation, Chromosomes, Genes and DNA > Flashcards

MGD S3 - Protein Regulation, Chromosomes, Genes and DNA Flashcards

1
Q

What does substrate availability affect?

A

Rate of enzyme activity. Some coenzymes will have limited availability

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2
Q

What are isoenzymes?

A

Different forms of the same enzyme (catalyse the same reaction) that have different kinetic properties. Different Km and Vmax - different amino acid sequences

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3
Q

Describe product inhibition

A

Accumulation of product of reaction inhibits forward reaction

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4
Q

Hexokinase and glucokinase are both involved in the first step of glycolysis. What is the difference between them?

A

Hexokinase - present in all cells and requires low glucose levels to become active. Glycolysis can occur at lowest [glucose] i.e. starvation. Important for glucose-dependent tissues Glucokinase - present in liver and pancreas. In both it acts as a glucose sensor, becoming active only when a response to high blood sugar is needed i.e. in liver glycolysis results in storage, in pancreas it results in insulin secretion

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5
Q

What does allosteric mean?

A

At a distance

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6
Q

What is the relationship between rate and substrate concentration?

A

Sigmoid, instead of the rectangular hyperbola seen for simple enzymes

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7
Q

What is the structure of allosteric enzymes?

A

Multi subunit

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8
Q

What are the two different conformations of allosteric enzymes?

A

T state - low affinity R state - high affinity

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9
Q

What is the effect of substrate binding to one subunit of an allosteric enzyme?

A

Makes subsequent binding to other subunits progressively easier

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10
Q

What does allosteric activators do?

A

Increase the proportion of (stabilise) enzyme in the R state

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11
Q

What do allosteric inhibitors do?

A

Increase the proportion of (stabilise) enzyme in the T state

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12
Q

What does phosphofructokinase do?

A

It is allosterically regulated and sets the pace of glycolysis- catalyses the third step (committing step), which can be up or down regulated depending on the energy needs of the cell

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13
Q

What are the activators and inhibitors for phosphofructokinase?

A

Activators = AMP, fructose-2,6-bisphosphate (low energy signals) Inhibitors = ATP, citrate, H+ (high energy signals)

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14
Q

What is covalent modification?

A

Post-translational modification e.g. tyrosine kinases, MAPKKK. Enzymes can be modified through the addition of an additional group

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15
Q

What groups can be added in covalent modification?

A
  • Phosphorylation by kinases (receptor tyrosine kinases) - Protein phosphatases - Carboxylation by carboxylate (FII, FVII, FIX, FX) - Acetylation (histones) - Ubiquitination (targets for protein destruction)
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16
Q

What happens in phosphorylation by kinases?

A

Transfer of terminal phosphate from ATP to -OH group if Series, Tyr, Thr. Switch enzyme on or off - different for different enzymes

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17
Q

What happens in phosphorylation by protein phosphatases?

A

Reverse effects of kinases by catalysing the hydrolytic removal (have to cut off because of covalent bond) of phosphoryl groups from proteins

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18
Q

What happens when enzymes activate enzymes?

A

The number of affected molecules increases geometrically in an enzyme cascade (enzyme 1 starts phosphorylating -> they all do)

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19
Q

Describe the action of signalling cascades

A

Amplification of signals by kinase cascades allows amplification of the initial signal by several orders of magnitude within a few milliseconds. Signalling cascades often use covalent modification to activate downstream effector proteins and amplify an extracellular signal e.g. MAPKKK pathway

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20
Q

How are glycogen breakdown and synthesis regulated?

A

Reciprocally

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21
Q

What is haemostasis?

A

Process which causes bleeding to stop via clotting cascade

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22
Q

In haemostasis, what happens before damage?

A

Heparin-like molecules released to inhibit clotting. Endothelium is naturally anti-coagulative

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23
Q

In haemostasis, what happens in activation, localisation and regulation?

A
  • Inactive zymogens become activated by substances released only at site of vascular damage (i.e. tissue factor) - Proteolytic activation in a cascading process - Feedback activation through thrombin burst (positive feedback)
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24
Q

In haemostasis, what happens during termination and resolution?

A
  • Activation of plasminogen by t-PA - Removal of clotting factors by liver - Protein C (inactivates Factor Va and Factor VIIIa), Protein S (cofactor to Protein C) and AT III (anti-thrombin)
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25
Q

What forms of short-term protein regulation are there?

A
  1. Substrate and product concentration 2. Change in enzyme conformation: - allosteric regulation - covalent modification - proteolytic cleavage
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26
Q

What is Vitamin K?

A

A co-factor for gamma-glutamyl carboxylase. Adds carboxylase group to glutamate residues of proteins C, S, 2, 7, 9 and 10

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27
Q

What is specific proteolytic cleavage?

A

A common means of activating enzymes in biological systems - off -> on as don’t want to be active in wrong place

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28
Q

What are some examples of specific proteolysis?

A
  • Digestive enzymes are synthesised as zymogens (inactive precursors) in the stomach and pancreas i.e. pepsinogen is zymogens of pepsin - Some protein hormones (i.e. insulin) are synthesised as inactive precursors - Blood clotting is mediated by a cascade of proteolytic activations that ensures a rapid and amplified response - Many development processes are controlled by the activation of zymogens to contribute to tissue remodelling - Apoptosis is mediated by proteolytic enzymes, caspases, which are synthesised in inactivate (procaspase) form
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29
Q

How is the activation of pancreatic proteases controlled?

A

By trypsin (major molecule secreted from exocrine pancreas for protein digestion). Pancreatic proteases have a wide range of specificities

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30
Q

What kind of inhibitors regulate protease activity?

A

Endogenous inhibitors e.g. pancreatic trypsin inhibitor binds trypsin and stops activity. Ribosomes don’t work on these. Can’t switch zymogen off so cell must control

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31
Q

What is α1-antitrypsin?

A

53kDa plasma protein that inhibits a range of proteases

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32
Q

What is emphysema?

A

Deficiency of α1-antitrypsin. Destruction of alveolar walls by elastase

33
Q

What is FX -> FXa?

A

Key component of clotting cascade

34
Q

What forms of long-term protein regulation are there?

A
  • Altering rate of protein synthesis - can be modified at numerous levels, including the degree of promotion of a gene, the rate of mRNA destruction and enzyme induction/repression - Altering rate of protein degradation - a protein can be tagged for destruction through covalent modification e.g. ubiquitin-proteasome pathway
35
Q

Outline the blood clotting cascade

A

Intrinsic pathway (damages endothelial lining of blood cells promotes binding of factor XII) AND extrinsic pathway (trauma releases tissue factor, factor III) –> Factor X activation (common endpoint for both pathways) –> Thrombin activation –> Formation of fibrin clot

36
Q

How are proteins of blood coagulation (e.g. factor III = tissue factor) secreted?

A

As inactive precursors -> cut off part -> active. Triggers clotting when blood vessels damaged

37
Q

Is fibrin an enzyme?

A

No, it is a protein that forms clots

38
Q

What causes positive feedback in the coagulation cascade?

A

From thrombin –> : Protein C+ -> Active Protein C, Factor XI -> XIa, V -> Va, VIII -> VIIIa, XIII -> XIIIa

39
Q

What causes negatie feedback in the coagulation cascade?

A

TFPI, Thrombomodulin, Active Protein C, Antithrombin

40
Q

What happens in the extrinsic pathway of the coagulation cascade?

A

Activation of Factor VII: Membrane damage exposes extracellular domain of tissue (Factor III). Autocatalytic activation of Factor VII

41
Q

What happens in the intrinstic pathway of the coagulation cascade?

A

Keeps blood clotting going. Membrane damage plays a role in pathway activation. Factor IX and X are targeted to membrane by Gla domains. Ca2+ plays a role. Required for sustained thrombin activation

42
Q

Outline the process of clot breakdown (fibrinolysis)

A
43
Q

Outline the modular structure of prothrombin

A

Protease function (thrombin part) is contained in the C-terminal domain. Two kringle domains help keep prothrombin in the inactive form. Gla domains (carboxyglutamate) target it to appropriate site for its activation

44
Q

Outline the activation of thrombin

A

When Factor X comes. Involves proteolytic cleavage at Arg274 to release a fragment containing first 3 domains. Cleavage after Arg323 releases fully active thrombin consisting of two chains, 5kDa and 31kDa, linked by a disulphide bond

45
Q

What is the role of gamma-carboxyglutamate (Gla) residues?

A

Enzymes secreted through ER. Post-translational modification of factors II, VII, IX, X in the liver. Addition of COOH groups to glutamate residues to from Gla in Golgi - patches of negative charge. Allows interaction of sites of damage and brings together clotting factors

46
Q

Outline the role of the calcium-binding region of prothrombin

A

Prothrombin binds calcium ions via Gla residues. Only prothrombin next to site of damage will be activated. Clots will be localised to the site of damage

47
Q

Outline the structure of fibrinogen (inactive form of fibrin)

A
  • 340kDa protein
  • 2 sets of tripeptides - alpha, beta, gamma - joined at N-termini by disulphide bonds
  • 3 globular domains linked by rods
  • N-terminal regions of alpha and beta chains are highly negatively charged and prevent aggregation of fibrinogen (they repel)
48
Q

Outline the formation of a fibrin clot

A
  • Thrombin cleaves fibrinopeptides A and B from the central globular domain of fibrinogen
  • Globular domains at the C-terminal ends of the beta and gamma chains interact with exposed sequences at the N-termini of the cleaved beta and alpha chains to form a fibrin mesh or clot
  • Newly formed clot stabilised by formation of amide bonds between side chains of lysine and glutamine residues in different monomer - a cross-linking reaction
49
Q

How is the formation of a fibrin clot catalysed?

A

By transglutaminase, which is activated from protransglutaminase by thrombin

50
Q

What causes haemophilia A (classic haemophilia)?

A

A defect in factor VIII (antihaemophilic factor) - not a protease, but markedly stimulates activity of factor IXa, a serine protease. Activity of factor VIII is markedly increased by limited proteolysis by thrombin and factor Xa. This positive feedback amplifies clotting signal and accelerates clot formation. Treat with recombinant factor VIII

51
Q

What causes haemophilia B?

A

A defect in factor IX

52
Q

Outline the stopping of the clotting process

A
  • Localisation of (pro)thrombin. Dilution of clotting factors by blood flow, and removal by liver.
  • Digestion by proteases i.e. factors Va and VIIIa degraded by protein C, which is activated by thrombin binding to endothelial receptor, thrombomodulin. Defects in protein C can cause thrombotic disease.
  • To stop clotting: specific inhibitors. Antithrombin III (AT3), enhanced by heparin binding. AT3-heparin does not act n thrombomodulin-bound thrombin
53
Q

What is the shade of each form of chromatin in the nucleus?

A

Heterochromatin = dark

Euchromatin = light

54
Q

Is a nucleosome a rigid molecule?

A

No, it is flexible

55
Q

What does heterochromatin consist of?

A

Solenoid 30nm fibre

Genes not expressed

56
Q

What does euchromatin consist of?

A

Beads on a string - histone core and linker DNA of nucleosome

Genes expressed

57
Q

Are genes expressed in a chromosome?

A

No, DNA too tightly wound

58
Q

What are genes?

A

They carry the code for proteins and have a chromosomal location

59
Q

How many genes are there?

A

Humans have about 25,000

Fruitfly has about 15,000

E.coli has about 4,500

(Our regulation is far more complex)

60
Q

What is a genome?

A

The entire DNA sequence. Human Genome is 24 chromosomes (22 autosomes plus 2 sex chromosomes X and Y)

61
Q

How many base pairs are there in a genome?

A

Human: 3,200,000,000 bp

Fruitfly: 140,000,000 bp

E.coli: 4,600,000 bp

Studies re. bp needed for life: ~500

62
Q

What are DNA and RNA?

A

Nucleic acids

63
Q

What are nucleic acids?

A

Polynucleotides = linear polymers of nucleotides

64
Q

What is a nucleoside?

A

Base + sugar

65
Q

What is a nucleotide?

A

Base + sugar + phosphate

66
Q

What is the difference between ribonucleic acid (RNA) and deoxyribonucleic acid (DNA)?

A

RNA contains ribose (OH at carbon-2) and DNA contains 2-deoxyribose (H at carbon-2)

67
Q

What are the two types of nitrogenous base?

A

Purine - 2 rings

Pyrimidine - 1 ring

68
Q

What are the two types of main purines?

A

In both DNA and RNA: adenine and guanine

69
Q

What are the three types of main pyrimidines?

A

Cytosine (in RNA/DNA), uracil (in RNA) and thymine (in DNA)

There are derivatives in other molecules that we can use to interfere with, for example, transcription/replication

70
Q

Give examples of nucleic acid nomenclature in order: Base, Nucleoside, Nucleotide

A

In RNA:

Adenine, Adenosine, Adenosine Monophosphate (AMP)

Cytosine, Cytidine, Cytidine Monophosphate (CMP)

In DNA:
Adenine, Deoxyadenosine, Deoxyadenosine Monophosphate (dAMP)

71
Q

How are nucleotides joined?

A

By phosphodiester bonds

DNA and RNA are polymers

Chain has polarity - 5’ to 3’

Chain has distinct ends - 5’P and 3’OH

72
Q

What happens during base pairing?

A

Purine is flipped

G-C: 3 H bonds (all bonds almost same length, so logical that they bond)

A-U or A-T: 2 H bonds. Distance too far to form 3rd H bond

73
Q

When can nucleic acids form duplex structures?

A

When antiparallel (1 is flipped) and complementary

74
Q

What types of duplex structures can be formed?

A

DNA-DNA, RNA-RNA and DNA-RNA

Stable or temporary

In vivo and in the laboratory

75
Q

Describe the structure of RNA stem-loops, i.e. in tRNA

A

UUUC loop then 2 complementary stems. Hydrogen bonds are formed between anti-parallel, complementary sequences

76
Q

Describe the structure of the DNA double helix

A

Right-handed double helix

Anti-parallel strands of DNA

Major groove = rigid

Minor groove = flexible

Major and minor groove are asymmetrical

77
Q

How is a polynucleotide sequence depicted?

A

5’ A C C U 3’

(Can leave numbers off)

By convention, 5’ to 3’ from left to right

78
Q

How is a duplex sequence depicted?

A

5’ A C C T C G 3’

3’ T G G A G C 5’

(Can leave off 2nd strand)

Anti-parallel, complementary strands

By convention, top strand 5’ to 3’ from left to right

My ESA1 (11 decks)

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