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Chemistry and Disease > Molecular basis of disease (1) > Flashcards

Molecular basis of disease (1) Flashcards

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1
Q

DNA…….mRNA……….protein

A

Transcription, translation

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2
Q

What are the 3 main types of post-translational modifications?

A

Allosteric, proteolytic, covalent

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3
Q

List the 5 covalent modifications and the amino acids they affect

A

Acylation- Lys
Phosphorylation- ser, thr, tyr
Lipidation- Lys or n-terminus, or c-terminus of a protein via c-terminal cys-SH
Glycosylation (outside cell)- Asn, Ser, Thr
Methylation- Lys, Arg

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4
Q

What is needed for phosphorylation to take place?

A

Free OH

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5
Q

Describe some key points of phosphorylation

A

Addition of phosphate group- large negative charge can cause major changes in protein structure- may change function and large negative patch may attract some positively charged amino acids.
PO3- can be engaged in a few H-bonds- hence attracting other proteins/domain of same protein
Catalysed by protein kinases- use ATP as source of phosphate
Reversible- phosphate group removed by phosphatases
Phophorylation/de-p allows for reversible, flexible and controllable regulation of activity
Modulaion/amplification of signal- cell signalling cascades.

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6
Q

What are the enzymes that catalyse phosphorylation (on) and de-phosphorylation (off)?

A

on= kinases, off= phophatases

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7
Q

What are the 2 types of immune defences and how do they differ?

A

Innate and adaptive
Innate= recognition of only a few molecular fingerprints, fast, cheap
Adaptive= recognition of infinite # molecules, slow, expensive, can attack ‘self’, but UNLIMITED

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8
Q

What is the role of Pattern Recognition Receptors (PRR) and what is the main one?

A

Recognition of pathogen-associated molecular patterns= markers
eg LPS= lipopolysaccharide

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9
Q

What is the role of endocytic PRR?

A

Can discriminate between the surface molecules of the host and the pathogen (eg mannose-binding lectin).

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10
Q

What is the role of oxidative/respiratory burst?

A

Molecular bleaching

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11
Q

What are some examples of anti-bacterial molecules produced during oxidative burst?

A

NO, O2-, H2O2, .OH, OCL-

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12
Q

Describe the general scheme of signalling from outside cell to nucleus

A

Signal- coupling to receptor- transduction (effector)- amplification- specificity

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13
Q

What is the role of 1-9 TOLL PRRs (TLRs)?

A

Initiation of expression of molecular (protein-like) messengers of inflammation (cytokines and chemokines).

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14
Q

What are the main roles of signalling PRR?

A

Stimulation of phagocytosis, provision of the chemotactic guidance (chemokines leave molecular trails), induction of production of effector molecules (eg cytokines).

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15
Q

What are chemokines and cytokines crucial for and what are they also known as?

A

Crucial for initiation and maintenance of inflammation. Inter-cells regulatory molecules.

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16
Q

What is the key innate immune system response?

A

Separate infecting pathogen from the bloodstream and other tissues.

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17
Q

How do cytokines act further, what to they effect and what can this lead to?

A

Act further through fast and direct signalling pathway to effect changes in gene transcription through very potent transcription factors. Can lead to an overexpression of receptors for leukocytes on the walls of blood vessels to immobilise them at the site of the infection.

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18
Q

Give examples of some of the biological activities of cytokines (which help to coordinate the body’s response to infection)

A

Major effect on brain temp regulation centres and on the muscle and fat cells to alter energy flow.

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19
Q

Describe the general mechanism of inflammation

A
  1. Endocytosis and destruction of bacteria by macrophages (with help of PRRs)
  2. Macrophage starts the production of:
    (i) chemokines (CHK - chemical messengers of where bacteria are)
    (ii) cytokines (CK -messengers to other tissues – blood vessels - to express
    and produce receptors for neutrophils)
  3. Cytokines start inducing expression of neutrophils receptors (NR) in veins –
    (i) neutrophils stop rolling but are adhered in vein close to the infection
    (ii) cytokines help also in formation of gaps in veins that enable
    neutrophils penetration of the infected tissue
  4. Chemokine Receptors (CHR) on neutrophils sense chemokine gradient and guide
    neutrophils towards the site of infection
  5. Neutrophils at the site of infection:
    (i) endocyte bacteria and help macrophage to remove them from the
    tissue – they can use oxidative burst here as well.
    (ii) prolong action of neutrophils may lead to formation of pus.
  6. Local blood clotting – wound formation
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20
Q

What is the role of inflammation?

A
  • to deliver additional effectors molecules and cells to the site of infection
  • to augment the killing of invading pathogens by front-line macrophages
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21
Q

Which immune system acts on the macro-scale and which on the micro-scale?

A

Innate= macro, adaptive= micro

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22
Q

What are the initial steps of the adaptive immune system, and when do the t-cells recognise the antigen?

A

Initial steps involve antigen preparation-presentation, and its recognition (viral or bacterial). T-cells (T-Cell Receptor) recognise antigen only when its complexed with MHC (antigen presenting complex).

23
Q

What will the adaptive immune system lead to?

A 
Humoral = B-cell-mediated immune response leads to production of the immunoglobulins = antibodies 
Cellular = T-cell-mediated immune response results in formation of special killer cells
24
Q

What are innate and adaptive immunity mediated by?

A

Antigen presenting cells (APCs)

25
Q

What is the immunglobulin fold the structural basis for?

A

Major HistoCompatibility complex: MHC (used for presentation of antigens)
T-Cell Receptors (used for recognition of antigen-MHC complexes)
Immunoglobulins = antibodies (to bind many antigen-containing proteins from pathogens)

26
Q

What is the function of antibodies?

A
  1. blocking binding of pathogen toxins
  2. blocking binding of virus to human cells by engaging in complexes with viral surface proteins
  3. blocking bacterial colonisation by binding to bacterial surface proteins
27
Q

Describe phosphorylation cascades

A

Can be started in the T-cells only after formation of the immunological synapse: the molecular zipper of many receptors that have to confirm that the appropriate antigen is exposed by MHC complex and recognised by an appropriate TCR (e.g. MHC(I/II)-TCR-CD4(8)
and other receptor complexes) – this is the last line of immune defence.

28
Q

List Koch’s postulates

A

–the pathogen must be present in every case of the disease
–the pathogen must be isolated from the diseased host & grown in a pure culture
–the specific disease must be reproduced when a pure culture of the pathogen is inoculated into a
healthy susceptible host
–the pathogen must be recoverable from the experimentally infected host

29
Q

What are some exceptions to Koch’s postulates?

A

it is very difficult to show the presence of bacteria in all infected people for some infections (cholera- can be found experimentally only in a fraction of ill people but
cannot be detected in any healthy individual, therefore Cholera infection requires an additional rigorous
statistical validation).
-It is difficult to isolate some microbes and to grow them in a pure culture (e.g. some retroviruses (HIV,
leprosy bacteria
-healthy humans cannot often be infected to achieve the required symptoms (e.g. HIV) due to health
hazard and ethical reasons
-some microbes are very human-specific and will not cause an infection in the animal models (e.g.
hepatitis B/C, yellow fever)

30
Q

Describe the stages in pathogenesis

A

Encounter, Entry, Colonisation, Multiplication, Invasion, Evasion of host innate or acquired immunity, Transmission.

31
Q

What are the virulence factors?

A

Adhesins – Adherence
Invasins – Invasion of cell (+ secretion of the pathogen proteins into the host cell)
Agressins - (= toxins = exo-toxins + endo-toxin) – Cause direct damage to the host (toxins)

32
Q

What are the functional classes of exo-toxins? Give examples for each

A
  1. Enzymes (metalloproteases- tetanus, anthrax toxins)
  2. Non-enzymes: pore-forming proteins (hemolysins from E coli)
  3. Superantigens (proteins but NOT ENZYMES- cause massive prod of cytokines- toxic- septic shock, eg enterotoxins, toxic shock protein)
33
Q

What do endotoxins cause?

A

Panic signalling in body (NB not proteins).

34
Q

What are endotoxins?

A

= LPS – is a lipo-poli-saccharide (lipids + carbohydrates) derived from bacteria membrane. If abundant in the blood it causes Septic shock (too much TOLL signalling, too much cyto/chemo-kines!)

35
Q

Why are superantigens so toxic?

A

Have a unique mode of binding to both MHC II and T-cell Receptor (TR) molecules and activate large – 5-25% subsets of T-cells without proper antigen present.
This mode of stimulation does not prime an adaptive immune response specific for a pathogen: ‘antigen’ (e.g.
peptide from pathogen’s protein) has not been processed and presented in a normal way! Instead it causes a massive production of cytokines = TOXIC = SEPTIC shock – similar to presence of large amount of LPS in the blood.

36
Q

List some properties of a virus, what are the consequences of these?

A

Filterable agents/ are obligate intracellular parasites/ cannot make energy or proteins independently of a host cell/ viral genomes may be RNA or DNA but not both/ have a naked capsid or envelope morphology/components are assembled (are not binary fused) and do not replicate by ‘division’.

Consequences: viruses are not living/ must be infectious to endure in nature/ must be able to use host processes to produce their components/ must encode any required processes not provided by the cell/ viral components must self-assemble.

37
Q

What is the definition of a virus?

A

Organized associations of macromolecules- nucleic acid- contained within a protective shell of protein units.

38
Q

What does the virion/virus particle contain?

A

genome (DNA or RNA – not both!)
capsid (protein coat)
envelope (membrane)
virion may also contain some essential or accessory enzymes

39
Q

What is the difference between the viral capsid and envelope?

A

Capsid: is a rigid structure able to withstand harsh conditions, while envelope is lipidic membrane
(lipids + glyco-proteins = fragile, these viruses must be wet).

40
Q

Describe the roles of virion proteins

A 
- protect nucleic acid
• attach to receptors on cells
• penetrate cell membrane
• replicate nucleic acid (some viruses)
• begin program for replication (some viruses)
• modify host cell (some viruses)
41
Q

List the types of virus genomes

A
  • Single-stranded or double-stranded DNA OR RNA (but not both!)
  • Linear, circular or segmented
  • Single-stranded RNA virus genomes may be either:
  • positive (+) sense = mRNA
  • negative (-) sense,
  • ambisense.
42
Q

Describe the general virus life cycle

A 
- Adhesion
• Penetration
• Uncoating
• Replication of Nucleic Acid
• Maturation and Release
43
Q

What is the difference between antigenic drift and antigenic shift?

A 
Drift= minor mutation every 2/3 years
Shift= major mutation at ~10year intervals, animal vector (host) must be involved in incubation of different type of animal viruses (e.g. human and avian) to facilitate exchange of large parts of the genetic material between viruses.
44
Q

How does the method of invasion differ between influenza and HIV?

A 
Influenza= endocytosis- virus is engulfed by cell.
HIV= direct fusion with host cell membrane
45
Q

Name the enzyme that fuses HIV DNA with human DNA

A

Integrase enzyme

46
Q

List the 4 types of genetic disease

A

Single gene defects, multi-factorial/ complex disorders, chromosonal mutations disorders, mitochondrial mutations disorders

47
Q

What is an example of a complex disorder?

A

Type 2 diabetes (genetic and environmental)

48
Q

Describe the 3 classifications of single gene defects and give example of each

A 
1. autosomal recessive disorders: require the inheritance of TWO defective alleles, no functioning copies of the gene- implies that the disorder results from loss of
function (Cystic fibrosis, haemoglobinopathies, phenylketonuria,)
2. autosomal dominant disorders: result from the inheritance of only one mutant allele, usually results in a protein that has gained a novel function or it is expressing its normal function in an unregulated fashion (Huntington's disease, familial breast cancer, Alzheimer
disease, retinoblastoma)
3. X-chromosome linked disorders: located on X chromosome, males have only one copy of X = one copy a gene x they suffer more in this disorder (haemophilia, Fragile X-syndrome)
49
Q

What are the 2 types of chromosonal mutation disorders?

A

Sex chromosones and autosomes

50
Q

How do the symptoma of mitochondrial DNA-linked disorders link to aging?

A

Same common symptoms

51
Q

How are mitochondrial DNA-linked disorders inherited?

A

Maternally inherited

52
Q

Describe the 3 classes of models of amyloid-like fibrils

A

Refolding models:
- in the conversion from native to fibril the protein must unfold and then refold.
- it has been suggested that the sequence of amino acids is not important here
- main interactions are dictated by the main chain interactions
- models for prion, insulin fibrils
Natively disordered models:
- certain proteins are poorly ordered or disordered in their native states
- in the process of making the fibril all, or a part of the previously unstructured
polypeptide becomes structured to form the cross-beta spine
- serpentine arrangements of beta-strands each contributing to a separate b-sheet:
‘paralleled superplated beta-sheet’
- beta-amyloid (Ab) polypeptide, poly-Glu of huntingtin
Gain of interactions models:
- conformational change in a limited region of the native protein exposes previously
inaccessible surface.
- this newly exposed surface binds to a surface of another molecule building up the
fibril
- only the interaction surface and its links to the core domain are changed
(I) Direct stacking
(ii) Cross-b-spine
(iii) 3D domain swapping
(iv) 3D domain swapping with cross-b-spine

53
Q

What is the most highly infective form of human fibrils, and why is this?

A

~20 molecules oligomers, smaller aggregates have a higher proportion of normally buried side-chains on
their surface than fibrils.

54
Q

What is likely to trigger aberrant events in a crowded environment?

A

The non-native character of misfolded oligomers.

Chemistry and Disease (7 decks)

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