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A10HA > 18 - Antimicrobial Peptides > Flashcards

18 - Antimicrobial Peptides Flashcards

1
Q

General structure of AMPs

A
  • signal peptide
  • propeptide
  • mature peptide
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2
Q

Signal peptide

A
  • conserved
  • prompts cell to translocate/ secrete peptide
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3
Q

Propeptide

A
  • conserved (whole/partially)
  • anionic
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4
Q

Mature peptide

A
  • variable
  • cationic
  • becomes active following cleavage
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5
Q

What are the structures of conventional peptide

A

Post-translational modifications of AMPs important

1) cysteine-rich, disulphide bonds e.g., defensin (1- disulphide bond eg bactenecin, 2- disulphide bonds eg protegrin, 3- disulphide bonds eg defensin)

2) α-helical eg cecropin

3) Extended structure, peptide-enriched e.g. indolicidin

4) Loop structure e.g. θ-defensin

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6
Q

What are the structures of ‘unconventional’/antibacterial fragments of larger proteins?

A
  • histones
  • e.g., lactoferrin - kaliocin, lactoerricin, lactoferrampin
  • apolipoproteins, neuropeptides, pore forming toxins, fatty acids, respiratory/other pigments, lectins
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7
Q

Features of defensives in mammalian AMPs

A
  • Small, 3-6 kDa peptides
  • Active against Gram + & Gram – bacteria (some variation with individual peptides)
  • Structural motif: cysteines (6-8 residues), disulphide bonds (3-4) Arginine-rich
  • Bonds essential for maintaining hydrophobic  sheet
  • Active against Gram +ve & Gram -ve bacteria, fungi, some enveloped viruses and eukaryotic cells
    -Deficiencies associated with Crohn’s disease
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8
Q

What are the types of mammalian AMPs?

A

alpha, beta, and theta defensins, and mammalian cathelicidins

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9
Q

What is the structure of alpha-defensins?

A
  • signal - 19aa
  • propiece - 40-45aa
  • active peptide - 30aa
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10
Q

What are some features of alpha-defensins?

A
  • First reported 1960s from rabbit neutrophils
  • 6, α-defensins found in humans
  • 4 α-defensins isolated from azurophilic granules of neutrophils (HNP1-4) Also found in NK cells, B cells
  • Enteric defensins (α defensins HNP5 & 6) found in Paneth cells, uro-genital epithelial cells
  • Constitutive expression
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11
Q

Structure of beta-defensins (hBD)

A
  • signal & propiece - 20-30 aa
  • active peptide - 35-42aa
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12
Q

What are some features of beta defensins?

A
  • Predominantly found in epithelial tissues
  • Some β defensins have short alpha-helix
  • hBD1 – epithelial cells of urinary, respiratory system; Constitutive
  • hBD-2 & 3 also present in GI epithelia, psoriatic skin, upregulated
    by LPS or cytokines
  • hBD4-6 discovered in human epididymis
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13
Q

Where have beta defensins been found?

A
  • pig, rat, sheep, chimp, cow, goat, human, macaque, mouse
  • highest proportion found in cows
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14
Q

What are some features of theta defensins

A
  • 1999: circular θ mini-defensins identified in Rhesus monkeys
  • Heterodimeric peptide, expressed in monkey leukocytes
  • Broad spectrum antimicrobial activity, inhibits bacterial toxins, active against HIV
  • ‘Human’ θ defensins synthesized – christened ‘retrocyclins’
  • Of interest re development for topical microbicides: application to prevent HIV-1 and HSV infections
  • Human ancestral genes: possible re-awakening?
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15
Q

Structure of theta defensins?

A

18 a-a, 3 disulphide bonds

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16
Q

Structure of mammalian cathelicidins

A
  • three parts: signal (20-30aa), cathelin domain (100-120aa) and peptide (19-94aa)
  • and the conserved prepare region and the variable active domain
17
Q

Features of mammalian cathelicidins

A
  • Primarily in mammals, ca. 40 members
  • N-terminal highly conserved, identifies cathelicidins
  • Expressed in bone marrow, stored in peroxidase-negative neutrophil granules, then exocytosed from activated cells
  • Most are without antibacterial activity until C-terminal proteolytically removed
  • One cathelicidin found in humans - LL-37 (α-helical)
18
Q

How do AMPs work?

A
  • clustering of cationic and hydrophobic domains
  • AMPs may be expressed constitutively and stored before release at site or time of need
  • in some cells/tissues, AMP expression induced by microorganisms
19
Q

Types of interactions of AMPs

A
  • hydrophobic interactions (weak) on plasma membrane of a multicellular animal
  • electrostatic and hydrophobic interactions (strong) on bacterial cytoplasmic membrane
20
Q

Name the models related to AMPs

A
  • The Shai-Matsuzaki-Huang Model
  • Barrel Stave Killing
  • Toroidal Pore Killing
  • Carpet Model
21
Q

What does the Shai Matsuzaki Huang Model propose?

A
  • it involves the association of AMPs with the membrane surface, parallel to it, with the hydrophilic face of the helix oriented towards the water phase
  • a ccording to this model, membrane perturbation is caused by the strain produced in the outer layer of the membrane by peptide insertion
  • when a threshold membrane-bound peptide/lipid ratio is reached, this strain is released by the formation of membrane defects
22
Q

What does the Barrel Stave Killing Model propose?

A
  • One of the first hypotheses put forward was the “barrel-stave” mechanism
  • peptides insert into the membrane in a transbilayer orientation, and aggregate to form a pore, with their hydrophilic faces lining the water-filled lumen of the channel and their apolar residues pointing towards the membrane
  • even though this model was proposed more than 30 years ago, a conclusive demonstration of its validity was obtained only for the peptaibol alamethicin
23
Q

What does the Toroidal Pore Killing Mechanism propose?

A
  • AMPs bind to lipids, at critical concentration, bacterial membrane is caused to curve inwards through the pore
  • Some association of the AMP-pore components with the lipid head groups of the bacterial membrane retained (e.g. the fish AMP piscidin from the striped bass, Morone)
24
Q

What does the Carpet Model propose?

A
  • AMPs aggregate on bacterial membrane
  • Disruption of bilayer occurs in a detergent-like fashion
  • This leads to the formation of micelles (e.g. dermaseptin from the frog genus Phyllomedusa)
24
Q

What does the Carpet Model propose?

A
  • AMPs aggregate on bacterial membrane
  • Disruption of bilayer occurs in a detergent-like fashion
  • This leads to the formation of micelles (e.g. dermaseptin from the frog genus Phyllomedusa)
25
Q

Summary of AMP modes of action

A
  • AMPs can cause direct neutralisation with membrane disruption (i.e., carpet, barrel stave & toroidal pore models) and targeting internal structures
  • AMPs can cause immunomodulation of PMNs & monocytes resulting in increased bacterial clearance and inflammation control
26
Q

what anti-cancer activity do AMPs have?

A
  • Not all AMPs kill cancer cells
  • Examples of naturally-occurring anti-cancer AMPs include LL-37, HNP-1, lactoferricin, magainin-2
  • Killing believed to be linked to different membrane properties
27
Q

AMPs: cancer vs. normal

A

CANCER:
- net negative charge: phosphatidylserine (PS), O-glycosylated mucins
- greater membrane fluidity
- greater surface area, more microvilli

NORMAL:
- neutral: sphingomyelin, phosphatidylethanolamine (PE), phosphatidylcholine (PC)
- cholesterol - may interfere with AMP insertion into membrane

28
Q

AMPs: cancer vs. normal

A

CANCER:
- net negative charge: phosphatidylserine (PS), O-glycosylated mucins
- greater membrane fluidity
- greater surface area, more microvilli

NORMAL:
- neutral: sphingomyelin, phosphatidylethanolamine (PE), phosphatidylcholine (PC)
- cholesterol - may interfere with AMP insertion into membrane

A10HA (18 decks)

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