Defensins are an ancient, evolutionarily conserved class of antimicrobial peptides made by many eukaryotic organisms, including mammals, insects, and plants (Fig. 2.10). They are short cationic peptides of around 30–40 amino acids that usually have three disulfide bonds stabilizing a common amphipathic structure—a positively charged region separated from a hydrophobic region. Defensins act within minutes to disrupt the cell membranes of bacteria and fungi, as well as the membrane envelopes of some viruses. The mechanism is thought to involve insertion of the hydrophobic region into the membrane bilayer and the formation of a pore that makes the membrane leaky (see Fig. 2.10). Most multicellular organisms make many different defensins
Fig. 2.9 Lysozyme digests the cell walls of Gram-positive and Gram-negative bacteria. Upper panels: the peptidoglycan of bacterial cell walls is a polymer of alternating residues of β-(1,4)-linked N-acetylglucosamine (GlcNAc) (large turquoise hexagons) and N-acetylmuramic acid (MurNAc) (purple circles) that are cross-linked by peptide bridges (red bars) into a dense three-dimensional network. In Gram-positive bacteria (upper left panel), peptidoglycan forms the outer layer in which other molecules are embedded such as teichoic acid and the lipoteichoic acids that link the peptidoglycan layer to the bacterial cell membrane itself. In Gram-negative bacteria (upper right panel), a thin inner wall of peptidoglycan is covered by an outer lipid membrane that contains proteins and lipopolysaccharide (LPS). Lipopolysaccharide is composed of a lipid, lipid A (turquoise circles), to which is attached a polysaccharide core (small turquoise hexagons). Lysozyme (lower panels) cleaves β-(1,4) linkages between GlcNAc and MurNAc, creating a defect in the peptidoglycan layer and exposing the underlying cell membrane to other antimicrobial agents. Lysozyme is more effective against Gram-positive bacteria because of the relatively greater accessibility of the peptidoglycan.
Anatomic barriers and initial chemical defenses.
Fig. 2.10 Defensins are amphipathic peptides that disrupt the cell membranes of microbes. The structure of human β1-defensin is shown in the top panel. It is composed of a short segment of α helix (yellow) resting against three strands of antiparallel β sheet (green), generating an amphipathic peptide with charged and hydrophobic residues residing in separate regions. This general feature is shared by defensins from plants and insects and allows the defensins to interact with the charged surface of the cell membrane and become inserted in the lipid bilayer (center panel). Although the details are still unclear, a transition in the arrangement of the defensins in the membrane leads to the formation of pores and a loss of membrane integrity (bottom panel).
—the plant Arabidopsis thaliana produces 13 and the fruitfly Drosophila melanogaster at least 15. Human Paneth cells make as many as 21 different defensins, many of which are encoded by a cluster of genes on chromosome 8.