Pardaxin is a

peptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty am ...

produced by the Red Sea sole (P4, P5) and the Pacific Peacock sole (P1, P2, P3) that is used as a

shark Sharks are a group of elasmobranch cartilaginous fish characterized by a ribless endoskeleton, dermal denticles, five to seven gill slits on each side, and pectoral fins that are not fused to the head. Modern sharks are classified within the ...

repellent. It causes

lysis Lysis ( ; from Greek 'loosening') is the breaking down of the membrane of a cell, often by viral, enzymic, or osmotic (that is, "lytic" ) mechanisms that compromise its integrity. A fluid containing the contents of lysed cells is called a ...

mammalia A mammal () is a vertebrate animal of the class Mammalia (). Mammals are characterised by the presence of milk-producing mammary glands for feeding their young, a broad neocortex region of the brain, fur or hair, and three middle ear bon ...

n and bacterial cells, similar to

melittin Melittin is the main component (40–60% of the dry weight) and the major pain-producing substance of honeybee (''Apis mellifera'') venom. Melittin is a basic peptide consisting of 26 amino acids. Function The principal function of melittin a ...

Synthesis

In the lab, pardaxin is synthesized using an automated peptide synthesizer. Alternatively, the secretions of the Red Sea sole can be collected and purified.

Functions

Antibacterial peptide

Pardaxin has a helix-hinge-helix structure. This structure is common in peptides that act selectively on bacterial membranes and cytotoxic peptides that lyse mammalian and bacterial cells. Pardaxin shows a significantly lower

hemolytic Hemolysis or haemolysis (), also known by several other names, is the rupturing (lysis) of red blood cells (erythrocytes) and the release of their contents (cytoplasm) into surrounding fluid (e.g. blood plasma). Hemolysis may occur in vivo ...

activity towards human red blood cells compared to melittin. The C-terminal tail of pardaxin is responsible for this non-selective activity against the

erythrocytes Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood cel ...

and bacteria. The amphiphilic C-terminal helix is the ion-channel lining segment of the peptide. The N-terminal α-helix is important for the insertion of the peptide to the

lipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes form a continuous barrier around all cell (biology), cells. The cell membranes of almost all organisms and many viruses a ...

of the cell. The mechanism of pardaxin is dependent on the membrane composition. Pardaxin significantly disrupts lipid bilayers composed of

zwitterionic In chemistry, a zwitterion ( ; ), also called an inner salt or dipolar ion, is a molecule that contains an equal number of positively and negatively charged functional groups. : (1,2-dipolar compounds, such as ylides, are sometimes excluded from t ...

lipids, especially those composed of 1-palmitoyl-2-oleoyl-phosphatidylcholine ( POPC). This suggests a carpet mechanism for cell

. The carpet mechanism is when a high density of peptides accumulates on the target membrane surface. The phospholipid displacement changes in fluidity, and the cellular contents leak out. The presence of anionic lipids or

cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...

was found to reduce the peptide's ability to disrupt bilayers.

Shark repellent

''P. marmoratas'' and ''P. pavoninus'' release pardaxin when threatened by sharks. Pardaxin targets the

gills A gill () is a respiratory organ that many aquatic organisms use to extract dissolved oxygen from water and to excrete carbon dioxide. The gills of some species, such as hermit crabs, have adapted to allow respiration on land provided they are ...

and pharyngeal cavity of the sharks. It results in severe struggling, mouth

paralysis Paralysis (: paralyses; also known as plegia) is a loss of Motor skill, motor function in one or more Skeletal muscle, muscles. Paralysis can also be accompanied by a loss of feeling (sensory loss) in the affected area if there is sensory d ...

, and temporary increase of

urea Urea, also called carbamide (because it is a diamide of carbonic acid), is an organic compound with chemical formula . This amide has two Amine, amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest am ...

leakage in the gills. This distress is caused by the attack of the cellular membrane of the gills, which causes a large influx of salt ions. Research into creating a commercial shark repellent using pardaxin was discontinued because it dilutes in the water too quickly. It is only effective if sprayed almost directly into a shark's mouth.

Cancer treatment

Pardaxin inhibits proliferation and induces

apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...

of human cancer cell lines. Its 33-

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...

structure contains many cationic and

amphipathic In chemistry, an amphiphile (), or amphipath, is a chemical compound possessing both hydrophilic (''water-loving'', polar) and lipophilic (''fat-loving'', nonpolar) properties. Such a compound is called amphiphilic or amphipathic. Amphiphilic c ...

amino acids. This makes it easier for it to interact with anionic membranes, such as those in

tumor A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...

cells, which are inherently more acidic because of the acidic environment created by more

glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvic acid, pyruvate and, in most organisms, occurs in the liquid part of cells (the cytosol). The Thermodynamic free energy, free energy released in this process is used to form ...

. Pardaxin initiates

caspase Caspases (cysteine-aspartic proteases, cysteine aspartases or cysteine-dependent aspartate-directed proteases) are a family of protease enzymes playing essential roles in programmed cell death. They are named caspases due to their specific cyste ...

-dependent and caspase-independent apoptosis in human cervical carcinoma cells. Pardaxin triggers

reactive oxygen species In chemistry and biology, reactive oxygen species (ROS) are highly Reactivity (chemistry), reactive chemicals formed from diatomic oxygen (), water, and hydrogen peroxide. Some prominent ROS are hydroperoxide (H2O2), superoxide (O2−), hydroxyl ...

(ROS). ROS production disrupts

protein folding Protein folding is the physical process by which a protein, after Protein biosynthesis, synthesis by a ribosome as a linear chain of Amino acid, amino acids, changes from an unstable random coil into a more ordered protein tertiary structure, t ...

and induces the unfolded protein response (UPR). This causes stress on the

endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...

, which releases

calcium Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...

. This leads to an increase in mitochondrial calcium, dropping its

membrane potential Membrane potential (also transmembrane potential or membrane voltage) is the difference in electric potential between the interior and the exterior of a biological cell. It equals the interior potential minus the exterior potential. This is th ...

. The pore permeability changes, and Cytochrome c (Cyt c) is released. Cyt c activates the caspase chain that leads to apoptosis. ROS also activates the

JNK c-Jun N-terminal kinases (JNKs), were originally identified as kinases that bind and phosphorylate c-Jun on Ser-63 and Ser-73 within its transcriptional activation domain. They belong to the mitogen-activated protein kinase family, and are r ...

pathway. JNK is phosphorylated, which leads to the phosphorylation of AP-1 (transcription factor consisting of cFOS and Cjun). This results in the activation of caspases as well. ROS also causes a caspase independent pathway that results in apoptosis. When the mitochondrial membrane potential changes, apoptosis-inducing factors (AIFs) are also released. These trigger apoptosis when they enter the nucleus, not needing to involve caspases.

References

{{InterPro content, IPR009990 Protein families Antimicrobial peptides