Editing Pardaxin

{{Short description|Type of peptide}}
{{Infobox protein family
| Symbol = Pardaxin
| Name = Pardaxin
| image = PDB 1xc0 EBI.jpg
| width = 
| caption = twenty lowest energy structures of pa4 by solution nmr
| Pfam = PF07425
| Pfam_clan =  
| InterPro = IPR009990
| SMART = 
| PROSITE = 
| MEROPS = 
| SCOP = 
| TCDB = 1.A.66
| OPM family = 208
| OPM protein = 1xc0
| CAZy = 
| CDD = 
}}

'''Pardaxin''' is a [[peptide]] produced by [[Pardachirus marmoratus|the Red Sea sole]] (P4, P5) and the Pacific Peacock sole (P1, P2, P3) that is used as a [[shark]] repellent.<ref name="pmid3996550">{{cite journal | vauthors = Primor N | title = Pharyngeal cavity and the gills are the target organ for the repellent action of pardaxin in shark | journal = Experientia | volume = 41 | issue = 5 | pages = 693–5 | date = May 1985 | pmid = 3996550 | doi = 10.1007/bf02007726 | s2cid = 8299619 }}</ref><ref>{{cite journal | vauthors = Shai Y, Fox J, Caratsch C, Shih YL, Edwards C, Lazarovici P | title = Sequencing and synthesis of pardaxin, a polypeptide from the Red Sea Moses sole with ionophore activity | journal = FEBS Letters | volume = 242 | issue = 1 | pages = 161–6 | date = December 1988 | pmid = 2462511 | doi = 10.1016/0014-5793(88)81007-x | s2cid = 1400091 | doi-access = free | bibcode = 1988FEBSL.242..161S }}</ref><ref>{{cite journal | vauthors = Adermann K, Raida M, Paul Y, Abu-Raya S, Bloch-Shilderman E, Lazarovici P, Hochman J, Wellhöner H | title = Isolation, characterization and synthesis of a novel paradaxin isoform | journal = FEBS Letters | volume = 435 | issue = 2–3 | pages = 173–7 | date = September 1998 | pmid = 9762902 | doi = 10.1016/S0014-5793(98)01057-6 | s2cid = 86408190 | doi-access = free | bibcode = 1998FEBSL.435..173A }}</ref> It causes [[lysis]] of [[mammalia]]n and bacterial cells, similar to [[melittin]].<ref name="Oren, Shai 303–310">{{cite journal | vauthors = Oren Z, Shai Y | title = A class of highly potent antibacterial peptides derived from pardaxin, a pore-forming peptide isolated from Moses sole fish Pardachirus marmoratus | journal = European Journal of Biochemistry | volume = 237 | issue = 1 | pages = 303–10 | date = April 1996 | pmid = 8620888 | doi = 10.1111/j.1432-1033.1996.0303n.x | doi-access = free }}</ref>

[[File:1-s2.0-S0014579398010576-gr1.gif|thumb|Amino acid alignment of pardaxins. Variable residues are bold-faced.]]

==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.<ref name="Oren, Shai 303–310"/> Pardaxin shows a significantly lower [[hemolytic]] 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]] and bacteria.<ref name="Oren, Shai 303–310"/> 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]] of the cell.<ref>{{cite journal | vauthors = Shai Y, Bach D, Yanovsky A | title = Channel formation properties of synthetic pardaxin and analogues | journal = The Journal of Biological Chemistry | volume = 265 | issue = 33 | pages = 20202–9 | date = November 1990 | doi = 10.1016/S0021-9258(17)30490-8 | pmid = 1700783 | url = http://www.jbc.org/content/265/33/20202.long | doi-access = free }}</ref>

The mechanism of pardaxin is dependent on the membrane composition. Pardaxin significantly disrupts lipid bilayers composed of [[zwitterionic]] lipids, especially those composed of 1-palmitoyl-2-oleoyl-phosphatidylcholine ([[POPC]]). This suggests a carpet mechanism for cell [[lysis]].<ref name="Hallock 1004–1013">{{cite journal | vauthors = Hallock KJ, Lee DK, Omnaas J, Mosberg HI, Ramamoorthy A | title = Membrane composition determines pardaxin's mechanism of lipid bilayer disruption | journal = Biophysical Journal | volume = 83 | issue = 2 | pages = 1004–13 | date = August 2002 | pmid = 12124282 | pmc = 1302204 | doi = 10.1016/s0006-3495(02)75226-0 | bibcode = 2002BpJ....83.1004H }}</ref> 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.<ref>{{cite journal | vauthors = Yeaman MR, Yount NY | title = Mechanisms of antimicrobial peptide action and resistance | journal = Pharmacological Reviews | volume = 55 | issue = 1 | pages = 27–55 | date = March 2003 | pmid = 12615953 | doi = 10.1124/pr.55.1.2 | s2cid = 6731487 }}</ref> The presence of anionic lipids or [[cholesterol]] was found to reduce the peptide's ability to disrupt bilayers.<ref name="Hallock 1004–1013"/>

===Shark repellent===
''P. marmoratas'' and ''P. pavoninus'' release pardaxin when threatened by sharks. Pardaxin targets the [[gills]] and [[pharyngeal cavity]] of the sharks. It results in severe struggling, mouth [[paralysis]], and temporary increase of [[urea]] leakage in the gills.<ref name="pmid3996550"/> 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.<ref>{{cite book|last1=Sisneros|first1=Joseph|first2=Donald | last2 = Nelson |title=The behavior and sensory biology of elasmobranch fishes: An anthology in memory of Donald Richard Nelson |chapter=Surfactants as chemical shark repellents: Past, present, and future | name-list-style = vanc |journal=Environmental Biology of Fishes|date=2001|volume=60|pages=117–129 | chapter-url = http://faculty.washington.edu/sisneros/Sisneros%20and%20Nelson%202001.pdf | doi=10.1007/978-94-017-3245-1_9|series=Developments in environmental biology of fishes|isbn=978-90-481-5655-9}}</ref>

===Cancer treatment===
Pardaxin inhibits proliferation and induces [[apoptosis]] of human cancer cell lines. Its 33-[[amino acid]] structure contains many cationic and [[amphipathic]] amino acids. This makes it easier for it to interact with anionic membranes, such as those in [[tumor]] cells, which are inherently more acidic because of the acidic environment created by more [[glycolysis]].<ref name="Huang 1833–1842">{{cite journal | vauthors = Huang TC, Chen JY | title = Proteomic analysis reveals that pardaxin triggers apoptotic signaling pathways in human cervical carcinoma HeLa cells: cross talk among the UPR, c-Jun and ROS | journal = Carcinogenesis | volume = 34 | issue = 8 | pages = 1833–42 | date = August 2013 | pmid = 23615400 | doi = 10.1093/carcin/bgt130 | doi-access = free }}</ref>

Pardaxin initiates [[caspase]]-dependent and caspase-independent apoptosis in human cervical carcinoma cells. Pardaxin triggers [[reactive oxygen species]] (ROS). ROS production disrupts [[protein folding]] and induces the unfolded protein response (UPR). This causes stress on the [[endoplasmic reticulum]], which releases [[calcium]]. This leads to an increase in mitochondrial calcium, dropping its [[membrane potential]]. The pore [[Semipermeable membrane|permeability]] changes, and [[Cytochrome c]] (Cyt c) is released. Cyt c activates the caspase chain that leads to apoptosis. ROS also activates the [[JNK]] pathway. JNK is phosphorylated, which leads to the phosphorylation of [[AP-1 transcription factor|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.<ref name="Huang 1833–1842"/>

== References ==
{{Reflist}}
{{InterPro content|IPR009990}}

[[Category:Protein families]]
[[Category:Antimicrobial peptides]]