Physalaemin

Last updated
Physalaemin
Physalaemin.svg
Names
Other names
H-Pyr-Ala-Asp-Pro-Asn-Lys-Phe-Tyr-Gly-Leu-Met-NH2
Identifiers
3D model (JSmol)
ChEMBL
MeSH Physalaemin
PubChem CID
UNII
  • C[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC2=CC=CC=C2)C(=O)N[C@@H](CC3=CC=C(C=C3)O)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N)NC(=O)[C@@H]4CCC(=O)N4
Properties
C58H84N14O16S
Molar mass 1265.45 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Physalaemin is a tachykinin peptide obtained from the Physalaemus frog, closely related to substance P. Its structure was first elucidated in 1964. [1] [2]

Contents

Like all tachykinins, physalaemin is a sialagogue (increases salivation) and a potent vasodilator with hypotensive effects. [3]

Structure

Physalaemin (PHY) is known to take on both a linear and helical three dimensional structure. Grace et al. (2010) have shown that in aqueous environments,  PHY preferentially takes on the linear conformation whereas in an environment that simulates a cellular membrane, PHY takes on a helical confirmation from the Pro4 residue to the C-Terminus. This helical conformation is essential to allow the binding of PHY to neurokinin-1 (NK1) receptors. Consensus sequences between Substance P (a mammalian tachykinin and agonist of NK1) and PHY have been used to confirm that the helical confirmation is necessary for PHY to bind to NK1. [4]

Use In Research

Not only is PHY closely related to Substance P (SP), but it also has a higher affinity for the mammalian neurokinin receptors that Substance P can bind to. Researchers can make use of this behavior of PHY to study the behavior of smooth muscle -  a tissue where NK1 can be found. Shiina et al. (2010) used PHY to show that tachykinins as a whole can cause the longitudinal contraction of smooth muscle tissue in esophageal tissue. [5]

Singh et Maji made use of PHY's similarity to SP along with its sequence similarity to Amyloid B-peptide 25-35 [AB(25-35)]. Despite its sequence similarity to SP, Singh et Maji showed that PHY had distinct amyloid forming capabilities . Under artificially elevated concentrations of tetrafluoroethylene (TFE) and a short incubation time, PHY was able to form amyloid fibrils. These fibrils originating from tackynins like PHY were also shown to reduce the neurotoxicity of other Amyloid fibers associated with amyloid induced diseases such as  Alzheimer's disease. [6]

Related Research Articles

Collagen is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole-body protein content. Collagen consists of amino acids bound together to form a triple helix of elongated fibril known as a collagen helix. It is mostly found in connective tissue such as cartilage, bones, tendons, ligaments, and skin.

Substance P Chemical compound

Substance P (SP) is an undecapeptide member of the tachykinin neuropeptide family. It is a neuropeptide, acting as a neurotransmitter and as a neuromodulator. Substance P and its closely related neurokinin A (NKA) are produced from a polyprotein precursor after differential splicing of the preprotachykinin A gene. The deduced amino acid sequence of substance P is as follows:

Amyloid Insoluble protein aggregate with a fibrillar morphology

Amyloids are aggregates of proteins characterised by a fibrillar morphology of 7–13 nm in diameter, a beta sheet (β-sheet) secondary structure and ability to be stained by particular dyes, such as Congo red. In the human body, amyloids have been linked to the development of various diseases. Pathogenic amyloids form when previously healthy proteins lose their normal structure and physiological functions (misfolding) and form fibrous deposits in amyloid plaques around cells which can disrupt the healthy function of tissues and organs.

Amylin

Amylin, or islet amyloid polypeptide (IAPP), is a 37-residue peptide hormone. It is co-secreted with insulin from the pancreatic β-cells in the ratio of approximately 100:1 (insulin:amylin). Amylin plays a role in glycemic regulation by slowing gastric emptying and promoting satiety, thereby preventing post-prandial spikes in blood glucose levels.

Tachykinin peptides

Tachykinin peptides are one of the largest families of neuropeptides, found from amphibians to mammals. They were so named due to their ability to rapidly induce contraction of gut tissue. The tachykinin family is characterized by a common C-terminal sequence, Phe-X-Gly-Leu-Met-NH2, where X is either an Aromatic or an Aliphatic amino acid. The genes that produce tachykinins encode precursor proteins called preprotachykinins, which are chopped apart into smaller peptides by posttranslational proteolytic processing. The genes also code for multiple splice forms that are made up of different sets of peptides.

Kassinin Chemical compound

Kassinin is a peptide derived from the Kassina frog. It belongs to tachykinin family of neuropeptides. It is secreted as a defense response, and is involved in neuropeptide signalling.

Neurokinin 1 (NK1) antagonists (-pitants) are a novel class of medications that possesses unique antidepressant, anxiolytic, and antiemetic properties. NK-1 antagonists boost the efficacy of 5-HT3 antagonists to prevent nausea and vomiting. The discovery of neurokinin 1 (NK1) receptor antagonists was a turning point in the prevention of nausea and vomiting associated with cancer chemotherapy.

Alpha sheet

Alpha sheet is an atypical secondary structure in proteins, first proposed by Linus Pauling and Robert Corey in 1951. The hydrogen bonding pattern in an alpha sheet is similar to that of a beta sheet, but the orientation of the carbonyl and amino groups in the peptide bond units is distinctive; in a single strand, all the carbonyl groups are oriented in the same direction on one side of the pleat, and all the amino groups are oriented in the same direction on the opposite side of the sheet. Thus the alpha sheet accumulates an inherent separation of electrostatic charge, with one edge of the sheet exposing negatively charged carbonyl groups and the opposite edge exposing positively charged amino groups. Unlike the alpha helix and beta sheet, the alpha sheet configuration does not require all component amino acid residues to lie within a single region of dihedral angles; instead, the alpha sheet contains residues of alternating dihedrals in the traditional right-handed (αR) and left-handed (αL) helical regions of Ramachandran space. Although the alpha sheet is only rarely observed in natural protein structures, it has been speculated to play a role in amyloid disease and it was found to be a stable form for amyloidogenic proteins in molecular dynamics simulations. Alpha sheets have also been observed in X-ray crystallography structures of designed peptides.

Preprotachykinins are precursor proteins that are modified into tachykinin peptides. Via alternative splicing and post-translational modifications, preprotachykinins produce multiple peptide neurotransmitters.

Neurokinin A Chemical compound

Neurokinin A (NKA), formerly known as Substance K, is a neurologically active peptide translated from the pre-protachykinin gene. Neurokinin A has many excitatory effects on mammalian nervous systems and is also influential on the mammalian inflammatory and pain responses.

Neurokinin B Chemical compound

Neurokinin B (NKB) belongs in the family of tachykinin peptides. Neurokinin B is implicated in a variety of human functions and pathways such as the secretion of gonadotropin-releasing hormone. Additionally, NKB is associated with pregnancy in females and maturation in young adults. Reproductive function is highly dependent on levels of both neurokinin B and also the G-protein coupled receptor ligand kisspeptin. The first NKB studies done attempted to resolve why high levels of the peptide may be implicated in pre-eclampsia during pregnancy. NKB, kisspeptin, and dynorphin together are found in the arcuate nucleus (ARC) known as the KNDy subpopulation. This subpopulation is targeted by many steroid hormones and works to form a network that feeds back to GnRH pulse generator.

Surfactant protein C Protein-coding gene in the species Homo sapiens

Surfactant protein C (SP-C), is one of the pulmonary surfactant proteins. In humans this is encoded by the SFTPC gene.

Tachykinin receptor 1 Protein-coding gene in the species Homo sapiens

The tachykinin receptor 1 (TACR1) also known as neurokinin 1 receptor (NK1R) or substance P receptor (SPR) is a G protein coupled receptor found in the central nervous system and peripheral nervous system. The endogenous ligand for this receptor is Substance P, although it has some affinity for other tachykinins. The protein is the product of the TACR1 gene.

Tachykinin receptor 2 Protein-coding gene in the species Homo sapiens

Substance-K receptor is a protein that in humans is encoded by the TACR2 gene.

Tachykinin receptor 3 Protein-coding gene in the species Homo sapiens

Tachykinin receptor 3, also known as TACR3, is a protein which in humans is encoded by the TACR3 gene.

Trefoil factor 2 Protein-coding gene in the species Homo sapiens

Trefoil factor 2 is a protein that in humans is encoded by the TFF2 gene.

TAC3

Tachykinin-3 is a protein that in humans is encoded by the TAC3 gene.

TAC1

Preprotachykinin-1,, is a precursor protein that in humans is encoded by the TAC1 gene.

Osanetant

Osanetant (developmental code name SR-142,801) is a neurokinin 3 receptor antagonist which was developed by Sanofi-Synthélabo and was being researched for the treatment of schizophrenia but was discontinued. It was the first non-peptide NK3 antagonist developed in the mid-1990s, Other potential applications for osanetant is in the treatment of drug addiction, as it has been found to block the effects of cocaine in animal models.

Vittorio Erspamer

Vittorio Erspamer was an Italian pharmacologist and chemist, known for the identification, synthesis and pharmacological studies of more than sixty new chemical compounds, most notably serotonin and octopamine.

References

  1. ↑ Erspaemer V, Anastasi A, Bertaccini G, Cei JM (1964). "Structure and pharmacological actions of physalaemin, the main active polypeptide of the skin of Physalaemus fuscumaculatus". Experientia. 20 (9): 489–90. doi:10.1007/BF02154064. PMID   5857249. S2CID   25448266.
  2. ↑ Anastasi A, Erspamer V, Cei JM (1964). "Isolation and amino acid sequence of physalaemin, the main active polypeptide of the skin of Physalaemus fuscumaculatus". Arch Biochem Biophys. 108 (2): 341–8. doi:10.1016/0003-9861(64)90395-9. PMID   14240587.
  3. ↑ Severini C, Improta G, Falconieri-Erspamer G, Salvadori S, Erspamer V (2002). "The tachykinin peptide family". Pharmacol Rev. 54 (2): 285–322. doi:10.1124/pr.54.2.285. PMID   12037144. S2CID   85570180.
  4. ↑ Grace, Christy Rani R.; Cowsik, Sudha Mahajan (2011). "Solution conformation of non-mammalian tachykinin physalaemin in lipid micelles by nuclear magnetic resonance". Biopolymers. 96 (3): 252–259. doi:10.1002/bip.21519. PMID   20632396.
  5. ↑ Shiina, Takahiko; Shima, Takeshi; Hirayama, Haruko; Kuramoto, Hirofumi; Takewaki, Tadashi; Shimizu, Yasutake (February 2010). "Contractile responses induced by physalaemin, an analogue of substance P, in the rat esophagus". European Journal of Pharmacology. 628 (1–3): 202–206. doi:10.1016/j.ejphar.2009.11.039. PMID   19958761.
  6. ↑ Singh, Pradeep K.; Maji, Samir K. (September 2012). "Amyloid-Like Fibril Formation by Tachykinin Neuropeptides and Its Relevance to Amyloid β-Protein Aggregation and Toxicity". Cell Biochemistry and Biophysics. 64 (1): 29–44. doi:10.1007/s12013-012-9364-z. ISSN   1085-9195. PMID   22628076. S2CID   17460410.


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