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Definition
Tuftsin is a physiologic tetrapeptide, which has recently been shown to possess immunoadjuvant properties including the stimulation of macrophage and granulocyte phagocytosis, migration, bactericidal, and tumoricidal activities 1.

Related Peptides
Numerous proteins and peptides contain within them tuftsin or tuftsin-like sequences. Some of these, such as C-reactive protein, are known mediators of inflammation. In addition, two other pro-inflammatory peptides, substance P and neurotensin, both contain tuftsin-like sequences, stimulate phagocytosis, and can compete with [3H] tuftsin for binding to macrophages. Moreover fragments of substance P and neurotensin containing the tuftsin-like sequences maintain their tuftsin-like activity even though their interactions with the known substance P and neurotensin receptors are greatly reduced. Although a number of tuftsin-like peptides reportedly share the biological activity of tuftsin, several similar peptides, such as TKPPR, are potent tuftsin antagonists, indicating that there are highly specific structural requirements for tuftsin agonists 2.

Discovery
Tuftsin, a naturally occurring peptide with the sequence TKPR, was originally described in 1970 by Najjar and Nishioka as a phagocytosis-stimulating peptide derived from the proteolytic degradation of IgG 2.

Structural Characteristics
Tuftsin, Thr-Lys-Pro-Arg (TKPR), is an immunostimulatory peptide with reported nervous system effects as well. Tuftsin and a higher affinity antagonist, TKPPR, bind selectively to neuropilin-1 and block vascular endothelial growth factor (VEGF) binding to that receptor. Dimeric and tetrameric forms of TKPPR had greatly increased affinity for neuropilin-1 based on competition binding experiments. On endothelial cells tetrameric TKPPR was found to inhibit the VEGF165-induced autophosphorylation of vascular endothelial growth factor receptor-2 (VEGFR-2) even though it did not directly inhibit VEGF binding to VEGFR-2. Homology between exon 8 of VEGF and TKPPR suggests that the sequence coded for by exon 8 may stabilize VEGF binding to neuropilin-1 to facilitate signaling through VEGFR-2. Given the overlap between processes involving neuropilin-1 and tuftsin, we propose that at least some of the previously reported effects of tuftsin are mediated through neuropilin-1 2.

Tuftsin Analogs:  
Cyclic analogs of the physiological immunostimulating peptide tuftsin (Thr-Lys-Pro-Arg), cyclo (Thr-Lys-Pro-Arg-Gly) (ctuf-G) and cyclo (Thr-Lys-Pro-Arg-Asp) (ctuf-D), were synthesized based on molecular modeling studies, and assayed for the ability to stimulate phagocytosis by human polymorphonuclear leukocytes. As predicted, the synthesis of ctuf-D resulted in two isomers with the correct molecular mass and amino acid composition. In phagocytosis assays, tuftsin, ctuf-G and two isomers of ctuf-D showed the usual bell-shaped activity profiles. The optimum concentration of ctuf-G was 50-fold less than that of tuftsin, whereas the degree of stimulation was similar. One isomer of ctuf-D was almost inactive, and the other ctuf-D exhibited the same degree of phagocytosis as tuftsin but its optimum concentration was 5-fold lower. The enhanced potency of ctuf-G and one isomer of ctuf-D may be due to conformational effects and/or to the possibility that these cyclic peptides are resistant to proteolytic degradation 3.


Mode of Action
Cultured human aortic and umbilical vein endothelial cells possess tuftsin receptors and that in these cells the binding target for tuftsin is neuropilin-1. Since neuropilin-1 plays a critical role in the immune, vascular, and nervous systems and interacts with a number of different ligands, cell surface receptors, adhesion proteins, and intracellular proteins, it was proposed that at least some of the previously reported effects of tuftsin are mediated through neuropilin-1 2.

Functions
Several reports indicate that tuftsin or tuftsin-like peptides exert multiple stimulatory effects on a subset of immunologic effector cells, including enhanced migration/chemotaxis, enhanced phagocyte respiratory burst, enhanced antigen presentation, and other undefined immunologic effects that result in increased antimicrobial and antitumor activities by immune cells. Additionally tuftsin is reported to have effects on the nervous system, including induction of analgesia and inhibition of axonal regeneration 2.

References

1.     Phillips JH, Babcock GF, Nishioka K (1981). Tuftsin: a naturally occurring immuno- potentiating factor. I. In vitro enhancement of murine natural cell-mediated cytotoxicity. J Immunol., 126(3):915-921.

2.     von Wronski MA, Raju N, Pillai R, Bogdan NJ, Marinelli ER, Nanjappan P, Ramalingam K, Arunachalam T, Eaton S, Linder KE, Yan F, Pochon S, Tweedle MF, Nunn AD (2006). Tuftsin Binds Neuropilin-1 through a Sequence Similar to That Encoded by Exon 8 of Vascular Endothelial Growth Factor. J Biol Chem., 281(9):5702-5710.

3.     Nishioka K, Obeyesekere NU, McMurray JS (1995). Enhanced phagocytosis activity of cyclic analogs of tuftsin. Biochemical Pharmacology, 49(5):735-738.

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