Thymopoietin (TP) Fragments

Definition
Thymopoietin (TP) was originally isolated as a 5-kDa, 49-amino acid protein from bovine thymus in studies of the effects of thymic extracts on neuromuscular transmission and was subsequently observed to affect T-cell differentiation and function 1.

Related Peptides
The pentapeptide thymopentin (TP5), which represents the active sequence of the originally described TP. TP was identified as a fragment of the thymopoietins (TMPOs), a family of nuclear proteins 2. Three alternatively spliced mRNAs encode three distinct human T-cell TPs. Proteins encoded by these mRNAs have been named TPa (75 kDa), TPß (51 kDa), and TP? (39 kDa), which contain identical N-terminal regions, including sequences nearly identical to that of the originally isolated 49-amino acid protein, but divergent C-terminal regions 1.

Discovery
Three alternatively spliced mRNAs that encode three distinct human T-cell TPs were identified by Harris et al., in 1994 and named the proteins encoded by these mRNAs, TPa, TPß, and TP? 1.

Structural Characteristics
Distinct structural domains and functional motifs in TPs a, ß and ? suggest that the proteins have unique functions and may be directed to distinct subcellular compartments. The first 49 amino acid predicted by the human TP a, ß and ? cDNAs are closely similar to the sequence determined for the originally purified bovine 5-kDa TP, differing at only 5 amino acids. The sequences predicted from the human TP a, ß and ? cDNAs are similar to the sequence predicted from the bovine cDNA reported by Zevin-Sonkin et al., from amino acid 1 through amino acid 81, differing only at positions 13 (Asp in human, Glu in bovine) and 53-56 (Pro-Ala-Gly-Thr in human, Ala-Thr-Ser-Ala in bovine); but beyond amino acid 81 there is no further homology, either in nucleotide or in amino acid sequence 1.

Mode of Action
In vitro assays show that TP5 affects the function of T cells and monocytes measured by enhanced cGMP level and the triggering of cellular signalling, respectively 2.

Functions
Thymopentin, an active fragment of TP, reduces endocrine and behavioral responses to experimental stress, possibly by lowering plasma TP (pTP) levels. (The significant association of elevated pTP with nonresponsiveness to antidepressant drugs may signify a distinct pathogenesis for the depression of patients with elevated pT 3. The maturation and activity of T lymphocytes can be augmented by the TP fragments TP-3, TP-4 and TP-5. T cell differentiation is enhanced with these TP fragments at a rather early phase in bone marrow and at a later phase in the circulation. The ability of the TP fragments TP-3, TP-4 and TP-5 to restore antibody production and phagocytosis was analysed in a study. The phagocytic capacity of peritoneal macrophages was reduced by vincristine, methotrexate and cyclophosphamide treatment. In this respect, TP-3 protected the function of macrophages against vincristine and cyclophosphamide treatment. TP-4 was active in the case of damage caused by vincristine and methotrexate, and TP-5 interfered with the phagocytosis-inhibiting effect of methotrexate. Each TP fragment seems to have a specific target orientation within the immune system. This also means that the proper TP fragment should always be chosen for combination therapy with various types of cytotoxic drugs 4.

References
1. Crafford A. Harris, Paula J. Andryuk, Scott Cline, H. Karen Chan, Anan Natarajan, John J. Siekierka and Gideon Goldstein (1994). Three distinct human thymopoietins are derived from alternatively spliced mRNAs. PNAS.,91:6283-6287..
2. Gonser S, Weber E, Folkers G (1999). Peptides and polypeptides as modulators of the immune response: thymopentin — an example with unknown mode of action. Pharmaceutica Acta Helvetiae, 73(6):265-273.
3. Goldstein G, Fava M, Culler M, Fisher A, Rickels K, Lydiard RB, Rosenbaum J (2000). Elevated plasma thymopoietin associated with therapeutic nonresponsiveness in major depression. Biological Psychiatry, 48(1):65-69.
4. Dénes L, Szende B, Hajós G, Szporny L, Lapis K (1990). Selective restoration of immunosuppressive effect of cytotoxic agents by thymopoietin fragments. Cancer Immunol Immunother., 32:51-54.

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