Leitung: Prof. Dr. Ewald Hannappel
Studies on thymosins were initiated by the group of Klein, Goldstein and White in 1965. They prepared thymosin fraction 5 in a five step procedure from calf thymus. This mixture of peptides ranging from 1 to 15 kDa was the starting material for the isolation of various thymosins. The thymosins are divided into three main groups according to their isoelectric points: Î±-thymosins below 5.0, Î²-thymosins up to 7.0, and Î³-thymosin above 7.0. The first two peptides which have been isolated were Î±1 and Î²1. While the former was named a thymosin the latter was designated polypeptide Î²1. The polypeptide Î²1 is probably the most frequently sequenced and multiple-named polypeptide in biochemistry: polypeptide Î²1, ubiquitous immunopoietic polypeptide, UBIP, non-histone component of chromosomal protein A24, and ATP-dependent proteolysis factor 1 (APF-1). This polypeptide is nowadays known as ubiquitin and plays a central role in the proteasome.
Thymosin Î±1 is an N-terminally acetylated octacosapeptide and derives from the N-terminal region of prothymosin Î± (109-113 amino acid residues). Prothymosin lacks secretory signals, is highly hydrophilic and acid (pI ~ 3.5). Half the amino acid residues are aspartic and glutamic acid and are clustered in the central region. Four lysine (14, 17, 19, 20) and one arginine (30) residues are present within the first 39 amino acid residues (thymosin Î±11) and another arginine (91) and four lysine (104, 105, 107, 108) residues are clustered at the C-terminus. The lysine residues close to the C-terminus form a nuclear localization signal (KKQKK). The most unusual feature of the peptide, however, is a cluster of high-energy phosphates on glutamate residues in vivo. The glutamyl phosphates are hydrolyzed immediately in vitro. Quiescent cells generate prothymosin Î± when stimulated to proliferate, prothymosin Î± gene expression reflects the growth rate of normal and abnormal tissues and cells treated with prothymosin Î± antisense DNA cease to divide. Recently, a receptor for prothymosin Î± has been identified.
Parathymosin was first isolated from rat thymus as a by-product of the procedure used for the isolation of prothymosin Î± and named parathymosin because of its structural similarity to prothymosin Î±. It was speculated by Horecker that parathymosin might be a zinc-binding protein. This was latter confirmed by Brand and Söling who isolated a 11.5-kDa Zn2+-binding protein capable to inactivate phosphofructokinase-1 and identified this protein to be identical with parathymosin. Parathymosin binds several enzymes of glucose metabolism and might play a role in supramolecular organization of carbohydrate metabolism.
Thymosin Î²4 was the founding member of the Î²-thymosin family. All Î²-thymosins are N-terminally acetylated and very polar (8-9 Lys, 3 Asp, 7-8 Glu, 2-3 Gln of 40-44 amino acid residues). Some Î²-thymosins possess a methinonyl residue which is readily oxidizable and supposed to modify the biological function of the peptide. A tetrapeptide(AcSDKP, Seraspenide) could be generated from the N-terminus of thymosin Î²4 and inhibits bone marrow stem cell proliferation. Human tissues and cancer cells contain besides thymosin Î²4 two other members of the family, i.e. Î²10 and Î²15. Two of the three glutaminyl residues are substrates in transglutaminase reactions and could serve to attach Î²-thymosins to other molecules. Fluorescently labeled thymosin Î²4 was used to study the intracellular distribution of the peptide. We found that the peptide and the N-terminal fragment of thymosin Î²4 is accumulating in the nucleus while a labeled C-terminal fragment is distributed all over the cell.