Endocrine Abstracts (2019) 65 P441 | DOI: 10.1530/endoabs.65.P441

Inhibitory actions of diketopiperazines within the thyroid gland, and their system-wide presence

Umma Raja, Edwin Garcia, Crystalline The, Dijou Sun, Dominic Collis, Margaret Ghilchik, Peter King, Marta Korbonits & Derek Smyth

Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK

C-terminal derivatives of hormones commonly have secondary actions. This is a well-established phenomenon, seen in the case of oxytocin, parathyroid hormone and alpha-melanotropin. Such derivatives can either complement or antagonise the action of the parent hormone. Thyroid-releasing-hormone (TRH) undergoes cleavage and cyclisation to form the C-terminal derivative histidinyl-proline-diketopiperazine (His-Pro-DKP). Despite conventional function via the endocrine HPT axis, the local presence of TRH within the thyroid gland led to the investigation of TRH function upon thyroid follicular cells in culture, where it was found to have an inhibitory effect upon thyroglobulin (Tg) secretion. This is retained via the C-terminal His-Pro-DKP, and suggests a potential downstream inhibition upon thyroid hormone production. Such results imply bifunctional activities of hormones via actions of their secondary derivatives, where TRH conventionally acts to increase Tg secretion. The presence of TRH-like peptides, which differ to TRH due to a substitution of the histidine amino acid, encouraged the exploration of DKP formation from these peptides also. In addition to their presence within the thyroid, these peptides are present within organs such as the prostate and the testes. It was found that these also undergo intramolecular cyclisation to form such C-terminal derivatives, with structures specific to the parent peptide. Such cyclisation was increased in the presence of phosphate ion and is proposed to occur due to the function of a dipeptide cyclase. Hence, subsequent investigations were undertaken to study the effect of these DKPs on hormone activities in prostate and Leydig cell lines. Such functions may indicate an effect of DKPs upon regulation of cellular secretions in a system-wide manner, in addition to the conventional actions of the parent hormone.

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