Luteinizing Hormone-Releasing Hormone I (LHRH-I) and Its Metabolite in Peripheral Tissues

Abstract

Luteinizing hormone-releasing hormone (LHRH) was first isolated in the mammalian hypothalamus and shown to be the primary regulator of the reproductive system through its initiation of pituitary gonadotropin release. Since its discovery, this form of LHRH (LHRH-I) has been shown to be one of many structural variants with a variety of roles in both the brain and peripheral tissues. Enormous interest has been focused on LHRH-I and LHRH-II and their cognate receptors as targets for designing therapies to treat cancers of the reproductive system. LHRH-I is processed by a zinc metalloendopeptidase EC 3.4.24.15 (EP24.15) that cleaves the hormone at the fifth and sixth bond of the decapeptide (Tyr(5)-Gly(6)) to form LHRH-(1-5). We have previously reported that the autoregulation of LHRH gene expression can also be mediated by its processed peptide, LHRH-(1-5). Furthermore, LHRH-(1-5) has also been shown to be involved in cell proliferation. This review will focus on the possible roles of LHRH and its processed peptide, LHRH-(1-5), in non-hypothalamic tissues.

Hypothalamic neurohormones and immune responses

“…GnRH half-life normally is about 2–4 mins (Walters et al, 2008). Its short half-life is because of the rapid cleavage of the bonds between amino acids at positions 5–6, 6–7, and 9–10.…”

Evaluation of the Biological Properties and the Enzymatic Stability of Glycosylated Luteinizing Hormone-Releasing Hormone Analogs

“…The endopeptidase E24. 15 (44)(45)(46). The cleavage of the sugar entities was found to be processed in the later stage of the proteolytic reaction.…”

A Biological Role for the Gonadotrophin‐Releasing Hormone (GnRH) Metabolite, GnRH‐(1‐5)

“…However, recent studies clearly delineate the importance of the cleaved pentapeptide fragment, GnRH‐(1‐5), in both physiology and behaviour. GnRH‐(1‐5) has been demonstrated to have a role in sexual behaviour, the stimulation of GnRH‐I gene expression and cellular growth (62, 67, 72). One of the common themes in the design of a GnRH‐I analogue for the clinical treatment of infertility, precocious puberty, prostate cancer and endometriosis includes a d ‐amino acid on the side of the scissile bond that prevents the formation of the GnRH‐(1‐5) peptide.…”

“…EP24.15 cleaves GnRH‐I at the Tyr5‐Gly6 bond and is known to have an important role in the modulation of the GnRH‐I signal to the pituitary (12, 57). Any modification at the Tyr 5 ‐Gly 6 residues confers resistance to cleavage by EP24.15, as observed in GnRH‐I ‘super‐agonists’ (19, 59–62). In addition, a ten‐ to 15‐fold improvement in the K m for the cleavage of GnRH‐(1‐9) compared to GnRH‐I was also demonstrated (63).…”