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Is the metalloendopeptidase EC 3.4.24.15 (EP24.15), the enzyme that cleaves luteinizing hormone-releasing hormone (LHRH), an activating enzyme?

¹ Centre for Medical Education, University of Bristol, 39–41 St Michael's Hill, Bristol BS2 8DZ, UK
² Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814, USA

Correspondence should be addressed to T J Wu; Email: twu{at}usuhs.mil

K Cleverly is now at Newham University Hospital, Glen Road, London E13 8BL, UK

LHRH (GNRH) was first isolated in the mammalian hypothalamus and shown to be the primary regulator of the reproductive neuroendocrine axis comprising of the hypothalamus, pituitary and gonads. LHRH acts centrally through its initiation of pituitary gonadotrophin release. Since its discovery, this form of LHRH (LHRH-I) has been shown to be one of over 20 structural variants with a variety of roles in both the brain and peripheral tissues. LHRH-I is processed by a zinc metalloendopeptidase EC 3.4.24.15 [EC] (EP24.15) that cleaves the hormone at the fifth and sixth bond of the decapeptide (Tyr⁵-Gly⁶) to form LHRH-(1–5). We have previously reported that the auto-regulation of LHRH-I (GNRH1) gene expression and secretion can also be mediated by itself and its processed peptide, LHRH-(1–5), centrally and in peripheral tissues. In this review, we present the evidence that EP24.15 is the main enzyme of LHRH metabolism. Following this, we look at the metabolism of other neuropeptides where an active peptide fragments is formed during degradation and use this as a platform to postulate that EP24.15 may also produce an active peptide fragment in the process of breaking down LHRH. We close this review by the role EP24.15 may have in regulation of the complex LHRH system.