60 YEARS OF POMC: Purification and biological characterisation of melanotrophins and corticotrophins

Abstract

The remarkable conservation of the primary structures and anatomical location of dogfish α-melanocyte-stimulating hormone (MSH), corticotrophin-like intermediate lobe peptide (CLIP) and adrenocorticotrophic hormone (ACTH) compared with mammals reinforced the tissue-specific processing hypothesis of ACTH peptides in the pituitary gland. The cloning of dogfish pro-opiomelanocortin (POMC) led to the identification of δ-MSH and simultaneously revealed the high conservation of the γ-MSH sequence during evolution. These studies have also shown that β-MSH is much less conserved during evolution and in some species is not even processed from β-LPH. Human pro-γ-MSH potentiates the corticosteroidogenic activity of ACTH and peptides generated from its N-terminal, in particular big-γ-MSH, appear to have adrenal mitogenic activity. Human big-γ-MSH (from the zona intermedia) may also cause the adrenache. The review finishes with a cautionary note with regard to the misdiagnosis of the ectopic ACTH syndrome in which partial processing of ACTH can result in large concentrations of α-MSH and CLIP, which can interfere in the performance of two-site immunoassays, and the problem of the correct disulphide bridge arrangement in synthetic N-POMC peptides is also discussed.

Human POMC processing in vitro and in vivo revealed by quantitative peptidomics

“…We were surprised to readily detect spectra for β-MSH(1-18) whose existence has been disputed 20 , whereas we did not consistently detect spectra for α-MSH(1-13) which has been the subject of intense study 6,7,35,51,52 since it is produced in mice and suggested by some studies to be more stable than d-a-MSH 35 . Upon manual review, we could indeed detect peaks with m/z and column retention times appropriate for α-MSH.…”

“…Human hypothalamic POMC neurons might also produce b-MSH 14 , which is associated with human obesity when mutated [15][16][17] and inhibits feeding as potently as a-MSH when injected into mice 17 by activating MC4R [16][17][18] . However, b-MSH is not produced in the rodent brain and its existence and biological relevance in humans is controversial [19][20][21] . Since body weight is sensitive to changes in the concentration of POMC-derived peptides [22][23][24][25][26] , understanding POMC processing can provide insights into molecular mechanisms of obesity that might be therapeutically harnessed 3 .…”

60 YEARS OF POMC: N-terminal POMC peptides and adrenal growth

“…A final point is that although the N-POMC(1-28) used in the study was synthesised with the correct disulfide bridge arrangements and had been shown previously to be biologically active (Fassnacht et al 2003), the disulfide bridge arrangements in N-POMC are known to be unstable (Lowry 2015). It is thus possible that a rearrangement of the bridges to the 2-8, 20-24 configuration could have occurred and rendered the peptide biologically inactive as found in N-POMC(1-36) (Estivariz et al 1988a).…”

60 YEARS OF POMC: Lipotropin and beta-endorphin: a perspective

“…In 1974, we were successful in isolating a series of novel peptides from porcine pituitary (Bradbury et al 1975(Bradbury et al , 1976b and we observed that a group of them accounted for the sequence of adrenocorticotrophic hormone (ACTH) together with the sequence of lipotropin. At that time, it was not known that ACTH and lipotropin are formed from a common prohormone, although the possibility had been discussed informally at Meetings of the Endocrine Society (see Lowry 2016).…”