2. CAPÍTULO II: MARCO TEÓRICO
2.2 Bases teóricas
2.2.3 Bases legales en orden regular
ility tha’t this peptide is the 1 to "i 6 or 1 to 1'/ fragment of the ACTH molecule, and it vzould suggest that tumours have the ability to cleave ACTH, as in the pars intermedia
cells, but not to modify the N-terminal fragment to OC-MSH. Finally, there should be phylogenetic evidence for the presence of a a-MS.H and CLIP. Strong support for the present hypothesis comes from recent studies on the structure of the ACTH-like peptides of the dogfish
Sqnalus acanthias. (X-MSII has previously been isolated and characterised from nenrointermodiate lobe extracts of this species (Lowry & Chadwick, 1970a). More recently, (Bennett, Lowry, McMartin and Scott,unpublished observations) ACTH has been isolated from rostral lobe extracts, and character isation h.as revealed that it is thirty-nine amino acids in length and has an N-terminal 1 to 13 sequence identical to that of mammalian ACTH except for a methionine-for-valine replacement at position 13* This replacement is found in the dogfish OC-MSII. Studies of the neurointermediate lobe extracts resulted in the isolation and characterisation of a peptide identical in sequence to the 18 to 33 portion of dogfish ACTH (i.e. CLIP). There are eight amino acid
differences between the a ’"'portions of dogfish and
porcine ACTH, and these exact differences are found in the corresponding CLIP molecules. A separate genetic origin for ACTH and CLIP vzould seem very unlikely in the light of this evidence.
The stage in evolution at which the proposed
cleavage mechanism emerged cannot yet be assessed precisely. There is evidence hovzever, that MSI! activity antedates ACTH
significant amounts but not corticotropbin (se- >ve). It is possible that the presumptive ACTH molecu ; is present in the cyclestomes as a pro- a-MSH molecule. This
may latex” in evolution have found a role in stim.listing
adrenal cells. Independent formation and. release of these hormones might then depend upon the differentiation of’the pituitary gland into a part concerned with the release of intact ACTH (viz. t .c pars distalis) and one in which ACTH is cleaved ( viz. the pars intermedia). At a time during evolution when a-MSH and ACTII were both important to survival, amino acid substitutions within the 1 to 13 sequence would have been, subject to natural selection for both activities. Since it is likely that few
mutations would be advantageous for both these activities, this may explain the constancy of a-MSII (Lowry & Chadwick,
137Cb; Shapiro et a 1 . , 1972) and the amino-terminal part of ACTH during evolution.
Me chan ism o_f c leave. go
The present hypothesis envisages that ACTH synthesised in the intermediate lobe is a precursor of
a-MSH and CLIP, and the formation of the two latter peptides is controlled initially by intracellular proteolysis. This mechanism resembles that demonstrated or proposed for the formation of other active substances from their precursor forms. Thus the conversion of ’big gastrin* (Gregory f Tracy, 1972; to its active form, and proinsulin to insulin
(Steiner et_al. , 19^9 i Sando e_t a 1. , 1972) can be achieved by trypsin treatment. Several non-honnonal proteins have been shown to be activated by a very similar mechanism involving the partial proteolytic digestion of a precursor, resulting in the formation of a smaller active product e.g.
blood clotting- proteins, gut enzymes (Ottensen, - It has been suggested that the lipotr<* ph 3 c hormones (P-LPH and -LPH) isolated from ovine, porcine and human pituitaries are precursors of {3-MSI-I, since tie complete sequences of the P-MSHs from these three species arc present in the /+1 to i>S portions of the homologous LPHs (37 to 53 for human p-MSIl), The localisation of a-MSH and P-MSH in the pars intermedia of the pig and sheep pituitary (Dubois, 1972) suggests that the cleavage of LPH to p-MSII,. and of ACTH to 0C-MSH takes place in the same cell. Cleavage of LPH should yield, additional peptide
(analogous to CLIP) in the pars intermedia which have yet to be identified. By analogy with the ACTII-CLIP system,
intact p-LPII should be found in the corticotroyhs of the pars distalis.
At the proposed sites of cleavage of proinsulin,
P-LPH and ACTH a characteristic sequence of two or more
basic amino acids occurs (Fig. 26). This arrangement suggests that these regions may be more prone to cleavage by the specific enzyme involved than single basic residues. This would be of considerable functional importance,
preventing the enzymes from further splitting the active peptide into inactive fragments, as would occur if there were only single basic amino acids present. It also suggests that the arrangement of basic residues in ACTH is not solely concerned with the activity of the molecule
(i.e. binding the molecule to the adrenal receptor) but also exists for the formation of CC-MSH and CLIP.
Role .
So far CLIP has been considered as of secondary importance in the formation of CC-MSII from ACTII (i.e. it represents a
PROINSULIN ---ALA~AI?G-APG--- --- IYS-APG-GLY--- 30 31 32 62 63 64 INSULIN—a---C-PEPTIBE--- ft INSULIN-—*- p-LPH j- —-G LU-J. YS-LYS-ASP---ASP~LYS~ABG-T¥B, 38 59 40 41 58 59 60 (Si tf—~p-MSH--- ACT1I --- VAE-GLY-LYS-LYS-AHG-ARG-PRO- 13 14 15 16 17 18 19
---- cv-MSII--- —e? )l---CLIP——*-
Fig 26 : Amino acid sequences in the regions of the proposed sites of enzymatic cleavage of proinsulin , (3~ lipotrophin and ACTII , demonstratin the occurrence of pairs of basic amino acids.
-
discarded fragment). There i no reason for discounting
the possibility, however, that OLD? may possess a biological action.
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Cl K. , NIC ’ . . . . : . . . (l . >}
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