Enkephalins synthesis

In addition to the weU-defined opioid systems in the central nervous system, the three opioid peptides and their precursor mRNA have also been identified in peripheral tissues. ( -Endorphin is most abundant in the pituitary, where it exists in corticotroph cells with ACTH in the anterior lobe and in melanotroph cells with MSH in the intermediate lobe (59). Enkephalin and pre-pro-enkephalin mRNA have been identified in the adrenal medulla (60) and this has been the source of material for many studies of pro-enkephalin synthesis and regulation. Pre-pro-enkephalin mRNA has also been identified in the anterior and posterior lobes of the pituitary (61). mRNA for all three opioid precursors has been identified in the reproductive system (62—64). POMC... 

Homologues of the classical papaya papain that have been tested for peptide S5mthesis are plant-derived enzymes such as bromelain and ficain. Bromelain extracted from pineapple could be applied in Met- and Leu-enkephalin synthesis in a low water system, reaching 97% yield [27]. Ficain isolated from Ficus glabrata latex was tested in di- and tripeptide synthesis in frozen water medium [23] and was used in the synthesis of Lys and Met oligomers starting from the respective ethyl esters [29]. 

Pig. 3. Representation of promoter sites on the pro-enkephalin gene. The numbers represent the distance in nucleotides from the pro-enkephalin initiation codon the arrow indicates the direction of transcription. The TATA promoter box occurs immediately before the pro-enkephalin initiation site the AP-2 site, which binds immediate-early gene products, is 70 nucleotides upstream, and the CRE site, which binds a regulatory protein involved in cAMP induction of mRNA synthesis, is 107 nucleotides upstream from the initiation codon. The expanded section shows that the CRE site actually consists of two elements, ENKCRE-1 and ENKCRE-2, which separately confer cAMP sensitivity to pro-enkephalin mRNA synthesis. 

R. M.J. Solid-phase syntheses of peptoids using Fmoc-protected N-substituted glycines The synthesis of (retro) peptoids of leu-enkephalin and substance P. Euro. J. Chem. 1998, 4, 1570-1580. 

DiMaio J, Nguyen TM-D, Lemieux C, Schiller PW. Synthesis and pharmacological characterization in vitro of cyclic enkephalin analogs effect of conformational constraints on opiate receptor selectivity. J Med Chem 1982 25 1432-1438. 

Y Kiso, K Ukawa, T Akita. Efficient removal of /V-bcnzyloxycarbonyl group by a push-pull mechanism using thioanisole-trifluoroacetic acid, exemplified by a synthesis of Met-enkephalin. Chem Commun 101, 1980. 

MK Anwer, AF Spatola. An advantageous method for the rapid removal of hydro-genolysable protecting groups under ambient conditions synthesis of leucine-enkephalin. (ammmomum formate) Synthesis 929, 1980. 

Y Okada, N Ohta. Amino acids and peptides. VII. Synthesis of methionine-enkephalin using transfer hydrogenation, (cyclohexene) Chem Pharm Bull (Jpn) 30, 581, 1982. 

Cysteine endopeptidases, like serine endopeptidases, can also catalyze peptide synthesis under preparative conditions [66-68]. Thus, papain has been used to synthesize enkephalins and angiotensin. 

W. Kullmann, Kinetics of Chymotrypsin- and Papain-Catalysed Synthesis of (Leu-cine)enkephalin and (Methionine)enkephahn , Biochem. J. 1984, 220, 405 - 416 W. Kullmann, Protease-Catalyzed Peptide Synthesis , Adv. Biosci. 1987, 65, 135- 140. 

One of the very first papers reporting about endo-linkers was published by Elmore et al. (Scheme 10.4) [13]. They described a new linker containing a phos-phodiester group (19) for solid-phase peptide synthesis using a Pepsyn K (polyacrylamide) resin. After completion of coupling and deprotection cycles, the phos-phodiester (20) was cleaved with a phosphodiesterase. In this way / -casomorphin. Leu-enkephalin and a collagenase substrate (21) were synthesized in high yields. 

Other neurotransmitters are larger peptides, such as the enkephalins. These peptide neurotransmitters are synthesized in the cell body of the neuron, usually as part of larger polypeptides from which they are subsequently cleaved. Following synthesis, they are incorporated into secretory granules that bud off from the Golgi apparatus and are then transported down the axon to the terminals. 

An alternative to the synthesis of proteins by classical fragment synthesis in solution or by solid-phase synthesis on a support is the use of enzyme-catalyzed condensation of amino acids or peptides. This possibility was first demonstrated in 1938 91 with the synthesis of poorly soluble benzoyl-leucyl-leucine anilide by papain catalysis. After many years, this approach was extended to the preparation of peptide hormones such as Leu-enkephalin 92 and dynorphin(l -8).[93 This was made possible by the use of highly purified enzymes and by careful control of reaction conditions. The basic principles of protease-catalyzed peptide bond formation have been discussed.194 ... 

The methods presented in the sections above are all suitable for the synthesis of lanthionines as amino acid derivatives. However, a very important synthetic goal remains the synthesis of lanthionine-containing peptides, for example the synthesis of lantibiotics and other peptide analogues where lanthionine has replaced cystine. In the following Sections some syntheses of lanthionine-containing peptides comprising analogues of cystine peptides, such as enkephalin, somatostatin, and oxytocin are described. 

Scheme 13 Solid-Phase Peptide Synthesis of an Enkephalin Analogue by Macrocyclization of Cysteine and Dehydroalaninel271...

We have already discussed the co-occurrence of small amine and peptide neurotransmitters their release is normally Ca + dependent, and they operate through signal transmission. They are also capable of regulating each other s release and even the synthesis, clustering, and affinity of receptors. Neuroendocrine cells are capable of producing more than one peptide, and thus an amine-peptide as well as a peptide-peptide combination is possible. It is known, for instance, that the vagus nerve contains substance P, vasointestinal peptide, enkephalin, cholecystokinin, and somatostatin— peptides with a hybrid combination of neural and hormonal communication properties. 

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