Peptidsynthesen über N‐Phosphorylaminosäure‐phosphorsäure‐anhydride

N‐Dibenzylphosphoryl (DBP)‐aminosäuren (II) werden unter der Einwirkung von Diphenylphosphoryl(DPP)‐chlorid in gemischte Anthydride III übergeführt und diese mit Aminosäure‐benzylestern gekuppelt. Die erhaltenen N‐DBP‐Dipeptid‐ester IV werden durch katalytische Hydrierung oder durch Bromwasserstoff sämtlicher Benzylgruppen entledigt und unmittelbar in die freien Peptide VI übergeführt, da die intermediär sich bildenden N‐Phosphoryl‐peptide V infolge der herrschenden sauren Reaktion sofort entphosphoryliert werden. — Carbobenzoxy‐ bzw. Trityl‐aminosäuren lassen sich ebenfalls mit DPP‐Chlorid in gemischte Anhydride überführen und somit auch auf diese Weise mit anderen Aminosäuren verbinden. Copyright © 1961 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinhei

On Cysteine and Cystine Peptides. III. Synthesis of a Fragment of Insulin Containing the Intrachain Disulfide Bridge

The application of methods developed mostly in this laboratory permitted the synthesis of the fully S,N-protected heptapeptides N-carbobenzoxy-S-trityl-l-cys-teinyl- S-diphenylmethyl - L- cysteinyl-L - alanylglycyl -L-valyl-S-trityl-L-cysteinyl-L-serine methyl ester (VIII, Figure 2), N-t-butyloxycarbonyl-S-trityl-L-cysteinyl-S-diphenylmethyl-L- cysteinyl - L- alanylglycyl-L- valyl-S-trityl-L-cysteinyl-L-serine methyl ester (X, Figure 2), and N-o-nitrophenylsulfenyl-S-benzoyl-L-cysteinyl-S-trityl-L - cysteinyl - L - alanylglycyl -L- valyl -S-benzoyl -L-cysteinyl-L-serine methyl ester (XXII, Figure 3). For these syntheses, a variety of N- and S-protecting groups was used; this allowed selective removal of either the N-, or two of three S-protecting groups according to desired aims. Thus, selective removal of the two S-trityl groups from VIII and X and of the two S-benzoyl groups from XXII led to the formation of the corresponding dithiol compounds XXV, XXVI, and XXVII. By oxidation of these thiol compounds a disulfide bridge was established specifically between two of the three cysteine residues incorporated in the above three heptapeptides. The corresponding oxidation products XXVIII, XXIX, and XXX are derivatives of the 6-12 sequence of the A chain of sheep insulin bearing the 6-11 intrachain bridge (Figure 1). Removal of the N-protecting groups from the cyclic peptide esters XXIX and XXX afforded the cyclic peptide ester hydrochlorides XXXI and XXXII from which the remaining S-protecting group can be removed by established methods. The significance of the above cyclic peptides as regards the problem of insulin synthesis is discussed. The possibility of an S→N acyl migration should be taken into account when using S-acylcysteines in peptide synthesis. It was proved that such a migration does not take place, at least in detectable extent, during the course of the synthesis of the S,N-protected heptapeptide XXII. © 1965, American Chemical Society. All rights reserved

A New Cell Secreting Insulin

The pancreatic �-cell is the only cell in animals that expresses the insulin gene and secretes insulin protein. We have found copious release of immunoreactive and bioactive insulin into the medium from the primary culture of carp adipocytes. Glucose augmented this release to more than 2-fold, and glucose transporter, Glut2, was detected in these cells. These all reflect characteristics of a pancreatic �-cell. The expression of the adipocyte-specific flotillin gene, the presence of peroxisomal proliferator-activated receptor � and Glut4, and the colocalization of insulin and leptin confirmed the identity of these cells as adipocytes. Purified carp adipocyte insulin (AdpInsl) comigrated with porcine and bovine insulin in SDSPAGE, indicating the similarity of their molecular sizes (5.5 kDa). AdpInsl strongly reduced hyperglycemia in streptozotocin- induced diabetic rats. It also stimulated significantly higher glucose uptake in carp and hamster adipocytes than porcine insulin. Adipocyte RNA hybridized with rat and zebrafish insulin cDNA showing the expression of the insulin gene in this cell. Using oligonucleotide primers designed on the basis of conserved insulin domain, AdpInsl cDNA was reverse transcribed, cloned, and sequenced. The deduced amino acid sequence of AdpInsl A and B chain exhibited 98% homology with zebrafish and more than 70% homology with human, porcine, and murine insulin. To understand the structurefunction relationship between AdpInsl and mammalian �-cell insulin, we have analyzed the amino acid sequences and three-dimensional structure of AdpInsl. In the critical determinant segment for receptor binding, AdpInsl has His at the A8 position instead of Thr in human and porcine insulin, and this attributed greater biological activity to AdpInsl. Our results show that carp adipocyte is a unique cell. As an insulin target cell it can express the insulin gene and secrete highly active insulin protein; thus, it may serve as a natural alternative to pancreatic �-cell insulin. (Endocrinology 144: 1585–1593, 200

Hidradenitis suppurativa: an update on connecting the tracts

Hidradenitis suppurativa (HS) is a devastating disease involving abscesses, sinus tracts, and inflammation classically affecting the axilla, groin, and/or anogenital region. Although the disease pathogenesis is not fully understood, recent advances suggest that HS pathology runs much deeper than the cutaneous manifestations. It is now believed that HS is a systemic inflammatory disease that gives rise to the characteristic cutaneous manifestations. This disease is problematic for both patients and physicians to manage because of a variety of diagnostic and management difficulties. This article seeks to provide updates on the current understanding of HS to increase awareness and improve management