1. Genetic variation in human 5-HT receptors: potential pathogenetic and pharmacological role
M Göthert, P Propping, H Bönisch, M Brüss, M M Nöthen Ann N Y Acad Sci. 1998 Dec 15;861:26-30. doi: 10.1111/j.1749-6632.1998.tb10169.x.
Mutation screening identified variants of h5-HT1A (Gly-22-Ser, Ile-28-Val, Arg-219-Leu), h5-HT1B (Phe-124-Cys), h5-HT2A (Thr-25-Asn, His-452-Tyr), h5-HT2C (Cys-23-Ser) and h5-HT7 (Thr-92-Lys, Pro-279-Leu) receptors. Screening of h5-HT1D, h5-ht1e, h5-ht1f and h5-ht5 receptor genes failed to detect any significant mutations. No differences in radioligand binding properties were observed between the h5-HT1A Ile-28-Val variant receptor (VR) and the wildtype receptor (WTR). Binding profiles of the h5-HT1A Gly-22-Val variant and the WTR were also very similar, but the 8-OH-DPAT-induced down-regulation and desensitization of the VR was attenuated. The h5-HT1B Phe-124-Cys variant leads to considerable changes in [3H]5-carboxamidotryptamine binding: Bmax was decreased and the affinity of various h5-HT1B ligands was modified (usually increased; e.g., in the case of sumatriptan). The h5-HT2A His-452-Tyr variant causes an alteration of the amplitude and timing of intracellular calcium mobilization in platelets from 452-His/452-Tyr heterozygous compared to 452-His/452-His homozygous individuals. Most, but not all, of the VRs listed above were examined for association with, e.g., bipolar depression and schizophrenia, yet no relation was observed. The most consistent finding was an association between a silent mutation (102T/C) in the h5-HT2A receptor gene and schizophrenia; this association may be explained by linkage disequilibrium with a functional variant in the regulatory region of the gene. Studies of the therapeutic response to clozapine produced no homogeneous results with respect to the pharmacogenetic significance of the various mutations in the h5-HT2A and h5-HT2C receptor genes.
2. Sequence-assisted peptide synthesis (SAPS)
B Due Larsen, A Holm J Pept Res. 1998 Dec;52(6):470-6. doi: 10.1111/j.1399-3011.1998.tb01251.x.
In solid-phase peptide synthesis (SPPS) the growing peptide chain may undergo chain aggregation which can cause serious synthetic problems. A number of investigations concerning this problem have been reported in the chemical literature. During a study of such "difficult sequences" using the Fmoc-protection strategy, we have observed that peptide-chain aggregation may be significantly reduced when certain amino acid sequences are incorporated C-terminally (1). Thus, synthesis of the difficult poly-alanine, (Ala)n, sequence (n < or = 20) has been investigated with (Lys(Boc))m (m < or = 6) and (Glu(tBu))m (m > or = 6) as pre-sequences. With m > or = 3, peptides are obtained as single, homogeneous products while a complex mixture of deletion peptides and corresponding Fmoc-protected peptides is formed (n > or = 6) without the pre-sequence. A mixed pre-sequence, (Lys(Boc)Glu(tBu))3, has a similar favorable effect on the synthetic results, but the positive effect seems confined to a rather narrow framework of amino acids and side-chain protecting groups in the pre-sequence as discussed in the article. Among other reputedly difficult sequences the synthesis of H-(Thr-Val)5-OH, H-Val-Asn-Val-Asn-Val-Gln-Val-Gln-Val-Asp-OH, the Acyl Carrier Protein (65-74) and the human insulin B-chain has been investigated. In all cases introduction of a pre-sequence gives rise to satisfactory synthetic results. In the latter case, the lysine pre-sequence may be cleaved enzymatically to give the desB30 insulin B-chain. NIR-FT Raman studies of the synthesis of the poly-alanine, (Ala)n, sequences have shown that the pre-sequence (Lys(Boc))6 shifts the conformation of the growing peptide chain from a beta-structure (n > or = 6) to a random coil conformation (1c). This result is in agreement with the general observation that SPPS proceeds optimally under random coil conditions.
3. Nyuzenamide C, an Antiangiogenic Epoxy Cinnamic Acid-Containing Bicyclic Peptide from a Riverine Streptomyces sp
Joon Soo An, et al. J Nat Prod. 2022 Apr 22;85(4):804-814. doi: 10.1021/acs.jnatprod.1c00837. Epub 2022 Mar 16.
A new nonribosomal peptide, nyuzenamide C (1), was discovered from riverine sediment-derived Streptomyces sp. DM14. Comprehensive analysis of the spectroscopic data of nyuzenamide C (1) revealed that 1 has a bicyclic backbone composed of six common amino acid residues (Asn, Leu, Pro, Gly, Val, and Thr) and four nonproteinogenic amino acid units, including hydroxyglycine, β-hydroxyphenylalanine, p-hydroxyphenylglycine, and 3,β-dihydroxytyrosine, along with 1,2-epoxypropyl cinnamic acid. The absolute configuration of 1 was proposed by J-based configuration analysis, the advanced Marfey's method, quantum mechanics-based DP4 calculations, and bioinformatic analysis of its nonribosomal peptide synthetase biosynthetic gene cluster. Nyuzenamide C (1) displayed antiangiogenic activity in human umbilical vein endothelial cells and induced quinone reductase in murine Hepa-1c1c7 cells.
