Synthesis of new sugar amino acid derivatives of D-glucosamine

The synthesis of several new sugar amino acid derivatives of 2-acetamido-2-deoxy-D-glucose, bearing a C-glycosyl functionality as building blocks for the design and synthesis of natural glycoconjugates mimetics, is described. These compounds were prepared from the readily accessible per-benzylated amino C-allyl glucopyranosyl compounds, with TMSOTf/Ac(2)O-mediated selective acetolysis of the 6-O-benzyl group as the key step.     

Mass-spectrometric identification and sequence location of the ten residues of the new amino acid (gamma-Carboxyglutamic acid) in the N-terminal region of prothrombin.

The detailed mass-spectrometric evidence for our original findings [Magnusson et al. (1974) FEBS Lett. 44, 189-193] of ten gamma-carboxyglutamic acid residues in the N-terminal calcium-binding polypeptide of prothrombin is presented. The identification and sequence location of gamma-carboxyglutamic acid was made by electron-impact and field-desorption studies on acetyl permethyl peptide derivatives, and on the free amino acid. Details of the derivatives formed, and how this new amino acid may be easily recognized and sequenced from the mass spectrum, are given as a basis for future work.     

Synthesis and biological activity of new glycyrrhizic acid conjugates with amino acids and dipeptides

New glycyrrhizic acid (GA) conjugates were synthesized with the use of tert-butyl esters of amino acids or benzyl esters of dipeptides; they contained two residues of L-amino acids (Met, Phe, Pro, and Ile or dipeptides Gly-Leu and Gly-Phe). Activation of GA carboxy groups was carried out with the help of N-hydroxysuccinimide, N,N′-dicyclohexylcarbodiimide, or N-hydroxybenzotriazole with dicyclohexylcarbodiimide. A proline-containing GA derivative is a low-toxic substance; it raises the level of agglutinins by 3.7 times in the blood of mice and 3 times that of hemolysins compared with the control. Dipeptide GA derivatives possess an expressed anti-HIV-1 activity in cultures of MT-4 cells and are 90-70 times less cytotoxic than azidothymidine. The selectivity index of the compounds exceeds those of GA by 110 and 34 times, respectively.     

Statistical distribution of amino acid sequences: a proof of Darwinian evolution

MOTIVATION: The article presents results of the listing of the quantity of amino acids, dipeptides and tripeptides for all proteins available in the UNIPROT-TREMBL database and the listing for selected species and enzymes. UNIPROT-TREMBL contains protein sequences associated with computationally generated annotations and large-scale functional characterization. Due to the distinct metabolic pathways of amino acid syntheses and their physicochemical properties, the quantities of subpeptides in proteins vary. We have proved that the distribution of amino acids, dipeptides and tripeptides is statistical which confirms that the evolutionary biodiversity development model is subject to the theory of independent events. It seems interesting that certain short peptide combinations occur relatively rarely or even not at all. First, it confirms the Darwinian theory of evolution and second, it opens up opportunities for designing pharmaceuticals among rarely represented short peptide combinations. Furthermore, an innovative approach to the mass analysis of bioinformatic data is presented. CONTACT: eitner@amu.edu.pl SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.     

Synthesis and structure proof of morindone 6-O-gentiobioside from Morinda tinctoria

The naturally occurring 1,5-dihydroxy-2-methyl -6-O-β-gentiobiosylanthraquinone was synthesized and its structure confirmed.     

Synthesis of new branched-chain amino sugars

1,3-Dipolar cycloaddition of methylideneaniline N-oxide to sugar enones is described. The addition occurred exclusively from the side opposite to the aglycone affording the corresponding alkyl alpha-D-lyxo-hexopyranosid-(2,3:5',4')-phenylisoxazolidin-4-uloses. Hydrogenation of these compounds readily yielded the corresponding alkyl 3-deoxy-3-N-phenylaminomethyl-alpha-D-talopyranoside, that were readily transformed to the acetates. The structure and conformation of the bicyclic compounds were determined by 1H NMR studies and semi-empirical molecular orbital calculations employing the AM1 method.     

Synthesis of functionalized amino acid derivatives as new pharmacophores for designing anticancer agents

A new series of functionalized amino acid derivatives N-substituted 1-N-(tert-butoxycarbonyl)-2,2-dimethyl-4-phenyl-5-oxazolidine carboxamide (1-17) and 1-N-substituted-3-amino-2-hydroxy-3-phenylpropane-1-carboxamide (18-34) were synthesized and evaluated for their in vitro cytotoxicity against human cancer cell lines. Compound 6 has shown interesting cytotoxicity (IC₅₀ = 5.67 μm) in ovarian cancer, while compound 10 exhibited promising cytotoxicity in ovarian (IC₅₀ = 6.1 μm) and oral (IC₅₀ = 4.17 μm) cancers. These compounds could be of use in designing new anti-cancer agents.     

Synthesis of functionalized amino acid derivatives as new pharmacophores for designing anticancer agents

A new series of functionalized amino acid derivatives N-substituted 1-N-(tert-butoxycarbonyl)-2,2-dimethyl-4-phenyl-5-oxazolidine carboxamide (1-17) and 1-N-substituted-3-amino-2-hydroxy-3-phenylpropane-1-carboxamide (18-34) were synthesized and evaluated for their in vitro cytotoxicity against human cancer cell lines. Compound 6 has shown interesting cytotoxicity (IC(50) = 5.67 microm) in ovarian cancer, while compound 10 exhibited promising cytotoxicity in ovarian (IC(50) = 6.1 microm) and oral (IC(50) = 4.17 microm) cancers. These compounds could be of use in designing new anti-cancer agents.     

Distribution of amino acid residues in the primary protein structure

The amino acid composition and sequence in primary structure of 180 proteins have been studied. It is shown that the distribution of amino acid residues is near to a random one, i.e. it is determined by the amino acid composition. The ratio between statistical and unique character of protein primary structures has been discussed. The amino acid sequence is suggested to be unique in fibrous proteins. In contrast the amino acid sequence in globular proteins is a statistical one. The statistical character of amino acids distribution in globular proteins explains the possibility of sensible text generation under the frame shift mutations, deletions and insertions.     

Function and structure of heterodimeric amino acid transporters

Heterodimeric amino acid transporters are comprised of twosubunits, a polytopic membrane protein (light chain) and an associated type II membrane protein (heavy chain). The heavy chain rbAT (related to b^0,+ amino acid transporter) associates with the lightchain b^0,+AT (b^0,+ amino acid transporter) toform the amino acid transport system b^0,+, whereas thehomologous heavy chain 4F2hc interacts with several light chains toform system L (with LAT1 and LAT2), system y⁺L (withy⁺LAT1 and y⁺LAT2), system x(with xAT), or system asc (with asc1). The association of light chainswith the two heavy chains is not unambiguous. rbAT may interact withLAT2 and y⁺LAT1 and vice versa; 4F2hc may interact withb^0,+AT when overexpressed. 4F2hc is necessary fortrafficking of the light chain to the plasma membrane, whereas thelight chains are thought to determine the transport characteristics ofthe respective heterodimer. In contrast to 4F2hc, mutations in rbATsuggest that rbAT itself takes part in the transport besides servingfor the trafficking of the light chain to the cell surface. Heavy and light subunits are linked together by a disulfide bridge. The disulfidebridge, however, is not necessary for the trafficking of rbAT or 4F2heterodimers to the membrane or for the functioning of the transporter.However, there is experimental evidence that the disulfide bridge inthe 4F2hc/LAT1 heterodimer plays a role in the regulation of a cationchannel. These results highlight complex interactions between thedifferent subunits of heterodimeric amino acid transporters and suggestthat despite high grades of homology, the interactions between rbAT and4F2hc and their respective partners may be different.

     

Protein structure, neighbor effect, and a new index of amino acid dissimilarities.

Amino acids interact with each other, especially with neighboring amino acids, to generate protein structures. We studied the pattern of association and repulsion of amino acids based on 24,748 protein-coding genes from human, 11,321 from mouse, and 15,028 from Escherichia coli, and documented the pattern of neighbor preference of amino acids. All amino acids have different preferences for neighbors. We have also analyzed 7,342 proteins with known secondary structure and estimated the propensity of the 20 amino acids occurring in three of the major secondary structures, i.e., helices, sheets, and turns. Much of the neighbor preference can be explained by the propensity of the amino acids in forming different secondary structures, but there are also a number of intriguing association and repulsion patterns. The similarity in neighbor preference among amino acids is significantly correlated with the number of amino acid substitutions in both mitochondrial and nuclear genes, with amino acids having similar sets of neighbors replacing each other more frequently than those having very different sets of neighbors. This similarity in neighbor preference is incorporated into a new index of amino acid dissimilarities that can predict nonsynonymous codon substitutions better than the two existing indices of amino acid dissimilarities, i.e., Grantham's and Miyata's distances.     

Relation between the structure of oligopeptides and the amino acid sequence

The present paper deals with determination of the relationship between the order of the arrangement of amino acids in comparatively short-range oligopeptides (tetrapeptides) and their conformational potentialities. It is shown that the spatial and conformational possibilities of the tetrapeptides composed of the same amino acid residues exhibit high sensibility to their mutual arrangement, i. e. to the amino acid sequence. A detailed conformation analysis vividly demonstrated that the difference in conformational possibilities is manly determined by different conditions of realization of residual interactions. It is shown convincingly that energetic differences of the fragments are due to different interaction contributions for each of the considered fragments.