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S Sumiya

Publications and source records attributed to S Sumiya.

11 recordsLinked to original sources
PubMed1994

Clarification of substrate specificity of papain by crystal analyses of complexes with covalent-type inhibitors.

In order to investigate the stereo specificity of papain Sn subsites (n = 1-4) at the atomic level, two kinds of covalent-type inhibitors were designed based on the previous results on papain-E-64 and papain-E-64-c interactions, and their complex crystals with papain were analyzed by X-ray diffraction. The results show that the hydrophobic regions consisting of Val-133, Val-157 and Asp-158 and of Tyr-61, Gly-66 and Tyr-67 residues interact with the hydrophobic P2 and P3 side chains of inhibitors, thus indicating the function of the former and latter binding pockets as S2 and S3 subsites, respectively. Furthermore, the X-ray analysis suggests that the papain has no definite Sn subsite of n > or = 4, and the S3-P3 hydrophobic interaction is significantly affected by the Pn side chain (n > or = 4) of both the substrate and the inhibitor.

Cysteine Proteinase Inhibitors↗
PubMed1992

Crystal structure of papain-E64-c complex. Binding diversity of E64-c to papain S2 and S3 subsites.

In order to investigate the binding mode of E64-c (a synthetic cysteine proteinase inhibitor) to papain at the atomic level, the crystal structure of the complex was analysed by X-ray diffraction at 1.9 A (1 A is expressed in SI units as 0.1 nm) resolution. The crystal has a space group P2(1)2(1)2(1) with a = 43.37, b = 102.34 and c = 49.95 A. A total of 21,135 observed reflections were collected from the same crystal, and 14811 unique reflections of up to 1.9 A resolution [Fo > 3 sigma(Fo)] were used for the structure solution and refinement. The papain structure was determined by means of the molecular replacement method, and then the inhibitor was observed on a (2 magnitude of Fo-magnitude of Fc) difference Fourier map. The complex structure was finally refined to R = 19.4% including 207 solvent molecules. Although this complex crystal (Form II) was polymorphous as compared with the previously analysed one (Form I), the binding modes of leucine and isoamylamide moieties of E64-c were significantly different from each other. By the calculation of accessible surface area for each complex atom, these two different binding modes were both shown to be tight enough to prevent the access of solvent molecules to the papain active site. With respect to the E64-c-papain binding mode, molecular-dynamics simulations proposed two kinds of stationary states which were derived from the crystal structures of Forms I and II. One of these, which corresponds to the binding mode simulated from Form I, was essentially the same as that observed in the crystal structure, and the other was somewhat different from the crystal structure of Form II, especially with respect to the binding of the isoamylamide moiety with the papain S subsites. The substrate specificity for the papain active site is discussed on the basis of the present results.

Amino Acid Sequence↗
PubMed1992

Molecular design of potent inhibitor specific for cathepsin B based on the tertiary structure prediction.

To design a potent inhibitor specific for cathepsin B (rat liver), the tertiary structure was predicted based on the crystal structure of the papain complexed with (+)-(2S,3S)-3-(1-[N-(3-methylbutyl)amino]leucylcarbonyl)oxirane-2- carbolylic acid (E-64-c), a thiol protease inhibitor. Taking advantage of the structural characteristics of the predicted active site, seventeen inhibitors were chemically synthesized by molecular modeling, and one of them, N-(L-3-trans-propylcarbamoyloxirane-2-carbonyl)-L-isoleucyl-L-p rol ine (CA-074) was shown to be the first potent inhibitor specific for cathepsin B. The relationship between the structure and inhibitory activity is discussed based on the model structure of the cathepsin B-inhibitor complex.

Amino Acid Sequence↗
PubMed1991

Effects of enriched lactate solution (ELS) for resuscitation after burn injury.

Full skin thickness burns covering 35 per cent of the total body surface of rabbits were followed by measurements of Na-K ATPase and arterial blood gas analyses, before and after the burn injury. Studies of the effects of intravenous fluids with different compositions showed that the active transport of the cell membrane was depressed in vivo immediately after a burn injury, mainly due to acidosis. This phenomenon was not completely corrected by the Baxter formula which uses conventional lactated Ringer's solution. However, an improvement was observed in those groups given the 'Enriched Lactate Solution' (ELS) containing large quantities of lactate as the base source. These results suggest that ELS, which positively corrected acidosis in accordance with its concentration, is very effective and more appropriate than the conventional lactated Ringer's solution for early burn resuscitation.

Acidosis↗
PubMed1991

[Effect of inclusion complexation of decanoic acid with alpha-cyclodextrin on rectal absorption of cefmetazole sodium suppository in rabbits].

Inclusion complex of decanoic acid (DA) with alpha-cyclodextrin (alpha-CyD) was prepared as an additive of cefmetazole sodium (CMZ) suppository and rectally administered to rabbits. The resulting complexation was examined by the phase solubility method, differential scanning calorimetry (DSC) and X-ray diffractometry. Plasma concentration and AUC of CMZ after rectal administration of a suppository containing DA/alpha-CyD complex to rabbits increased more significantly than those with none additive.

Adjuvants, Pharmaceutic↗
PubMed1990

Molecular dynamics simulation of papain-E-64 (N-[N-(L-3-trans-carboxyoxirane-2-carbonyl)-L-leucyl]agmatine) complex.

To investigate the possible binding mode of E-64 (N-[N-(L-3-trans-carboxyoxirane-2-carbonyl)-L-leucyl]agmatine), a potent cysteine protease inhibitor, to papain active site, molecular dynamics simulations were applied to two complex forms: R- and S- configurational forms of E-64 C2 atom for the covalent bond formation with the papain Cys-25 SH group. The tertiary structures of the papain-E-64 complexes were built by visual interactive modelling and the energy minimization technique, and were subjected to the dynamics simulations of 10 ps. Although no significant difference was observed between the potential energies of energy-minimized R- and S-complex forms, the molecular dynamics simulations suggested that the hydrogen bonding mode of the former form is more advantageous than that of the latter one. Comparing with the hydrogen bonds observed in the papain-E-64 complex crystal, it could be concluded that the present molecular dynamics simulation reflects well the three-dimensional structure concerning the interaction of E-64 with the papain active site. The conformational characteristics of E-64 and its possible interaction mode with papain were also discussed.

Computer Simulation↗
PubMed1989

Crystal structure and molecular conformation of E-64, a cysteine protease inhibitor.

In order to elucidate the conformational characteristics of cysteine protease inhibitors contributing to their inhibitory activities, the conformation of E-64 (N-[N-(L-3-trans-carboxyoxiran-2-carbonyl)-L-leucyl]-agmatine), a potent inhibitor of papain, was determined by X-ray crystal structure analysis. The molecules were packed in the crystal through electrostatic forces and hydrogen bonding between the oppositely charged terminal groups and between the amide groups. Two crystallographically independent E-64 molecules both took a flattened and slightly curved structure, which is similar to that of loxistatin, a related cysteine protease inhibitor. Based on the present results, a possible inhibitory mechanism of E-64 is proposed, with reference to the binding mode observed in the crystal structure of papain-substrate analogue complex.

Crystallization↗
PubMed1967

[Neurography].

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