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Biomedical subjects

A Sali

Publications and source records attributed to A Sali.

At least 109 records · Page 6Linked to original sources
PubMed1992

Domain flexibility in aspartic proteinases.

Comparison of the three-dimensional structures of native endothiapepsin (EC 3.4.23.6) and 15 endothiapepsin oligopeptide inhibitor complexes defined at high resolution by X-ray crystallography shows that endothiapepsin exists in two forms differing in the relative orientation of a domain comprising residues 190-302. There are relatively few interactions between the two parts of the enzyme; consequently, they can move as separate rigid bodies. A translational, librational, and screw analysis of the thermal parameters of endothiapepsin also supports a model in which the two parts can move relative to each other. In the comparison of different aspartic proteinases, the rms values are reduced by up to 47% when the two parts of the structure are superposed independently. This justifies description of the differences, including those between pepsinogen and pepsin (EC 3.4.34.1), as a rigid movement of one part relative to another although considerable distortions within the domains also occur. The consequence of the rigid body movement is a change in the shape of the active site cleft that is largest around the S3 pocket. This is associated with a different position and conformation of the inhibitors that are bound to the two endothiapepsin forms. The relevance of these observations to a model of the hydrolysis by aspartic proteinases is briefly discussed.

Aspartic Acid Endopeptidases↗
PubMed1992

A variable gap penalty function and feature weights for protein 3-D structure comparisons.

We have developed a variable gap penalty function for use in the comparison program COMPARER which aligns protein sequences on the basis of their 3-D structures. For deletions and insertions, components are a function of structural features of individual amino acid residues (e.g. secondary structure and accessibility). We have also obtained relative weights for different features used in the comparison by examining the equivalent residues in weight matrices and in alignments for pairs of 3-D structures where the equivalencies are relatively unambiguous. We have used the new parameters and the variable gap penalty function in COMPARER to align protein structures in the Brookhaven Data Bank. The variable gap penalty function is useful especially in avoiding gaps in secondary structure elements and the new feature weights give improved alignments. The alignments for both azurins and plastocyanins and N- and C-terminal lobes for aspartic proteinases are discussed.

Amino Acid Sequence↗
PubMed1992

Primary bile duct stones and bacterial activity.

The results of this study suggest that infection with beta-glucuronidase active bacteria is the initial event in the nucleation of primary bile duct stones (PBDS). PBDS from five patients were morphologically fragile and "earthy" with alternating light and dark brown pigment layers with no evidence of a distinct central nucleus that may have been reminiscent of a different structure. Chemically, calcium bilirubinate and calcium palmitate were prominent throughout their structure. All bile duct biles had a positive culture and were always associated with at least one bacterial species which was beta-glucuronidase active. Moreover, fragments of PBDS nuclear areas had positive cultures that were comparable with those present in their individual bile duct bile. Microscopic examination of bile showed abundant precipitation of calcium bilirubinate granules in all samples. Thus, bile duct bile infection with beta-glucuronidase active bacteria (e.g. E. coli, C. perfringens) appears to be a key factor in PBDS pathogenesis, having a precursor role, rather than being a consequence. Bile stasis is likely to be a co-factor which must have a supportive role in subsequent stone growth.

Adult↗
PubMed1991

Rifampicin as cytotoxic agent for cholangiocarcinoma: preliminary report of seven cases.

Seven consecutive patients with unresectable cholangiocarcinoma of the major bile ducts, referred to one surgical department with a hepatobiliary interest, were treated by biliary decompression and with the antibiotic rifampicin in an uncontrolled preliminary study. Three patients were also given tamoxifen. Five of the seven are dead, the mean survival being 26 months (expected mean survival 8 months), and two are alive and well in May 1991, 48 and 30 months respectively from the time of presentation. A controlled study of rifampicin with and without tamoxifen is indicated in unresectable cholangiocarcinoma.

Adenoma, Bile Duct↗
PubMed1991

Primary "brown pigment" bile duct stones.

Bile duct stones from 42 patients were morphologically and chemically analysed. The calculi from 27 patients had important primary bile duct stone (PBDS) features, consisting of a general ovoid shape and fragile structure, with alternating light and dark brown pigmented layers on cross-section. Chemically these stones contained low levels of cholesterol, with high levels of bilirubin and calcium. Subsequent infrared spectroscopy analysis showed that calcium bilirubinate and calcium palmitate were the only calcium salts present. Calcium palmitate was prominent in the light brown layers. A morphological and chemical comparison with gallbladder stones showed that bile duct "stasis stones" were similar in morphological and chemical composition to the brown pigment gallbladder calculi. However, they were distinct from most gallbladder stones, indicating that primary bile duct calculi have an aetiology that is different to 90% of gallbladder calculi. Primary bile duct calculi were observed to occur with or without the presence of a gallbladder, and more interestingly, in the bile duct of two patients with cholesterol gallbladder stones. Bile duct bile of patients with primary choledocholithiasis were always moderately to profusely infected and with abundant calcium bilirubinate precipitation. Moreover, this study has shown that PBDS chemical analyses profiles were consistent and correlated well with their defined morphology. Consequently, PBDS may be accurately identified at the time of operation by morphology. An important aetiological factor would appear to be infection, which would seem to promote bile duct bile stasis and eventual stone growth.

Bile Duct Diseases↗
PubMed1990

X-ray analyses of aspartic proteinases. III Three-dimensional structure of endothiapepsin complexed with a transition-state isostere inhibitor of renin at 1.6 A resolution.

The aspartic proteinase, endothiapepsin (EC 3.4.23.6), was complexed with a highly potent renin inhibitor, H-261 (t-Boc-His-Pro-Phe-His-LeuOHVal-Ile-His), where OH denotes a hydroxyethylene (-(S) CHOH-CH2-) transition-state isostere in the scissile bond surrogate. Crystals were grown in a form that has the same space group P2(1) as the uncomplexed enzyme, but with a 10 A decrease in the length of the alpha-axis and a 13 degrees decrease in the beta-angle. X-ray data have been collected to a resolution of 1.6 A. The rotation and translation parameters defining the position of the enzyme in the unit cell were determined previously using another enzyme-inhibitor complex that crystallized isomorphously with that of H-261. The molecule was refined using restrained least-squares refinement and the positions of non-hydrogen atoms of the inhibitor and water molecules were defined by difference Fourier techniques. The enzyme-inhibitor complex and 322 water molecules were further refined to a crystallographic R-factor of 0.14. Apart from a small rigid group rotation of a domain comprising residues 190 to 302 and small movements in the flap, there is little difference in conformation between the complexed and uncomplexed forms of the enzyme. The inhibitor is bound in an extended conformation along the active site cleft, and the hydroxyl group of the hydroxyethylene moiety is hydrogen-bonded to both catalytic aspartate carboxylates. The complex is stabilized by hydrogen bonds between the main-chain of the inhibitor and the enzyme. All side-chains of the inhibitor are in van der Waals' contact with groups in the enzyme and define a series of specificity pockets along the active site cleft. The study provides useful clues as to how this potent renin inhibitor (IC50 value of 0.7 x 10(-9) M) may bind renin. In particular it defines the interactions of the hydroxyethylene transition-state isostere with the enzyme more precisely than has been previously possible and therefore provides a useful insight into interactions in the transition state complex.

Aspartic Acid Endopeptidases↗
PubMed1990

Tertiary structural constraints on protein evolutionary diversity: templates, key residues and structure prediction.

The pattern of residue substitution in divergently evolving families of globular proteins is highly variable. At each position in a fold there are constraints on the identities of amino acids from both the three-dimensional structure and the function of the protein. To characterize and quantify the structural constraints, we have made a comparative analysis of families of homologous globular proteins. Residues are classified according to amino acid type, secondary structure, accessibility of the sidechain, and existence of hydrogen bonds from sidechain to other sidechains or peptide carbonyl or amide functions. There are distinct patterns of substitution especially where residues are both solvent inaccessible and hydrogen bonded through their sidechains. The patterns of residue substitution can be used to construct templates or to identify 'key' residues if one or more structures are known. Conversely, analysis of conversation and substitution across a large family of aligned sequences in terms of substitution profiles can allow prediction of tertiary environment or indicate a functional role. Similar analyses can be used to test the validity of putative structures if several homologous sequences are available.

Amino Acid Sequence↗
PubMed1990

Definition of general topological equivalence in protein structures. A procedure involving comparison of properties and relationships through simulated annealing and dynamic programming.

A protein is defined as an indexed string of elements at each level in the hierarchy of protein structure: sequence, secondary structure, super-secondary structure, etc. The elements, for example, residues or secondary structure segments such as helices or beta-strands, are associated with a series of properties and can be involved in a number of relationships with other elements. Element-by-element dissimilarity matrices are then computed and used in the alignment procedure based on the sequence alignment algorithm of Needleman & Wunsch, expanded by the simulated annealing technique to take into account relationships as well as properties. The utility of this method for exploring the variability of various aspects of protein structure and for comparing distantly related proteins is demonstrated by multiple alignment of serine proteinases, aspartic proteinase lobes and globins.

Amino Acid Sequence↗
PubMed1990

Balloon dilatation of biliary strictures: experience and review of the literature.

Patients who develop strictures after repeated biliary surgery are a complex management problem. Reoperation in these patients, who may also have cirrhosis, portal hypertension and non-dilated ducts, is hazardous even in experienced centres. The new technique of percutaneous balloon dilatation has been used increasingly in such cases. A review of the literature and the experience with this technique in five patients with recurrent biliary strictures is presented. Its use is recommended in patients who present with recurrent problems when a previous biliary-intestinal anastomosis has failed as well as in those who develop stricture following multiple procedures involving the biliary system.

Bile Duct Diseases↗
PubMed1990

Limy bile cholecystitis: an in vitro study and a case report.

Limy bile is a rare condition characterized by excessive precipitation of calcium carbonate in the gall-bladder. It has been found to cause cholecystitis without obstruction at the neck of the gall-bladder. A patient with the appearance of limy bile on ultrasound films which was consistent with a large gallstone is described. An in vitro study with gall-bladders filled with lime utilizing ultrasonography is also presented for the first time.

Adult↗
PubMed1990

Gallstone decalcification and dissolution using chenodeoxycholate and citrate.

Gallstone dissolution may be possible only in selected patients. Patients with calcified or large gallstones are not suitable for dissolution. Citrate is normally present in bile and an oral citrate load can increase biliary citrate. A combination of chenodeoxycholic acid (C.D.C.A.) and citrate has been shown to dissolve calcified cholesterol gallstones in vitro. Patients with calcified or large gallstones were treated with a combination of C.D.C.A. and citrate. Partial decalcification was achieved in seven out of twenty patients with calcified stones (35%) and complete decalcification in four patients (20%). One of the patients with large stones had complete dissolution. Five patients who were suitable for C.D.C.A. treatment but did not respond were also treated with C.D.C.A. and citrate. One of the patients in this latter group had complete dissolution. Oral citrate can decalcify some calcified gallstones.

Adult↗
PubMed1990

Dietary fibre and fats in health and disease.

The recent discovery of varying types of dietary fibre and fats that have different functions has led to a more scientific understanding of nutrients (especially as they effect coronary heart disease and cancer). Soluble dietary fibres can decrease serum cholesterol as can certain fatty acids. Some fatty acids may also be protective against cancer.

Diet↗
PubMed1989

High-resolution X-ray diffraction study of the complex between endothiapepsin and an oligopeptide inhibitor: the analysis of the inhibitor binding and description of the rigid body shift in the enzyme.

The conformation of the synthetic renin inhibitor CP-69,799, bound to the active site of the fungal aspartic proteinase endothiapepsin (EC 3.4.23.6), has been determined by X-ray diffraction at 1.8 A resolution and refined to the crystallographic R factor of 16%. CP-69,799 is an oligopeptide transition--state analogue inhibitor that contains a new dipeptide isostere at the P1-P1' position. This dipeptide isostere is a nitrogen analogue of the well-explored hydroxyethylene dipeptide isostere, wherein the tetrahedral P1' C alpha atom has been replaced by trigonal nitrogen. The inhibitor binds in the extended conformation, filling S4 to S3' pockets, with hydroxyl group of the P1 residue positioned symmetrically between the two catalytic aspartates of the enzyme. Interactions between the inhibitor and the enzyme include 12 hydrogen bonds and extensive van der Waals contacts in all the pockets, except for S3'. The crystal structure reveals a bifurcated orientation of the P2 histidine side chain and an interesting relative rotation of the P3 phenyl ring to accommodate the cyclohexyl side chain at P1. The binding of the inhibitor to the enzyme, while producing no large distortions in the enzyme active site cleft, results in small but significant change in the relative orientation of the two endothiapepsin domains. This structural change may represent the action effected by the proteinase as it distorts its substrate towards the transition state for proteolytic cleavage.

Aspartic Acid Endopeptidases↗
PubMed1989

Klatskin tumours: a 20 year experience.

The management of 27 patients who presented with cholangiocarcinoma of the hepatic confluence over the past 20 years is reviewed, and the dramatic changes, both in accuracy of diagnosis and modes of treatment, are documented. All 27 presented with jaundice, three underwent laparotomy only, four had a T-tube inserted, one had a straight transhepatic tube inserted, seven U-tubes were placed and four patients underwent surgical resection. More recently, seven patients were drained percutaneously and a further patient was treated by an endoscopic stent. There were six postoperative deaths. Of the 24 who received active treatment, the mean survival was 8 months with a range of 0-40 months. The advantages and disadvantages of the various methods of diagnosis and treatment are discussed. The possible role of radiotherapy and chemotherapy are reviewed briefly.

Adenoma, Bile Duct↗