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L M Firsov

Publications and source records attributed to L M Firsov.

At least 19 recordsLinked to original sources

Expression, isolation, purification, and biochemical properties of trehalose-6-phosphate hydrolase from thermoresistant strain Bacillus sp. GP16.

Here we describe cloning, expression, and purification of the enzyme trehalose-6-phosphate hydrolase from thermoresistant strain Bacillus sp. GP16. Principal biochemical properties of the enzyme at different pH and temperature values were determined. Entropy and enthalpy of activation of the enzyme for substrates trehalose-6-phosphate and p-nitrophenyl glucoside were calculated, and the dependence of the kinetic parameters from ionic strength was established.

Amino Acid Sequence↗

alpha-Glucosidases.

This review highlights the main properties of mammalian, plant, and microbial alpha-glucosidases. Special attention is given to the classification of these enzymes, possible catalytic mechanisms, their tertiary structure, and the structure of major inhibitors. Experimental data on the elucidation of amino acid residues essential for catalysis are also discussed.

Amino Acid Sequence↗

Crystallographic complexes of glucoamylase with maltooligosaccharide analogs: relationship of stereochemical distortions at the nonreducing end to the catalytic mechanism.

Crystal structures at pH 4 of complexes of glucoamylase from Aspergillus awamori var. X100 with the pseudotetrasaccharides D-gluco-dihydroacarbose and acarbose have been refined to R-factors of 0.147 and 0.131 against data to 1.7- and 2.0-A resolution, respectively. The two inhibitors bind in nearly identical manners, each exhibiting a dual binding mode with respect to the location of the last sugar residues. The reduced affinity of D-gluco-dihydroacarbose (K1 = 10(-8) M) relative to acarbose (K1 = 10(-12) M) may stem in part from the weakening of hydrogen bonds of the catalytic water (Wat 500) to the enzyme. Steric contacts between the nonreducing end of D-gluco-dihydroacarbose and the catalytic water perturb Wat 500 from its site of optimal hydrogen bonding to the active site. Interactions within the active site displace the 6-hydroxymethyl group of the nonreducing end of both acarbose and D-gluco-dihydroacarbose toward a more axial position. In the case of D-gluco-dihydroacarbose the shift in the position of the 6-hydroxymethyl group occurs with a 12 degrees change in two dihedral angles of the glucopyranose ring toward a half-chair conformation. The observed conformational distortion of the first residue of D-gluco-dihydroacarbose is consistent with the generation of a glucopyranosyl cation in the transition state. Comparable distortions of stereochemistry in model compounds require approximately 2 kcal/mol, not more than 25% of the energy necessary to form the half-chair conformation in glucose. The magnitude of stereochemical distortion observed in the active site of glucoamylase suggests that favorable electrostatic interactions between the putative glucopyranosyl cation intermediate and the active site must be more important in stabilizing the transition state than mechanical distortion of the substrate.

Acarbose↗

Refined structure for the complex of D-gluco-dihydroacarbose with glucoamylase from Aspergillus awamori var. X100 to 2.2 A resolution: dual conformations for extended inhibitors bound to the active site of glucoamylase.

The crystal structure at pH 4 of the complex of glucoamylase II(471) from Aspergillus awamori var. X100 with the pseudotetrasaccharide D-gluco-dihydroacarbose has been refined to an R-factor of 0.125 against data to 2.2 A resolution. The first two residues of the inhibitor bind at a position nearly identical to those of the closely related inhibitor acarbose in its complex with glucoamylase at pH 6. However, the electron density bifurcates beyond the second residue of the D-gluco-dihydroacarbose molecule, placing the third and fourth residues together at two positions in the active site. The position of relatively low density (estimated occupancy of 35%) corresponds to the location of the third and fourth residues of acarbose in its complex with glucoamylase at pH 6. The position of high density (65% occupancy) corresponds to a new binding mode of an extended inhibitor to the active site of glucoamylase. Presented are possible causes for the binding of D-gluco-dihydroacarbose in two conformations at the active site of glucoamylase at pH 4.

Aspergillus↗

NMR spectroscopy of exchangeable protons of glucoamylase and of complexes with inhibitors in the 9-15-ppm range.

1H-NMR spectra have been recorded for glucoamylases I and II from Aspergillus awamori var. X100 and from A. niger in the 9-15-ppm region. At least 17 distinct peaks, many of them arising from single protons, are observed. These are designated A-Q, A being the furthest downfield. At least 9 of these are lost rapidly by exchange when the enzyme is placed in D2O. Peaks A, B, E and H undergo distinct shifts with pH change in the pH region 3-7. Several others undergo smaller shifts. Small differences are also seen between the enzymes from the two different sources. Binding of the pseudotetrasaccharide inhibitor acarbose leads to a 0.50-ppm downfield shift of peak B, other smaller changes, and retention of two additional protons in D2O. delta-D-gluconolactone induces shifts in peaks E, H, and L. The slow substrate maltitol causes peak A to broaden and shift, peaks J and K to shift and a new or greatly shifted resonance to appear at 15.4 ppm. It disappears as the maltitol is hydrolyzed. Treatment with iodoacetamide or diethyl pyrocarbonate leads to disappearance of peak D at 12.3 ppm. When this peak was irradiated strong nuclear Overhauser effects (NOE) were observed at 8.01 ppm and 7.22 ppm, positions expected for the C epsilon 1 and C delta 2 protons of an uncharged imidazole ring. We identify D as arising from the N epsilon 2 proton of His254 which is uncharged except at the lowest pH values. Other NOE and two-dimensional NOE spectra have provided additional information. Three mutant forms of the A. niger enzyme, in which tryptophan residues have been replaced by phenylalanine, have been examined. Because of shifts induced by changes in ring current and other environmental effects it is hard to make a direct identification of the resonances from the replaced indole NH protons. However, on the basis of a distinct NOE between peaks E and H we have identified these resonances as arising from the indole NH protons of Trp52 and Trp120. Other possible assignments are considered. The NMR spectra of the glucoamylases I, which have a starch binding domain of about 104 residues at the carboxyl terminus, show four sharp resonances in the 9.7-10.6-ppm range that are not present in the glucoamylases II, which lack this domain. These resonances no doubt represent the four indole NH ring protons from Trp543, Trp562, Trp590 and Trp615. Three of these are very sharp suggesting a high mobility of this domain.

Aspergillus↗

Refined structure for the complex of acarbose with glucoamylase from Aspergillus awamori var. X100 to 2.4-A resolution.

The three-dimensional structure of the pseudotetrasaccharide acarbose complexed with glucoamylase II(471) from Aspergillus awamori var. X100 has been determined to 2.4-A resolution. The model includes residues corresponding to 1-471 of glucoamylase I from Aspergillus niger, a single molecule of bound acarbose, and 535 sites for water molecules. The crystallographic R factor from refinement is 0.124, and the root-mean-squared deviation in bond distances is 0.013 A. Electron density for a single molecule of bound acarbose defines what may be the first four subsites in the binding of extended maltooligosaccharides. Hydrogen bonds between acarbose and the enzyme involve Arg54, Asp55, Arg305, carbonyl177, main chain amide121, Glu179, Glu180, and carbonyl179. Glu179 forms a salt link to the imino linkage between the first and second residues of acarbose. This buried salt link probably contributes significantly to the unusually tight association (Kd approximately 10(-12) M) of acarbose with glucoamylase. In addition, a significant hydrophobic contact between the third residue of acarbose and the side chain of Trp120 distorts the three-center angle of the glucosidic linkage between the second and third residues of acarbose. A water molecule (water500) hydrogen bonds to Glu400 and the 6-hydroxyl of the valienamine moiety of acarbose and is at an approximate distance of 3.7 A from the "anomeric" carbon of the inhibitor. The relevance of the acarbose-glucoamylase complex to the mechanism of enzymic hydrolysis of oligosaccharides is discussed.

Acarbose↗

Refined crystal structures of glucoamylase from Aspergillus awamori var. X100.

The refined crystal structures of a proteolytic fragment of glucoamylase from Aspergillus awamori var. X100 have been determined at pH 6 and 4 to a resolution of 2.2 A and 2.4 A, respectively. The models include the equivalent of residues 1 to 471 of glucoamylase from Aspergillus niger and a complete interpretation of the solvent structure. The R-factors of the pH 6 and 4 structures are 0.14 and 0.12, respectively, with root-mean-square deviations of 0.014 A and 0.012 A from expected bondlengths. The enzyme has the general shape of a doughnut. The "hole" of the doughnut consists of a barrier of hydrophobic residues at the center, which separates two water-filled voids, one of which serves as the active site. Three clusters of water molecules extend laterally from the active site. One of the lateral clusters connects the deepest recess of the active site to the surface of the enzyme. The most significant difference in the pH 4 and 6 structures is the thermal parameter of water 500, the putative nucleophile in the hydrolysis of maltooligosaccharides. Water 500 is associated more tightly with the enzyme at pH 4 (the pH of optimum catalysis) than at pH 6. In contrast to water 500, Glu179, the putative catalytic acid of glucoamylase, retains the same conformation in both structures and is in an environment that would favor the ionized, rather than the acid form of the side-chain. Glycosyl chains of 5 and 8 sugar residues are linked to Asparagines 171 and 395, respectively. The conformations of the two glycosyl chains are similar, being superimposable on each other with a root-mean-square discrepancy of 1.9 A. The N-glycosyl chains hydrogen bond to the surface of the protein through their terminal sugars, but otherwise do not interact strongly with the enzyme. The structures have ten serine/threonine residues, to each of which is linked a single mannose sugar. The structure of the ten O-glycosylated residues taken together suggests a well-defined conformation for proteins that have extensive O-glycosylation of their polypeptide chain.

Aspergillus↗

Refined structure for the complex of 1-deoxynojirimycin with glucoamylase from Aspergillus awamori var. X100 to 2.4-A resolution.

The three-dimensional structure of the complex of 1-deoxynojirimycin with glucoamylase II-(471) from Aspergillus awamori var. X100 has been determined to 2.4-A resolution. The model includes residues corresponding to residues 1-471 of glucoamylase I from Aspergillus niger, two molecules of bound 1-deoxynojirimycin and 605 sites for water molecules. The crystallographic R factor from refinement is 0.119, and the root-mean-squared deviation in bond distances is 0.012 A. The inhibitor complex confirms the location of the active site in the packing void of the alpha/alpha-barrel as proposed by Aleshin et al. [Aleshin, A., Golubev, A., Firsov, L., & Honzatko, R. B. (1992) J. Biol. Chem. 267, 19291-19298]. One inhibitor molecule is associated with strong electron density and represents the principal site of interaction of 1-deoxynojirimycin with the enzyme. The other 1-deoxynojirimycin molecule is associated with weak electron density and therefore, probably represents a binding site of low affinity. Interactions of 1-deoxynojirimycin with the enzyme at its principal site involve Arg 45, Asp 55, Arg 305, and carbonyl 177. In addition, a water molecule (water 500) hydrogen bonds to Glu 400 and the 6-hydroxyl of 1-deoxynojirimycin and is at an approximate distance of 3.3 A from the "anomeric" carbon of the inhibitor. The structural arrangement of functional groups near the inhibitor molecule suggests that Glu 179 is a catalytic acid, Glu 400 a catalytic base, and water 500 the attacking nucleophile in the hydrolysis of maltooligosaccharides. The relevance of the X-ray work to proposed mechanisms of enzymatic hydrolysis of oligosaccharides is discussed.

1-Deoxynojirimycin↗

Effect of modification of carbohydrate component on properties of glucoamylase.

In this study, we investigated enzymatic deglycosylation of glucoamylase from Aspergillus awamori X 100/D27, a glycoprotein which has two N-linked and about forty short mannose-bearing O-linked sugars per molecule. O-Linked sugars were modified by treatment with alpha-mannosidase and N-linked sugars were removed using endo-beta-N-acetylglucosaminidase F. Analysis of conformational changes following deglycosylation suggests that O-linked sugars essentially contribute to the stabilization of glucoamylase domains. Modification of the carbohydrate component by adding 1-deoxymannojirimycin to the culture medium induced inhibition of alpha-mannosidases involved in the processing, leading to a more complete glycosylation and, consequently, to a higher stability of the enzyme.

1-Deoxynojirimycin↗

A model for cleavage of O-glycosidic bonds in glycoproteins.

The present work investigated the possibility of cleavage of alpha-linkages between mannose or galactose and serine/threonine residues by alpha-mannosidase and alpha-galactosidase. The study was carried out initially with model synthetic compounds imitating the O-glycosidic bond in glycoproteins, and further with glucoamylase. It was shown that alpha-mannosidase and alpha-galactosidase can hydrolyse these linkages after proteolytic digestion of glucoamylase.

Glucan 1,4-alpha-Glucosidase↗

Adsorption of glucoamylase from Asp. awamori X-100/D27 on cell walls.

Upon secretion, the major form of glucoamylase from Asp. awamori adsorbs on fungal cell walls. Its substrate binding site showing affinity for alpha-1-4 and alpha-1-6 wall glucans is responsible for adsorption. The minor form in which this site is absent has no sorption ability for cell walls.

Adsorption↗

[Cleavage of O-glycosyl bonds in glycopeptides].

The possibility of cleavage of the alpha-bond between mannose (or galactose) and serine (or threonine) in the presence of alpha-mannosidase and alpha-galactosidase has been studied. Using model compounds simulating the O-glycosyl bond in glycoproteins, several glycopeptides have been synthesized: N-tertbutyloxycarbonyl-O-alpha-mannopyranosyl-seryl-glycine methylamide (alpha-Man-Ser-Gly), tertbutyl-oxycarbonyl-O-alpha-mannopyranosyl-threonyl- glycine methylamide (alpha-Man-Thr-Gly), N-tertbutyloxy-carbonyl-O-alpha-galactopyranosyl-seryl-glycine methylamide (alpha-Gal-Ser-Gly) as well as N-tertbutyloxy-carbonyl-O-beta-mannopyranosyl-seryl-glycine methylamide (beta-Man-Ser-Gly). The cleavage has been shown to occur in glucoamylase after proteolytic degradation.

Amino Acid Sequence↗

Crystal structure of glucoamylase from Aspergillus awamori var. X100 to 2.2-A resolution.

The crystal structure of a catalytically active fragment of glucoamylase-I from Aspergillus awamori var. X100 has been determined to a resolution of 2.2 A. Twelve of its 13 alpha-helices are arranged into an "alpha/alpha-barrel." An inner core of six mutually parallel alpha-helices are connected to each other through a peripheral set of six alpha-helices. The peripheral helices are parallel to each other, but approximately antiparallel to the inner core of alpha-helices. The putative active site lies in the packing void of the inner set of helices. The last 30 residues of the enzyme comprise a separate domain containing 10 sites of O-glycosylation. Each instance of O-glycosylation involves a serine or threonine side chain linked to the alpha-anomer of a single mannosyl residue. The O-glycosylated domain is in an extended conformation, wrapping around the "waist" of the alpha/alpha-barrel. Two additional sites of N-glycosylation contribute well ordered glycosyl chains that lie in proximity to the belt of O-glycosylation. The model developed for glucoamylase is a rare and valuable structural example of a glycoprotein and an exo-acting amylolytic enzyme.

Amino Acid Sequence↗

[Effect of modifications of a series of amino acid radicals on the enzymatic activity of glucoamylase from Aspergillus awamori].

The effect of chemical modification of various amino acid residues on the enzymatic activity of glucoamylase from Asp. awamori was studied. Modification of the carboxyl groups by taurine in the presence of water-soluble carbodiimide results in complete inactivation of the enzyme. The inactivation process includes two steps, namely non-specific modification and modification of the active center carboxyls. The rate constants of inactivation at both steps were measured in the presence and absence of the substrate, i. e. maltose. It was shown that the enzyme is inactivated by N-bromosuccinimide. Based on the data on the protection of the enzyme active center by the substrates (maltooligosaccharides of various lengths), it was concluded that the essential tryptophane residue(s) is localized in the fourth subsite. Ethoxycarbonylation, nitration and acetylation of glucoamylase do not change the catalytic activity of the enzyme. The protein was shown to contain no SH-groups.

Amino Acids↗

[Active center of glycoamylase from Aspergillus awamori].

The maltooligosaccharides--triose, tetrose, pentose and hexose have been obtained by fractionation of partially hydrolyzed cyclohexamylose. The values of free energies for the binding of the first six sites of glucose residue binding in the enzyme active center were calculated according to the Hiromi model and were found to be equal to -0.6, -4.5, -1.68, -0.66, -0.25 and +-0.06 kcal/mole, respectively. The Hiromi model was extrapolated to p-nitrophenyl-alpha-D-glucoside, p-nitrophenyl-alpha-D-maltoside and methyl-alpha-D-glucoside. The energies for nitrophenol binding for the second, third and fourth centers and of the methyl group binding for the second and third centers were determined. The value of universal catalytic constant kcat is equal to 47.9 s-1 at 37 degrees.

Aspergillus↗

[Carboxyl groups in the active center of glucoamylase from Aspergillus awamori].

The values for the ionization constants of the catalytic groups of the active site of glucoamylase from Asp. awamori for the free enzyme and for the enzyme--substrate complex were calculated. The temperature dependence of the alkaline branch of the pH-dependence curve and the pH dependence in the presence of methanol were determined. The ionization enthalpy delta H = 1.5 +/- 0.3 kcal/mole, the ionization entropy delta S = 20.5 +/- 1.2 e. u. It was assumed that two carboxyl groups are involved in the catalytic act.

Aspergillus↗

[Comparative study of glycosidase from cattle liver and exoglycanase from Aspergillus awamori].

Anomerities of products were estimated for glucosidases from cattle liver and Aspergillus awamori. It was demonstrated that the enzyme from cattle liver is alpha-glucosidase and that from Asp. awamori is exogluconase. It was demonstrated that alpha-glucosidase hydrolyzes the C1--O bond in the course of reaction. delta-Lactone of gluconic acid is a competitive inhibitor for both enzymes. The secondary kinetic isotope effects for both enzymes were measured. The isotope effect for alpha-glucosidase is equal to 1, for exogluconase 1,1 for glycogen and 1,18 for maltose. Some aspects of mechanisms of both enzymes are discussed in terms of the data obtained.

Animals↗