PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Boronic Acids”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed1988

Proteus mirabilis urease. Partial purification and inhibition by boric acid and boronic acids.

Urease was purified 800-fold and partially characterized from Proteus mirabilis, the predominant microorganism associated with urinary stones. Boric acid is a rapid reversible competitive inhibitor of urease. The pH-dependence of inhibition exhibited pKa values of 6.25 and 9.3, where the latter value is probably due to the inherent pKa of boric acid. Three boronic acids also were shown to inhibit urease competitively.

Boric Acids↗
PubMed1983

The inhibition of class C beta-lactamases by boronic acids.

Aromatic boronic acids are reversible inhibitors of the recently classified class C beta-lactamases. The boronic acids studied include ortho-, meta- and para-methyl-, -hydroxymethyl- and -formyl-phenylboronic acid. The beta-lactamases were chromosomally-encoded enzymes, one from Pseudomonas aeruginosa, and the other specified by the ampC gene of Escherichia coli. The inhibition may be correlated with our finding that these beta-lactamases are serine enzymes, i.e. their function entails the hydroxy group of a serine residue acting as a nucleophile.

Binding Sites↗
PubMed1995

Boronic acid adducts of technetium dioxime (BATO) complexes derived from quinuclidine benzilate (QNB) boronic acid stereoisomers: syntheses and studies of their binding to the muscarinic acetylcholine receptor.

We have investigated the possibility of using BATO complexes derivatized with the muscarinic acetylcholine receptor (mAChR) antagonist, quinuclidinyl benzilate (QNB), for mAChR imaging. The BATO complexes, TcCl(DMG)3B-QNB, were prepared using QNB derivatives containing a 4'-boronic acid substituent on one of the benzilic benzene rings (QNB-boronic acid). The QNB-boronic acid molecule has two chiral centers, and all four QNB-BATO stereoisomers were made and evaluated. When studied using in vitro receptor binding assays based on tissue from rat brain caudate-putamen (which contains primarily M1 and M4 mAChR) and rat heart (M2 mAChR), the QNB-boronic acid stereoisomers had binding affinities (KA) in the range 2 x 10(5)-1 x 10(8), at least 10-fold lower than the KA for QNB (ca 2 x 10(9)). The stereochemistry of both centers had some influence on the affinity constant. When the TcCl(DMG)3B-QNB complexes were studied, none of the stereoisomeric complexes displayed measurable specific binding (KA < 10(6)), but all showed high non-specific binding. In vitro autoradiography with rat brain slices confirmed the absence of specific binding in these tracers. In vivo, the 99mTcCl(DMG)3B-QNB complexes displayed minimal brain uptake, and modest heart uptake; the latter was unlikely to be related to uptake by the mAChR. In light of these findings, we conclude that the interaction between the TcCl(DMG)3B-QNB complexes and biological membranes is dominated by the hydrophobicity of the BATO moiety. The TcCl(DMG)3B-QNB complexes, therefore, have little potential for mAChR imaging.

Animals↗
PubMed1989

Do inert beta-lactamase inhibitors act as synergizers of beta-lactam antibiotics? Utility of boric and boronic acids.

Boric and boronic acids were used as inhibitors of beta-lactamases produced by two Citrobacter diversus strains and by one strain of Pseudomonas aeruginosa; all strains were clinical isolates. The beta-lactamases produced by the two Citrobacter diversus strains were inhibited by both borates and boronates, using cephazolin as substrate. The enzyme from Pseudomonas aeruginosa was inhibited only by boronates, using benzylpenicillin as substrate. These inhibitors were also used in combination with selected beta-lactams so as to determine if a synergism of antimicrobial activity occurred. All data reported in the present paper indicate that the minimum inhibitory concentration (MIC) values were lowered in the presence of these inhibitors for the two Citrobacter diversus strains. In the Pseudomonas aeruginosa strains the MIC values were not significantly altered, thus indicating the presence of a permeability barrier for 3-aminophenylboronic acid.

Anti-Bacterial Agents↗
PubMed1980

Boronic acid inhibitors of porcine pancreatic lipase.

Porcine pancreatic lipase was inhibited by alkane and arene boronic acids. The inhibition by octadecane boronic acid was competitive when measured against the hydrolysis of dissolved tripropionin in the presence of siliconized glass beads. The value of Ki in this system was 1.34 x 10(3) molecules micron-2. The ratio of substrate to inhibitor concentrations giving 50% inhibition was in the range of 700 to 2200, indicating that lipase has a greater affinity for boronic acids than for tripropionin. Boronic acids did not interfere with the interaction of lipase with the siliconized glass/water interface, demonstrating that the binding of lipase to substrate interfaces, the first step in lipase action, was not the step at which inhibition occurred. The boronic acid binding site on lipase is at or near the active center serine since modification of this residue by diethyl p-nitrophenyl phosphate was prevented by boronic acids. Modification of the active center serine residue by diethyl p-nitrophenyl phosphate also prevented boronic acid binding. Binding of a chromophoric boronic acid, 7-nitrobenzo-2-oxa-1,3-diazolyl m-aminobenzene boronic acid, to lipase was demonstrated by equilibrium gel filtration on polyacrylamide beads (Bio-Gel P-60) in the presence of 4 mM sodium taurodeoxycholate. The complex contained 1 molecule of boronic acid per molecule of lipase and had a dissociation constant Kd of 5 x 10(-6) M. The boronic acid was not bound in the absence of taurodeoxycholate. Boronic acids are believed to be analogs of the tetrahedral intermediate in the action of lipase.

Animals↗
PubMed1988

Kinetic properties of the binding of alpha-lytic protease to peptide boronic acids.

The kinetic parameters for peptide boronic acids in their interaction with alpha-lytic protease were determined and found to be similar to those of other serine proteases [Kettner, C., & Shenvi, A. B. (1984) J. Biol. Chem. 259, 15106-15114]. alpha-Lytic protease hydrolyzes substrates with either alanine or valine in the P1 site and has a preference for substrate with a P1 alanine. The most effective inhibitors are tri- and tetrapeptide analogues that have a -boroVal-OH residue in the P1 site. At pH 7.5, MeOSuc-Ala-Ala-Pro-boroVal-OH has a Ki of 6.4 nM and Boc-Ala-Pro-boroVal-OH has a Ki of 0.35 nM. Ac-boroVal-OH and Ac-Pro-boroVal-OH are 220,000- and 500-fold less effective, respectively, than the tetrapeptide analogue. The kinetic properties of the tri- and tetrapeptide analogues are consistent with the mechanism for slow-binding inhibition, E + I in equilibrium EI in equilibrium EI*, while the less effective inhibitors are simple competitive inhibitors. MeO-Suc-Ala-Ala-Pro-boroAla-OH is a simple competitive inhibitor with a Ki of 67 nM at pH 7.5. Other peptide boronic acids, which are analogues of nonsubstrates, are less effective than substrate analogues but still are effective competitive inhibitors. For example, MeOSuc-Ala-Ala-Pro-boroPhe-OH has a Ki of 0.54 microM although substrates with a phenylalanine in the P1 position are not hydrolyzed. Binding for boronic acid analogues of both substrate and nonsubstrate analogues is pH dependent with higher affinity near pH 7.5. Similar binding properties have been observed for pancreatic elastase. Both enzymes have almost identical requirements for an extended peptide inhibitor sequence in order to exhibit highly effective binding and slow-binding characteristics.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗
PubMed1985

Acylamino boronic acids and difluoroborane analogues of amino acids: potent inhibitors of chymotrypsin and elastase.

A series of 1-acylamino boronic acids (IA-VA), analogues of the amino acids phenylalanine, phenylglycine, alanine, valine, and isoleucine, were prepared as potential transition-state inhibitors of the serine proteases alpha-chymotrypsin and elastase, by a boronate homologation reaction. The corresponding difluoroboranes (IB-VB), produced from the boronic acids by treatment with HF, were more easily purified than the boronic acids. Since the difluoroboranes readily hydrolyze in water, they proved to be convenient precursors for the boronic acids. The phenylalanine and phenylglycine analogues I and II were good competitive inhibitors of alpha-chymotrypsin (Ki = 0.3-8 microM), and the alanine, valine, and isoleucine analogues (III-IV) proved to be good inhibitors of elastase (Ki = 0.1-35 microM). On the basis of their high affinity and the tendency of boronic acids to form borate complexes, these acylamino boronic acids may be behaving as transition-state inhibitors.

Acylation↗
PubMed1988

Peptide boronic acids, substrate analogs, inhibit chymase, and histamine release from rat mast cells.

Peptide boronic acids, such as methoxysuccinyl-Ala-Ala-Pro-(L)boro-Phe-OH, its pinacol ester, and t-butyloxycarbonyl-Phe-Pro-(L)boro-Phe-pinacol, inhibited the activity of chymase from connective tissue mast cells approximately 40- to 80-fold more than atypical chymase from mucosal mast cells, and did not inhibit trypsin. Only peptide boronic acids containing "L" forms of boronic acids were inhibitory. The Ki values of these peptide boronic acids for chymase were in the 60-170 nM concentration range, like those of the natural inhibitors tested, but all the natural inhibitors tested except Eglin C and chymostatin inhibited both chymase and trypsin. Thus these peptide boronic acids should be useful for selective inhibition of chymase with less inhibitory activity for atypical chymase and without inhibition of trypsin. These peptide boronic acids markedly inhibited histamine release induced by anti-rat immunoglobulin E, suggesting that chymase in connective tissue mast cells plays some role in the process of histamine release. These peptides are assumed to be therapeutically useful for treatment of allergic inflammations catalyzed by chymase.

Animals↗
PubMed1988

Beta-lactamase inhibitors. The inhibition of serine beta-lactamases by specific boronic acids.

Many beta-lactamases have active-site serine residues, and are competitively inhibited by boronic acids. Hitherto, the boronic acids used have lacked any structural resemblance to the substrates of beta-lactamases. Phenylacetamidomethaneboronic acid, trifluoroacetamidomethaneboronic acid and 2,6-dimethoxybenzamidomethaneboronic acid have now been synthesized. The first of these contains the side-chain moiety of penicillin G, and the last that of methicillin. The pH-dependence of binding of the first inhibitor to beta-lactamase I from Bacillus cereus revealed pK values of 4.7 and 8.2 for (presumably) active-site groups in the enzyme. The kinetics of inhibition were studied by cryoenzymology and by stopped-flow spectrophotometry. These techniques provided evidence for a two-step mechanism of binding of the first two boronic acids mentioned above to beta-lactamase I, and for benzeneboronic acid to a beta-lactamase from Pseudomonas aeruginosa. The slower step is probably associated with a change in enzyme conformation as well as the formation of an O-B bond between the active-site serine hydroxy group and the boronic acid.

Bacillus cereus↗
PubMed1992

Identification of serine and histidine adducts in complexes of trypsin and trypsinogen with peptide and nonpeptide boronic acid inhibitors by 1H NMR spectroscopy.

We have previously shown, in 15N NMR studies of the enzyme's active site histidine residue, that boronic acid inhibitors can form two distinct types of complexes with alpha-lytic protease. Inhibitors that are structural analogs of good alpha-lytic protease substrates form transition-state-like tetrahedral complexes with the active site serine whereas those that are not form complexes in which N epsilon 2 of the active site histidine is covalently bonded to the boron of the inhibitor. This study also demonstrated that the serine and histidine adduct complexes exhibit quite distinctive and characteristic low-field 1H NMR spectra [Bachovchin, W. W., Wong, W. Y. L., Farr-Jones, S., Shenvi, A. B., & Kettner, C. A. (1988) Biochemistry 27, 7689-7697]. Here we have used low-field 1H NMR diagnostically for a series of boronic acid inhibitor complexes of trypsin and trypsinogen. The results show that H-D-Val-Leu-boroArg and Ac-Gly-boroArg, analogs of good trypsin substrates, form transition-state-like serine adducts with trypsin, whereas the nonsubstrate analog inhibitors boric acid, methane boronic acid, butane boronic acid, and triethanolamine borate all form histidine adducts, thereby paralleling the previous results obtained with alpha-lytic protease. However, with trypsinogen, Ac-Gly-boroArg forms predominantly a histidine adduct while H-D-Val-Leu-boroArg forms both histidine and serine adducts, with the histidine adduct predominating below pH 8.0 and the serine adduct predominating above pH 8.0.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1983

A calorimetric investigation of the binding of indole and phenylethane boronic acid to chymotrypsin.

The heat of formation of the chymotrypsin-phenylethane boronic acid complex has been observed calorimetrically from pH 4 to 8 at 25 degrees C and is found to be pH-dependent, changing from near -6 kcal/mol at pH 4 to -13 kcal/mol at pH 8. The heat of formation of the chymotrypsin-indole complex is a nearly constant -6 kcal/mol over most of the same pH range. alpha-Chymotrypsin has been purified by pH gradient elution from an immobilized lima bean inhibitor column. Solutions of the enzyme up to 400 microM, prepared in this manner, have a zero heat of dilution from pH 5 to 8 in 0.1 M KCl, with or without added 0.05 M Tris, N-(tris[hydroxy-methyl]methyl-2-amino) ethanesulfonic acid, 4-morpholineethanesulfonic acid, or acetate buffers. Binding of phenylethane boronic acid causes a pH-dependent decrease in proton binding to chymotrypsin; the decrease in proton binding evoked by formation of the indole complex is much less, with a much smaller pH dependence. The calorimetric and proton-binding results are applied to a model for boronic acid binding (Hanai, K. (1976) J. Biochem. (Tokyo) 79, 107-116). We conclude that the thermodynamics of formation of the trigonal boronic acid complex are quite similar to those for the formation of the noncovalent complex formed by indole and related ligands. The trigonal-tetrahedral tautomerism in the boronic acid-chymotrypsin complex is characterized by thermodynamic changes similar to those accompanying the binding of virtual substrates to chymotrypsin.

Boronic Acids↗
PubMed1988

Interaction of peptide boronic acids with elastase: circular dichroism studies.

Boronic acid derivatives of good peptide substrates of the serine proteases cause slow-binding inhibition, manifested as biphasic binding (Kettner and Shenvi: J. Biol Chem. 259:15106-15114, 1984). These inhibitors are thought to act as reaction-intermediate analogs. Three peptide boronic acids--Ac-Pro-boro-Val-OH, DNS-Ala-Pro-boro-Val-OH, and Ac-Ala-Ala-Pro-boro-Val-OH--were chosen for far-ultraviolet circular dichroism (CD) studies in order to determine whether the second phase involves a conformational change of pancreatic elastase. The dipeptide is a simple competitive inhibitor (Ki = 0.27 microM) and the latter are slow-binding inhibitors (Ki = 16.4 and 0.25 nM, respectively). Spectral deconvolution and correction for the formation of antiparallel beta-sheet by the peptide inhibitor itself indicate that there is no significant change in the secondary structure of the enzyme in either the initial or final inhibitor complex. A kinetic experiment confirmed that the slow-binding step was not associated with a CD spectral change, and that therefore a protein conformational change was not responsible for the slow binding.

Animals↗
PubMed1989

Inhibition of human milk bile-salt-dependent lipase by boronic acids. Implication to the bile salts activator effect.

The bile-salt-dependent lipase from human milk, which catalyzes the hydrolysis of the water-soluble substrate 4-nitrophenyl acetate and the water-insoluble substrate tributyrin, is competitively inhibited by phenyl boronic acid. This inhibitor does not interfere with the interaction of lipase either with the siliconized glass beads/water interface or with the activator bile-salt binding site. The boronic acid binds near or at the active site serine, since modification of this residue by diisopropylphosphofluoridate (DFP) was prevented by phenyl boronic acid. Phenyl boronic acid binds 15-fold as tightly to bile-salt-dependent lipase as does 4-nitrophenyl acetate. Therefore, phenyl boronic acid bears analogy to a substrate rather than to a tetrahedral intermediate analog. Bile salts such as sodium taurocholate which are non-essential activators for the milk lipase activity on water-soluble substrates decrease the Km as well as the enzyme inhibitor dissociation constant (Ki). They have a slight effect on kcat. These results are interpreted in terms of an increase of the stability of the enzyme-substrate tetrahedral intermediate and in general of any transition states for the formation and for the decomposition of these intermediates upon the enzyme bile salts interaction.

Adsorption↗
PubMed1975

Comparative study of the activity of boric, benzene-boronic and methyl-benzene-boronic acids upon respiration, general metabolism and systemic hemodynamics of the anesthetized dog.

The authors compared the action of boric, benzene-boronic and p-methyl-benzene-boronic acids on respiration and general metabolism and on systemic hemodynamics of the anesthetized dog. They further investigated the effects on the arterial blood pressure in the rat and on the isolated rabbit heart. In the dogs, the three acids were shown to have no significant action on the systolic, diastolic and mean arterial blood pressures and a slight stimulating action on the differential arterial blood pressure. On the contrary, in the rat, all the acids were hypotensive. This action was dose dependent. In the entire animal, as well as in the isolated rabbit heart, benzene-boronic and p-methyl-benzene-boronic acids depressed the myocardial contractility. Whereas boric acid did not act on the heart contractility in situ in anesthetized dogs, it slightly stimulated the myocardial contractility of the isolated rabbit heart. The two acids seemed to be directly active on the myocardial cell. In the anesthetized dog, cardiac performances were first depressed then stimulated. Both benzene-boronic and p-methyl-benzene-boronic acids were ventilatory depressors: they reduced ventilatory output and rhythm, they first decreased then increased total O2 consumption and CO2 production.

Animals↗
PubMed1988

Nitrogen-15 NMR spectroscopy of the catalytic-triad histidine of a serine protease in peptide boronic acid inhibitor complexes.

15N NMR spectroscopy was used to examine the active-site histidyl residue of alpha-lytic protease in peptide boronic acid inhibitor complexes. Two distinct types of complexes were observed: (1) Boronic acids that are analogues of substrates form complexes in which the active-site imidazole ring is protonated and both imidazole N-H protons are strongly hydrogen bonded. With the better inhibitors of the class this arrangement is stable over the pH range 4.0-10.5. The results are consistent with a putative tetrahedral intermediate like complex involving a negatively charged, tetrahedral boron atom covalently bonded to O gamma of the active-site serine. (2) Boronic acids that are not substrate analogues form complexes in which N epsilon 2 of the active-site histidine is covalently bonded to the boron atom of the inhibitor. The proton bound to N delta 1 of the histidine in these histidine-boronate adducts remains strongly hydrogen bonded, presumably to the active-site aspartate. Benzeneboronic acid, which falls in this category, forms an adduct with histidine. In both types of complexes the N-H protons of His-57 exchange unusually slowly as evidenced by the room temperature visibility of the low-field 1H resonances and the 15N-H spin couplings. These results, coupled with the kinetic data of the preceding paper [Kettner, C. A., Bone, R., Agard, D. A., & Bachovchin, W. W. (1988) Biochemistry (preceding paper in this issue)], indicate that occupancy of the specificity subsites may be required to fully form the transition-state binding site. The significance of these findings for understanding inhibitor binding and the catalytic mechanism of serine proteases is discussed.

Binding Sites↗
PubMed1982

Inhibition of lipoprotein lipase by benzene boronic acid. Effect of apolipoprotein C-II.

The catalytic mechanism of triacylglycerol hydrolysis by lipoprotein lipase was studied. We found lipoprotein lipase to be inhibited by benzene boronic acid, with an apparent Ki of 8.9 micro M at pH 7.4. This indicates the presence of serine and histidine in the active site of the enzyme. Inhibition of lipoprotein lipase by benzene boronic acid is likely to be due to the formation of an inhibitor-enzyme complex having analogous bonding to the active site histidine and serine as the transition-state complex which precedes the formation of an obligatory acyl-enzyme intermediate. The presence of apolipoprotein C-II, the apolipoprotein activator of lipoprotein lipase, partly reverses the inhibition of lipoprotein lipase by benzene boronic acid. This reversal by apolipoprotein C-II has a distinct pH optimum in the range of 8-9.

Animals↗
PubMed1995

NMR studies of the alpha-chymotrypsin-(R)-1-acetamido-2-(4-fluorophenyl)ethane-1-boronic acid complex at pH 7.

The interaction of (R)-1-acetamido-2-(4-fluorophenyl)ethane-1-boronic acid with alpha-chymotrypsin at pH 7 was studied by a variety of fluorine and proton NMR experiments and the results compared to observations made at pH 4. It was demonstrated that this compound forms a complex with a 1:1 stoichiometry at pH 7; proton NMR indicates that the boronic acid likely is coordinated to the serine-195 residue at the active site. Analysis of fluorine T1 relaxation behavior and 19F(1H) NOE data shows that the rate constant for dissociation of the complex is 4.7 s-1, somewhat faster than is observed at pH 4. The data analysis and the results of two-dimensional 19F(1H) NOE experiments show that interactions between the fluoroaromatic ring of the inhibitor and the enzyme are weaker at the higher pH value, although the motion of the fluoroaromatic ring within the complex appears to be just as restricted as is the case at pH 4.

Boronic Acids↗