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PubMed1979

Rhesus monkey aqueous humor composition and a primate ocular perfusate.

The composition of rhesus monkey aqueous humor has been studied in large-volume, pooled samples. Replicate determinations of the concentrations of a number of constituents have been carried out for both aqueous humor and serum from large veins by means of automatic analyzing equipment. Since aqueous humor has been obtained by anterior chamber paracentesis, it is a mixture of anterior and posterior chamber aqueous. When compared to serum, the pooled aqueous contains an excess of chloride, bicarbonate, ascorbate, lactate, uric acid, and several neutral amino acids. Rhesus monkey aqueous humor is deficient in calcium, urea nitrogen, phosphates, glucose, protein, creatinine, iron, bilirubin, cholesterol, triglycerides, a number of serum enzymes, acidic and basic amino acids, and several neutral amino acids. Sodium, potassium, magnesium, and two neutral amino acids (cysteine and valine) are of equal concentration in aqueous humor and serum. Glutathione concentration is very low in both aqueous humor and serum. Pooled rhesus monkey aqueous humor and serum are isosmolar, with measured osmolality being about 303 mOsm. Based upon the chemical analysis, a new solution has been formulated to substitute for primate aqueous humor during anterior ocular perfusion. This new solution causes very little change in the physiologic integrity of the outflow pathways during prolonged, repeated perfusion. In this respect, its effects are very similar to those of pooled rhesus monkey aqueous humor during perfusion of rhesus monkey eyes. In contrast, perfusion of rhesus monkey eyes with glutathione-bicarbonate-Ringer's solution has been shown to cause progressive increase of the total facility. To minimize physiologic alterations during operative procedures, a solution similar to this new one could be formulated for irrigation of the inside of the human eye.

Animals↗
PubMed1991

Structural features influencing hemagglutinin cleavability in a human influenza A virus.

The cleavability of the hemagglutinin (HA) molecule is related to the virulence of avian influenza A viruses, but its influence on human influenza virus strains is unknown. Two structural features are involved in the cleavage of avian influenza A virus HAs: a series of basic amino acids at the cleavage site and an oligosaccharide side chain in the near vicinity. The importance of these properties in the cleavability of a human influenza A virus (A/Aichi/2/68) HA was investigated by using mutants that contained or lacked an oligosaccharide side chain and had either four or six basic amino acids. All mutants except the one that contains a single mutation at the glycosylation site were cleaved, although not completely, demonstrating that a series of basic amino acids confers susceptibility to cellular cleavage enzymes among human influenza virus HAs. The mutants containing six basic amino acids at the cleavage site showed limited polykaryon formation upon exposure to low pH, indicating that cleavage was adequate to impart fusion activity to the HA. Deletion of the potential glycosylation site had no effect on the cleavability of these mutants; hence, the oligosaccharide side chain appears to have no role in human influenza virus HA cleavage. The inability to induce high cleavability in a human influenza A virus HA by insertion of a series of basic amino acids at the cleavage site indicates that other, as yet unidentified structural features are needed to enhance the susceptibility of these HAs to cellular proteases.

Amino Acid Sequence↗
PubMed1998

Glutamine uptake at the blood-brain barrier is mediated by N-system transport.

The mechanism of unidirectional transport of glutamine from blood to brain in pentobarbital-anesthetized rats was examined using in situ perfusion. Amino acid uptake into brain across the blood-brain barrier (BBB) is classically thought to be via the Na-independent large neutral (L-system), acidic and basic amino acid transporters. In the presence of physiological concentrations of amino acids in the perfusate, which should saturate the known amino acid transporters at the BBB, the cortical transfer constant (Ki) for L-[14C]glutamine was 11.6 +/- 1.1 microl/g/min. The addition of either 10 mM 2-amino-2-norbornanecarboxylic acid or 10 mM 2-amino-2-norbornanecarboxylic acid and 5 mM cysteine had no effect on the cortical Ki for L-[14C]glutamine, indicating that glutamine transport under these conditions does not occur by the L-, A-, or ASC-systems. Decreasing perfusate Na from 140 to 2.4 mM by Tris substitution reduced the cortical Ki for L-[14C]glutamine by 62% (p < or = 0.001). The Na-dependent uptake has the characteristics of N-system transport. It was inhibited by L-histidine and L-glutamine, both N-system substrates, and it was pH sensitive and moderately tolerant of Li substitution for Na. This putative N-system transporter at the luminal membrane of the BBB plays an important role in mediating brain glutamine uptake.

Animals↗
PubMed1963

Amino acids in the proteins from aragonite and calcite in the shells of Mytilus californianus.

Hydroxylysine and hydroxyproline are absent in the calcified proteins of Mytilus. The organic matrices from the calcite layers have a consistently higher ratio of acidic to basic amino acids than the aragonitic shell units. The uncalcified shell units periostracum and outer ligament, have very few acidic residues, which may in part account for the lack of mineralization.

Acids↗
PubMed1992

Sequence requirements for processing of proinsulin in transfected mouse pituitary AtT20 cells.

To investigate the sequence requirements for proteolytic processing of prohormones at pairs of basic amino acids, normal and mutant proinsulins were expressed in the mouse pituitary corticotrophic cell line AtT20. The extent of processing was determined by h.p.l.c. analysis of insulin-like immunoreactivity secreted into the media of transfected cells. In this model system, normal proinsulin was efficiently processed to insulin. The mutant des-38-62-proinsulin, in which all but six amino acids of the C-peptide were deleted, was also processed to insulin but less efficiently than the wild-type. The mutant Lys64-Arg65 to Thr64-Arg65 was partially processed to insulin, while the mutant Arg31-Arg32 to Arg31-Gly32 was not processed at either site. These results indicate: (i) that a six-amino-acid spacer between the two pairs of basic amino acids in proinsulin is sufficient to permit processing at both sites; (ii) that the endoproteinase responsible for cleavage at the Lys64-Arg65 site will also recognize Thr64-Arg65; (iii) that the endoproteinase responsible for cleavage at the Arg31-Arg32 site will not recognize Arg31-Gly32; and (iv) that the change Arg31-Arg32 to Arg31-Gly32 affects processing at the Lys64-Arg65 site.

1-Methyl-3-isobutylxanthine↗
PubMed1978

Effect of the basic amino-acid side chain length and the penultimate residue on the hydrolysis of benzoldipeptides by carboxypeptidase B.

The kinetic parameters Km and k cat/K m have been determined for the carboxypeptidase B (CPB, EC 3.4.12.3) catalyzed hydrolysis of benzoylglycyl-DL-homolysine and benzoylglycyl-L-homorginine. Plots of these data and those for Bz-Gly-Orn and Bz-Gly-Arg (Wolff, E. C., Schirmer, E.W. & Folk, J. E. (1962) J. Biol. Chem. 237, 3094-3099) and Bz-Gly-Lys versus the length of the side chain of the basic amino acid indicate that unlike trypsin (EC 3.4.21.4) (Seely, J. H. & Benoiton, N. L. (1970) Can. J. Biochem. 48, 1122-1131) CPB has a higher bending affinity for a guanidino group than for an amino group at the side chain of the substrate C-terminus. On the other hand, CPB is similar to trypsin (ibid) in that the best substrate would have a side chain length between those of lysine and arginine. Studies with Bz-MeGly-Lys and Bz-Ala-Lys showed that the former is very slowly hydrolyzed by CPB but that the latter is a good substrate with a high affinity for the enzyme, indicative of considerable participation of the Calpha-methyl group of alanine in the binding of the substrate to the enzyme.

Benzoates↗
PubMed1992

Molecular determinants of human prorenin processing.

In humans, active renin is generated by the removal of a 43-amino acid prosegment from the zymogen prorenin. This cleavage event is highly specific, occurring at only one of the seven pairs of basic amino acids in the body of preprorenin. This cleavage site selectivity is also displayed by a number of other proteases in vitro and in mouse pituitary AtT-20 cells transfected with a human preprorenin expression vector, suggesting that specificity of cleavage is directed in part by the primary sequence, the higher order structure, or both of prorenin itself. To test this hypothesis, single amino acid mutations were introduced in the region of human preprorenin surrounding the natural cleavage site, and the resultant recombinant proteins were expressed in cultured Chinese hamster ovary and AtT-20 cells. The results suggest that amino acids in addition to the pair of basic amino acids surrounding the cleavage site affect the ability of both trypsin and the endogenous AtT-20 processing enzyme to cleave prorenin. Notably, although a proline at position -4 is essential for processing of prorenin in AtT-20 cells and is correlated with predicted formation of a beta-turn at this position, site-directed mutations suggest that this structural feature in addition to a pair of basic amino acids is not sufficient to lead to proteolytic activation of prorenin. Displacement of sequences surrounding the cleavage site to a position 10 amino acids toward the amino terminus led to partial processing of a mutated prorenin.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1996

Primary structure and effect of pH on the expression of the plasma membrane H(+)-ATPase from Dunaliella acidophila and Dunaliella salina.

The plasma membrane H(+)-ATPase gene was cloned and sequenced from the extremely acidophilic green alga Dunaliella acidophila and from the extremely halotolerant Dunaliella salina. A special feature of the Dunaliella H(+)-ATPase is an extended C-terminal domain. The deduced amino acid sequences of the two proteins are 75% identical but differ in their C terminus. A hydrophilic loop within this domain in D. salina, which presumably faces the cell exterior, has a high ratio of acidic over basic amino acids, typical of halophilic proteins. The amount of the ATPase protein in plasma membranes and the level of its mRNA transcript in D. acidophila are far higher than in D. salina, suggesting that D. acidophila overexpresses the enzyme. A pH shift from 9.0 to 7.0 induces in D. salina a large increase in the level of the H(+)-ATPase mRNA and in the amount of the H(+)-ATPase protein. This suggests that the expression of the H(+)-ATPase in D. salina is pH-regulated at the transcriptional level. The implications of these findings are discussed with respect to the adaptive pressures imposed on these algal species by their exceptional environmental conditions.

Amino Acid Sequence↗
PubMedDate not supplied

An efficient, convenient solid-phase synthesis of amino acid-modified peptide nucleic acid monomers and oligomers.

An efficient and highly versatile method for the synthesis of amino acid-modified peptide nucleic acid (PNA) monomers is described. By using solid-phase Fmoc techniques, such monomers can be assembled readily in a stepwise manner and obtained in high yield with minimal purification. Protected neutral hydrophilic, acidic, and basic amino acids were coupled to 2-chlorotrityl chloride resin. Following Fmoc removal, innovative conditions for the key step, reductive alkylation with N-Fmoc-aminoacetaldehyde, were developed to circumvent problems encountered with previously reported methods. Activation and coupling of pyrimidine and purine nucleobases to the resulting secondary amines afforded amino acid-modified PNA monomers. The mild reaction conditions utilized were compatible with sensitive and labile functional groups, such as tert-butyl ethers and tert-butyl esters. PNA monomers were obtained in 36-42% overall yield and very high purity, after cleavage and purification. Using standard solid-phase Fmoc chemistry, two of these monomers were incorporated with high coupling efficiency into a variety of modified PNA oligomers, including four tetradecamers designed to target bcl-2 mRNA. Such modified oligomers have the potential to enhance water solubility and cell portability, while maintaining hybridization affinity and promoting favorable biodistribution properties.

Amino Acids↗
PubMed1992

Electron microscopic visualization of collagen aggregates without chemical staining.

Lateral, uni-directional aggregates of collagen, segment-long-spacing crystallites (SLS), were made by dialyzing collagen solutions against acetic acid containing ATP, and were examined by transmission electron microscopes without electron staining. There detected were at least 20 dark (electron dense) cross-striations within SLS. The banding pattern was compared with the biochemical and biophysical properties of the amino acid side chains along the collagen molecule. The banding pattern of unstained SLS was mostly correlated with the intramolecular distribution of basic amino acid residues. Since basic amino acids have relatively large side chains, the distribution of mass (molecular weight of amino acids) along the molecule (local density profile) partially explained the cross-striation. Addition of fractions of molecular weight of ATP to basic residues made the local density profile much better correlate to the banding pattern. We conclude that the electron microscopic banding pattern of unstained SLS was generated by the local amount of material or local density profile along the collagen aggregates, which was enhanced by ATP bound to positively charged basic residues. The concept that the electron density correlates with the amount of material is fundamental in electron microscopy, and it has been proven with biological materials in this paper.

Adenosine Triphosphate↗
PubMed2000

Mono- and dibasic proteolytic cleavage sites in insect neuroendocrine peptide precursors.

Regulatory peptides are synthesized as part of larger precursors that are subsequently processed into the active substances. After cleavage of the signal peptide, further proteolytic processing occurs predominantly at basic amino acid residues. Rules have been proposed in order to predict which putative proteolytic processing sites are actually used, but these rules have been established for vertebrate peptide precursors and it is unclear whether they are also valid for insects. The aim of this paper is to establish the validity of these rules to predict proteolytic cleavage sites at basic amino acids in insect neuropeptide precursors. Rules describing the cleavage of mono- and dibasic potential processing sites in insect neuropeptide precursors are summarized below. Lys-Arg pairs not followed by an aliphatic or basic amino acid residue are virtually always cleaved in insect regulatory peptide precursors, but cleavages of Lys-Arg pairs followed by either an aliphatic or a basic amino acid residue are ambiguous, as is processing at Arg-Arg pairs. Processing at Arg-Lys pairs has so far not been demonstrated in insects and processing at Lys-Lys pairs appears very rare. Processing at single Arg residues occurs only when there is a basic amino acid residue in position -4, -6, or -8, usually an Arg, but Lys or His residues work also. Although the current number of such sites is too limited to draw definitive conclusions, it seems plausible that cleavage at these sites is inhibited by the presence of aliphatic residues in the +1 position. However, cleavage at single Arg residues is ambiguous. When several potential cleavage sites overlap the one most easily cleaved appears to be processed. It cannot be excluded that some of the rules formulated here will prove less than universal, as only a limited number of cleavage sites have so far been identified. It is likely that, as in vertebrates, ambiguous processing sites exist to allow differential cleavage of the same precursor by different convertases and it seems possible that the precursors of allatostatins and PBAN are differentially cleaved in different cell types. Arch. Insect Biochem. Physiol. 43:49-63, 2000.

Amino Acid Sequence↗
PubMed1996

Site-directed mutagenesis of the double-stranded RNA binding domain of bacterially-expressed sigma 3 reovirus protein.

The affinity of the reovirus sigma 3 protein for double-stranded RNA (dsRNA) is well established, and efforts have been made to identify the amino acids involved in this property. In the present study, we further examined the importance of two basic amino acids motifs, located in the carboxy-terminal third of the protein. Mutants, previously characterized in COS cells, were expressed in bacterial cells using the pET expression system. The capability of the different mutants to interact with dsRNA was then determined by the binding of radiolabeled dsRNA to proteins resolved by SDS-polyacrylamide gel electrophoresis and transferred to nitrocellulose filters. It appears that the most carboxy-terminal motif is absolutely required for the binding but the second motif also contributes to this property. However, only the carboxy-terminal motif is required for normal binding upon removal of the amino-terminal domain of the protein by proteolytic cleavage, a procedure previously shown to increase dsRNA-binding. The basic charges in both motifs are important, while breaking of their potential to adopt an alpha helical configuration does not affect binding efficiency. Furthermore, alanine substitution of a single basic amino acid in the carboxy-terminal motif can be sufficient to strongly reduce the binding of dsRNA to the protein. Altogether, these data suggest that basic amino acids of the sigma 3 carboxy-terminal motif are directly involved in dsRNA binding, while the other basic motif may contribute by preventing an inhibitory effect of the amino-terminal portion of the protein.

Animals↗
PubMed1991

Nucleotide sequence of tomato aspermy virus RNA 2.

RNA 2 of the V strain of tomato aspermy virus (TAV) consists of 3074 nucleotides and contains one open reading frame of 2487 nucleotides. Thus, it resembles RNA 2 of cucumber mosaic virus (CMV) strains Q and Fny (62% identical to both), brome mosaic virus (42% identical) and cowpea chlorotic mottle virus (40% identical). In comparisons between amino acid sequences, three different regions of similarity could be distinguished. These were the central part (amino acids 224 to 757 for V-TAV), which was most similar among the four viruses, and the N and C ends; sequences conserved among RNA polymerase species were found in the C half of the central part. Hydrophobicity patterns, and distributions of acidic and basic amino acids in the proteins encoded by V-TAV RNA 2, Q-CMV RNA 2 and Fny-CMV RNA 2 were very similar except at the extreme ends of the molecules. Structures that have been reported to act as regulatory signals for minus- and plus-strand synthesis were found in the 5' and 3' non-coding regions of the RNA.

Amino Acid Sequence↗
PubMed1986

Influence of the amino acid moiety on deconjugation of bile acid amidates by cholylglycine hydrolase or human fecal cultures.

The influence of the chemical structure of the amino acid (or amino acid analogue) moiety of a number of synthetic cholyl amidates on deconjugation by cholylglycine hydrolase from Clostridium perfringens was studied in vitro at pH 5.4. Conjugates with alkyl homologues of glycine were hydrolyzed more slowly as the number of methylene units increased (cholylglycine greater than cholyl-beta-alanine greater than cholyl-gamma-aminobutyrate). In contrast, for conjugates with the alkyl homologues of taurine, cholylaminopropane sulfonate was hydrolyzed slightly faster than cholyltaurine, whereas cholylaminomethane sulfonate was hydrolyzed much more slowly. When glycine was replaced by other neutral alpha-amino acids, rates of hydrolysis decreased with increasing steric hindrance near the amide bond (cholyl-L-alpha-alanine much much greater than cholyl-L-leucine much greater than cholyl-L-valine greater than cholyl-L-tyrosine much greater than cholyl-D-valine). Conjugation with acidic or basic amino acids also greatly reduced the rates of hydrolysis, as cholyl-L-aspartate, cholyl-L-cysteate, cholyl-L-lysine, and cholyl-L-histidine were all hydrolyzed at a rate less than one-tenth that of cholylglycine. Methyl esterification of the carboxylic group of the amino acid moiety reduced the hydrolysis, but such substrates (cholylglycine methyl ester and cholyl-beta-alanine methyl ester) were completely hydrolyzed after overnight incubation with excess of enzyme. In contrast, cholyl-cholamine was not hydrolyzed at all, suggesting that a negative charge at the end of the side chain is required for optimal hydrolysis. Despite the lack of specificity for the amino acid moiety, a bile salt moiety was required, as the cholylglycine hydrolase did not display general carboxypeptidase activity for other non-bile acid substrates containing a terminal amide bond: hippuryl-L-phenylalanine and hippuryl-L-arginine, as well as oleyltaurine and oleylglycine, were not hydrolyzed. Fecal bacterial cultures from healthy volunteers also hydrolyzed cholyl-L-valine and cholyl-D-valine more slowly than cholylglycine, suggesting that cholylglycine hydrolase from Clostridium perfringens has a substrate specificity similar to that of the deconjugating enzymes of the fecal flora. The results indicate that modification of the position of the amide bond, introduction of steric hindrance near the amide bond, or loss of a negative charge on the terminal group of the amino acid moiety of the bile acid conjugate greatly reduces the rate of bacterial deconjugation in vitro when compared to that of the naturally occurring glycine and taurine conjugates.

Amides↗
PubMed1989

Gastrin releases a blood calcium-lowering peptide from the acid-producing part of the rat stomach.

Gastrin-17 induces hypocalcemia in the rat without stimulating calcitonin release. The gastrin-induced hypocalcemia persisted after thyroparathyroidectomy or parathyroidectomy. In contrast, gastrectomy or extirpation of the acid-producing part of the stomach prevented the hypocalcemic effect, suggesting the involvement of the proximal stomach in the gastrin-evoked lowering of blood calcium. The drop in blood calcium upon injection of gastrin-17 did not reflect a loss of calcium via the gastric juice or via the urine. Extracts of the acid-producing mucosa of the rat stomach had a hypocalcemic effect. The extracts were purified by gel chromatography and reversed-phase high-performance liquid chromatography. Digestion with leucine aminopeptidase destroyed the hypocalcemic activity, while trypsin had no effect, suggesting a peptide (or peptides) with an unprotected NH2 terminus and without basic amino acid residues (or with protected basic amino acids). Both gastrin-17 and the mucosal extract stimulated the uptake of 45Ca into bone (radius and sternum). Gastrin-17 was without effect in rats that had undergone gastrectomy, while the mucosal extract was equally effective in gastrectomized and unoperated rats. We suggest that the effects of gastrin-17 on blood calcium and on calcium transfer into bone are indirect and that gastrin-17 stimulates the release of a peptide hormone, tentatively named gastrocalcin, from the acid-producing mucosa of the stomach. Gastrocalcin stimulates the uptake of 45Ca into bone, thereby causing hypocalcemia.

Animals↗
PubMed1990

Alteration of renal amino acid transport system in cadmium-intoxicated rats.

Effects of cadmium intoxication on renal transport systems for various amino acids were studied. Subcutaneous injections of CdCl2, at a dose of 2 mg Cd/kg.day for 2 weeks, resulted in polyuria, proteinuria, glycosuria, phosphaturia, and aminoaciduria, as observed in chronic cadmium-intoxicated humans and experimental animals. The nature of aminoaciduria was nonspecific, including iminoacid as well as almost all species of neutral, acidic, and basic amino acids. In renal cortical brush border membrane vesicles isolated from cadmium-intoxicated rats, Na(+)-dependent transport of L-proline, L-alanine, and L-lysine was markedly attenuated, whereas the amino acid transport in the basolateral membrane vesicle was not significantly affected. Similar results were obtained in the normal membrane vesicles directly exposed to inorganic cadmium. These results indicate that cadmium intoxication impairs various Na(+)-amino acid cotransport systems in the renal brush border membrane, which leads to panaminoaciduria.

Amino Acids↗
PubMed1977

Structural analysis of the molecular evolution of some gastro-entero-pancreatic hormones.

By means of a statistical analysis of the occurrence of amino-acid residues in the polypeptide chains of several gastro-entero-pancreatic (GEP) hormones an investigation was undertaken to determine whether any of these hormones might be related to each other--possibly from an evolutionary point of view. Particular interest was paid to the occurrence of small charged segments, i.e. those with acidic or basic amino acid residues, since such segments can be presumed to play a role in hormonal receptor binding mechanisms. By this method hormonal relationships were suggested by the observation that these small charged amino-acid sequences, contained in the hormonal structures, match as a result of non-randomness. It was found that hagfish and human insulin were related on a molecular level not only to the newly discovered (avian, bovine, human) pancreatic polypeptide (PP) but also to some other GEP hormones (VIP, GIP, glucagon) as well as to calcitonin and to the alpha-subunit of the glycoprotein hormones. Interpretation of the statistical data suggests that all these peptide hormones are related by a common hexapeptide sequence which contributed, at an evolutionary point, to their molecular architecture. A hexapeptide segment of APP is statistically related to a sequence of equal size in the carboxy terminal region of the A-chain of both hagfish and human insulin, providing the first instance of their structural similarity. Correlations between PP, insulin, glucagon, VIP, and calcitonin provide a tentative basis for predicting the production of one or more of these peptide hormones by immature or de-differentiated cells of neoplasms and non-neoplastic pathologic lesions of the GEP endocrine system.

Amino Acid Sequence↗
PubMed1991

Protein stability and molecular adaptation to extreme conditions.

Proteins, due to the delicate balance of stabilizing and destabilizing interactions, are only marginally stable. Adaptation to extreme environments tends to shift the 'mesophilic' characteristics of proteins to the respective extremes of temperature, hydrostatic pressure, pH and salinity, such that, under the mutual physiological conditions, the molecular properties are similar regarding overall topology, flexibility and solvation. Enhanced intrinsic stability requires only minute local structural changes so that general strategies of stabilization cannot be established. Apart from mutative changes of amino-acid sequences, extrinsic factors (or cellular components) may be involved in 'extremophilic adaptation'. The molecular basis of acidophilic, alkalophilic and barophilic adaptation is still obscure. Mechanisms of enhanced thermal stability involve improved packing density, as well as specific local interactions. In halophiles, water and salt binding of the intrinsically stable protein inventory is accomplished by favoring acidic over basic amino acid residues and decreased hydrophobicity. General limits of viability are: (a) the susceptibility of the covalent structure of the polypeptide chain toward hydrolysis or hydrothermal degradation; (b) the competition of extreme solvent parameters with the weak electrostatic and hydrophobic interactions involved in protein stabilization; (c) perturbations of the folding and assembly of proteins; and (d) 'dislocation' of biochemical pathways due to effects of extreme conditions on the intricate network of metabolic reactions.

Amino Acid Sequence↗