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PubMed1999

Interactions between the thiol-group reagent N-ethylmaleimide and neutral and basic amino acid transporter-related amino acid transport.

The neutral and basic amino acid transport protein (NBAT) expressed in renal and jejunal brush-border membranes is involved in amino acid and cystine absorption. NBAT mutations result in Type 1 cystinuria. A C-terminal myc-tagged NBAT (NBATmyc) retains the amino acid transport and protein-protein interaction properties of NBAT when expressed in Xenopus oocytes. Neutral amino acid (Ala, Phe)-cationic amino acid (Arg) heteroexchanges related to NBATmyc expression in oocytes are inactivated by treatment with the thiol-group reagent N-ethylmaleimide (NEM), although significant Arg-Arg and Ala-Ala homoexchanges persist. Inactivation of heteroexchange activity by NEM is accompanied by loss of >85% of alanine and cystine uptake, with smaller (<50%) inhibition of arginine and phenylalanine uptake. NEM-sensitive cystine uptake and arginine-alanine heteroexchange (system b(0,+) activity) are not expressed by an NBAT truncation mutant (NBATmyc-Sph1) lacking the 13 C-terminal amino acid residues, but the mutant expresses NEM-resistant transport activity (system y(+)L-like) equivalent to that of full-length NBATmyc. The deleted region of NBATmyc-Sph1 contains two cysteine residues (671/683) which may be the targets of NEM action. The synthetic amino acid 2-trifluoromethylhistidine (TFMH) stimulated alanine efflux at pH 7.5 and arginine at pH 5.5, but not vice versa, establishing the existence of distinct pathways for cationic and neutral amino acid homoexchange (TFMH is zwitterionic at pH 7.5 and cationic at pH 5.5). We suggest that NBAT expresses a combination of system b(0,+) and y(+)L-like activities, possibly by interacting with different light-chain subunits endogenous to oocytes (as does the homologous 4F2hc protein). The C-terminus of NBAT may also have an additional, direct role in the mechanism of System b(0,+) transport (the major transport activity that is defective in Type 1 cystinuria).

Amino Acid Sequence↗
PubMed1975

[Studies on the protein and amino acid metabolism of laying hens using 15N labeled casein. 4. Fecal excretion of nitrogen and amino acids, digestibility of crude protein and absorption of basic amino acids].

Generally, the faeces of laying hens fed 15N casein rations were found to contain equal proportions of TCE-precipitable and TCE-soluble nitrogen. Considerable variations were observed to occur between the 64 samples investigated (27%-75%) and no explanation was found to account for this fact. The content of basic amino acids in faecal proteins was found to differ considerably from that of the proteins in the intestinal contents. A high lysine content was found after the feeding of wheat. The present trial substantiated this result, provided the casein contained a certain proportion of non-available lysine. The apparent and true digestibility of dietary N was 88% or 91%, that of 15N (2nd and 6th day of experiment) and 92%. During the feeding of labelled casein a higher level of N labelling was found in the TCE-soluble portion of the faeces, whereas on the 8th to 12th day a higher level of labelling was observed in the TCE-precipitable portion of the faeces. The peak of 15N excretion occurred on the 3rd day of experiment. When 15N administration terminated the atom% 15N in the faeces and in urine was found to decrease rapidly approximating the initial level of labelling asymptotically.

Amino Acids↗
PubMed2000

Cysteine residues in the C-terminus of the neutral- and basic-amino-acid transporter heavy-chain subunit contribute to functional properties of the system b(0,+)-type amino acid transporter.

The neutral- and basic-amino-acid-transport glycoprotein NBAT (rBAT, D2) expressed in renal and jejunal brush-border membranes interacts with the b(0,+)AT permease to produce a heteromeric transporter effecting amino acid and cystine absorption. NBAT mutations result in type I cystinuria. The b(0,+)AT permease is presumed to be the catalytic subunit, but we have been investigating the possibility that cysteine residues within the C-terminus of NBAT are also important for expression of transport function. NBAT mutants were produced with combinations of Cys(664/671/683)-->Ala substitutions. Mutants with Cys(664)-->Ala show decreased arginine and cystine transport and specifically lose sensitivity to inhibition of transport by the thiol-group reagent N-ethylmaleimide (NEM). We suggest that the C-terminus of NBAT may have a direct role in the mechanism of System b(0,+) transport (the major transport activity defective in type I cystinuria) and that Cys(664) of NBAT is the major target for NEM-induced inactivation of the transport mechanism.

Amino Acid Sequence↗
PubMed1985

Inhibition of protein reabsorption in the renal proximal tubule by basic amino acids.

The effects of basic and neutral amino acids on the reabsorption of 125I-lysozyme by the renal proximal tubule were examined in rats. In whole animal experiments control animals were given an intravenous (i.v.) injection of 125I-lysozyme alone while experimental animals received an i.v. injection of either a basic or a neutral amino acid prior to the injection of 125I-lysozyme. In control animals the renal content of 125I-lysozyme 30 min after injection was 35% of the injected dose. After injection of basic amino acids there was a significant decrease in the renal uptake of lysozyme. There was no effect of neutral amino acids on the reabsorption of lysozyme. In microperfusion experiments proximal convoluted tubules were perfused in vivo for 3 min with a solution containing 125I-lysozyme and either lysine or alanine. In tubules perfused with lysine there was a significant decrease in the reabsorption of lysozyme, whereas alanine had no effect on lysozyme uptake. Electron microscope autoradiography revealed that lysozyme was located in endocytic vesicles and lysosomes in both experimental groups. However, the autoradiographic grain density was significantly decreased in tubules perfused with lysine as compared with those perfused with alanine. These findings demonstrate that basic amino acids inhibit the reabsorption of the cationic protein lysozyme by the proximal tubule cells.

Absorption↗
PubMed2001

A tale of two charges: distinct roles for an acidic and a basic amino acid in the structure and function of cytochrome c.

Cytochrome c is a small electron transport protein found in the intermembrane space of mitochondria. As it interacts with a number of different physiological partners in a specific fashion, its structure varies little over eukaryotic evolutionary history. Two highly conserved residues found within its sequence are those at positions 13 and 90 (numbering is based on the standard horse cytochrome c); with single exceptions, residue 13 is either Lys or Arg, and residue 90 is either Glu or Asp. There have been conflicting views on the roles to be ascribed to these residues, particularly residue 13, so the functional properties of a number of site-directed mutants of Saccaromyces cerevisiae iso-1 cytochrome c have been examined. Results indicate that the two residues do not interact specifically with each other; however, residue 13 (Arg) is likely to be involved in interactions between cytochrome c and other electrostatically oriented physiological partners (intermolecular), whereas residue 90 (Asp) is involved in maintaining the intrinsic structure and stability of cytochrome c (intramolecular). This is supported by molecular dynamics simulations carried out for these mutants where removal of the negative charge at position 90 leads to significant shifts in the conformations of neighboring residues, particularly lysine 86. Both charged residues appear to exert their effects through electrostatics; however, biological activity is significantly more sensitive to substitutions of residue 13 than of residue 90.

Animals↗
PubMed1999

Multiple functions for the basic amino acids of the human T-cell leukemia virus type 1 matrix protein in viral transmission.

We studied the involvement of the human T-cell leukemia virus type 1 (HTLV-1) Gag matrix protein in the cell-to-cell transmission of the virus using missense mutations of the basic amino acids. These basic amino acids are clustered at the N terminus of the protein in other retroviruses and are responsible for targeting the Gag proteins to the plasma membrane. In the HTLV-bovine leukemia virus genus of retroviruses, the basic amino acids are distributed throughout the matrix protein sequence. The HTLV-1 matrix protein contains 11 such residues. A wild-type phenotype was obtained only for mutant viruses with mutations at one of two positions in the matrix protein. The phenotypes of the other nine mutant viruses showed that the basic amino acids are involved at various steps of the replication cycle, including some after membrane targeting. Most of these nine mutations allowed normal synthesis, transport, and cleavage of the Gag precursor, but particle release was greatly affected for seven of them. In addition, four mutated proteins with correct particle release and envelope glycoprotein incorporation did not however permit cell-to-cell transmission of HTLV-1. Thus, particle release, although required, is not sufficient for the cell-to-cell transmission of HTLV-1, and the basic residues of the matrix protein are involved in steps that occur after viral particle release.

Amino Acid Sequence↗
PubMed2003

Design and application of basic amino acids displaying enhanced hydrophobicity.

Three noncoding basic amino acids, mono-, di-, and trimethyldiaminopropionic acid (mmdap, dmdap, and tmdap), have been synthesized for use in protein design. Covalent modification of a diaminopropionic acid (dap) side chain with an increasing number of methyl moieties results in a family of residues displaying short basic side chains with varying degrees of enhanced hydrophobic character. These residues may be used to introduce charged/polar interactions into the confining hydrophobic interior or interfacial spaces of proteins. As a demonstration of their utility, the ability of these residues to promote interior salt bridge formation at the helix/helix interface of GCN4-p1, a dimeric two-stranded coiled coil, was assessed. Heterodimerization mediated by buried salt bridge formation between a GCN4-based peptide containing either mmdap, dmdap, or tmdap at position 16 and an analogous peptide containing aspartic acid at the same position was studied. Mmdap-derived heterodimers are 0.5 kcal/mol more stable than the corresponding dap-derived heterodimers. This result indicates that the addition of one methyl group to the dap side chain can stabilize the heterodimeric fold. The stabilization can most likely be attributed to a decrease in the desolvation penalty incurred upon folding as well as enhanced van der Waals contacts in the folded state. The addition of three methyl groups to the dap side chain results in heterodimers that are significantly less stable than the corresponding dap-derived heterodimers, suggesting that increased steric bulk is not well accommodated in the interior of this protein. Unexpectedly, the addition of two methyl groups leads to homotrimerization of the dmdap-peptide. The resulting trimer is relatively stable (DeltaG(37)( degrees )(C) degrees = 11.8 kcal/mol) and undergoes cooperative thermal unfolding. The GCN4-p1 system exemplifies how small incremental changes in size and hydrophobicity can alter the folding preferences of a protein. Generally, this versatile suite of residues can be utilized in any protein and offer new options to the protein chemist.

Amino Acid Sequence↗
PubMed1994

Effect of alterations of basic amino acid residues of Escherichia coli heat-stable enterotoxin II on enterotoxicity.

Escherichia coli heat-stable enterotoxin II (STII) is composed of 48 amino acid residues. Among these, one histidine, two arginine, and six lysine residues are basic. Isoelectric focusing showed that the isoelectric point of STII is 9.7, indicating that the side chains of some of these basic amino acid residues project outside the molecule. To understand the role that these basic amino acid residues play in toxicity, STII was chemically modified with ethoxyformic anhydride, maleic anhydride, and phenylglyoxal, which alter the side chains of basic amino acid residues in proteins. Maleic anhydride, which modifies the epsilon amino group, caused a significant loss of enterotoxic activity, but the other two modifiers did not. This indicated that lysine residues play an important role in the expression of the enterotoxic activity of STII and that the contribution of the other basic amino acid residues to the toxicity is relatively low. To confirm this hypothesis, we substituted these nine basic amino acid residues by oligonucleotide-directed site-specific mutagenesis and examined the enterotoxicity of these purified mutant STIIs. The enterotoxic activity was reduced when the lysine residues at positions 18, 22, 23, and 46 were substituted. In particular, the substitution at positions 22 and 23 induced a remarkable reduction. These results demonstrate that the lysine residues at positions 22 and 23 are very important in the expression of the enterotoxic activity of STII.

Animals↗
PubMed1998

Chiral inversion and hydrolysis of thalidomide: mechanisms and catalysis by bases and serum albumin, and chiral stability of teratogenic metabolites.

The chiral inversion and hydrolysis of thalidomide and the catalysis by bases and human serum albumin were investigated by using a stereoselective HPLC assay. Chiral inversion was catalyzed by albumin, hydroxyl ions, phosphate, and amino acids. Basic amino acids (Arg and Lys) had a superior potency in catalyzing chiral inversion compared to acid and neutral ones. The chiral inversion of thalidomide is thus subject to specific and general base catalysis, and it is suggested that the ability of HSA to catalyze the reaction is due to the basic groups of the amino acids Arg and Lys and not to a single catalytic site on the macromolecule. The hydrolysis of thalidomide was also base-catalyzed. However, albumin had no effect on hydrolysis, and there was no difference between the catalytic potencies of acidic, neutral, and basic amino acids. This may be explained by different reaction mechanisms of the chiral inversion and hydrolysis of thalidomide. Chiral inversion is deduced to occur by electrophilic substitution involving specific and general base catalysis, whereas hydrolysis is thought to occur by nucleophilic substitution involving specific and general base as well as nucleophilic catalysis. As nucleophilic attack is sensitive to steric properties of the catalyst, steric hindrance might be the reason albumin is not able to catalyze hydrolysis. 1H NMR experiments revealed that the three teratogenic metabolites of thalidomide, in sharp contrast to the drug itself, had complete chiral stability. This leads to the speculation that, were some enantioselectivity to exist in the teratogenicity of thalidomide, it could result from fast hydrolysis to chirally stable teratogenic metabolites.

Algorithms↗
PubMed1986

Transport of basic amino acids in Candida albicans.

In Candida albicans, ATCC 46977, transport of basic amino acids is mediated by two systems (S1 and S2). Kinetic data and competitive inhibition studies of the different systems showed that transport of L-lysine, L-arginine and L-histidine have distinct specificities. System S1 of L-lysine and L-arginine was highly specific for the respective single basic amino acid. However, S2 of L-lysine and S1 of L-histidine were shown to be specific systems for most of basic amino acids. S2 of L-arginine was different from S2 of L-lysine and S1 of L-histidine. The effect of a thiol reagent, N-ethylmalemide, revealed that S2 of L-lysine and S1 of L-histidine were sensitive to this reagent, while all other systems were insensitive. The transport activity of different systems of L-lysine, L-arginine and L-histidine was followed during the growth of C. albicans. It was observed that different basic amino-acid systems have maximum activity during different stages of C. albicans growth.

Amino Acids↗
PubMed1981

Hemodialysis of amino acids: basic studies in vitro.

Amino acids were efficiently removed in vitro from blood plasma, or its saline equivalent, with a standard hemodialyzer (artificial kidney). The rate of dialysis, or clearance, of the smaller amino acids approached that of urea, while the larger amino acids were removed at a slightly slower rate. A generalized inverse correlation was found between amino acid molecular weights and their clearance rates. By increasing the standard "blood" flow rate and/or the dialysate flow rate, the efficiency of the artificial kidney in removing amino acids from simulated blood was significantly increased. In the absence of endogenous influx, hemodialysis is an effective means for removing the entire spectrum of amino acids from circulating blood or its saline equivalent. These findings have provocative implications for experimental therapy based upon nutritional deprivations involving amino acids or other vital circulating biochemical components that may be differentially required by normal and cancer cells.

Amino Acids↗
PubMed1996

Basic amino acid transport in plasma membrane vesicles of Penicillium chrysogenum.

The characteristics of the basic amino acid permease (system VI) of the filamentous fungus Penicillium chrysogenum were studied in plasma membranes fused with liposomes containing the beef heart mitochondrial cytochrome c oxidase. In the presence of reduced cytochrome c, the hybrid membranes accumulated the basic amino acids arginine and lysine. Inhibition studies with analogs revealed a narrow substrate specificity. Within the external pH range of 5.5 to 7.5, the transmembrane electrical potential (delta psi) functions as the main driving force for uphill transport of arginine, although a low level of uptake was observed when only a transmembrane pH gradient was present. It is concluded that the basic amino acid permease is a H+ symporter. Quantitative analysis of the steady-state levels of arginine uptake in relation to the proton motive force suggests a H+-arginine symport stoichiometry of one to one. Efflux studies demonstrated that the basic amino acid permease functions in a reversible manner.

Amino Acid Transport Systems↗