scholarly journals The Lepidopteran KAAT1 and CAATCH1: Orthologs to Understand Structure–Function Relationships in Mammalian SLC6 Transporters

2021 ◽  
Author(s):  
Michela Castagna ◽  
Raffaella Cinquetti ◽  
Tiziano Verri ◽  
Francesca Vacca ◽  
Matteo Giovanola ◽  
...  
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Structure Function ◽  
Biogenic Amines ◽  
Ph Dependence ◽  
Amino Acid Transporters ◽  
Electrochemical Gradient ◽  
Structural Relationships ◽  
Slc6 Family ◽  
Related Compounds

AbstractTo the SLC6 family belong 20 human transporters that utilize the sodium electrochemical gradient to move biogenic amines, osmolytes, amino acids and related compounds into cells. They are classified into two functional groups, the Neurotransmitter transporters (NTT) and Nutrient amino acid transporters (NAT). Here we summarize how since their first cloning in 1998, the insect (Lepidopteran) Orthologs of the SLC6 family transporters have represented very important tools for investigating functional–structural relationships, mechanism of transport, ion and pH dependence and substate interaction of the mammalian (and human) counterparts.

The immunosuppressant FK506 inhibits amino acid import in Saccharomyces cerevisiae

1993 ◽  
Vol 13 (8) ◽  
pp. 5010-5019 ◽  
Author(s):  
J Heitman ◽  
A Koller ◽  
J Kunz ◽  
R Henriquez ◽  
A Schmidt ◽  
...  
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Amino Acids ◽  
Amino Acid ◽  
Cyclosporin A ◽  
Secretory Pathway ◽  
Yeast Cells ◽  
Amino Acid Transporters ◽  
Yeast Saccharomyces Cerevisiae ◽  
Eukaryotic Microorganisms

The immunosuppressants cyclosporin A, FK506, and rapamycin inhibit growth of unicellular eukaryotic microorganisms and also block activation of T lymphocytes from multicellular eukaryotes. In vitro, these compounds bind and inhibit two different types of peptidyl-prolyl cis-trans isomerases. Cyclosporin A binds cyclophilins, whereas FK506 and rapamycin bind FK506-binding proteins (FKBPs). Cyclophilins and FKBPs are ubiquitous, abundant, and targeted to multiple cellular compartments, and they may fold proteins in vivo. Previously, a 12-kDa cytoplasmic FKBP was shown to be only one of at least two FK506-sensitive targets in the yeast Saccharomyces cerevisiae. We find that a second FK506-sensitive target is required for amino acid import. Amino acid-auxotrophic yeast strains (trp1 his4 leu2) are FK506 sensitive, whereas prototrophic strains (TRP1 his4 leu2, trp1 HIS4 leu2, and trp1 his4 LEU2) are FK506 resistant. Amino acids added exogenously to the growth medium mitigate FK506 toxicity. FK506 induces GCN4 expression, which is normally induced by amino acid starvation. FK506 inhibits transport of tryptophan, histidine, and leucine into yeast cells. Lastly, several genes encoding proteins involved in amino acid import or biosynthesis confer FK506 resistance. These findings demonstrate that FK506 inhibits amino acid import in yeast cells, most likely by inhibiting amino acid transporters. Amino acid transporters are integral membrane proteins which import extracellular amino acids and constitute a protein family sharing 30 to 35% identity, including eight invariant prolines. Thus, the second FK506-sensitive target in yeast cells may be a proline isomerase that plays a role in folding amino acid transporters during transit through the secretory pathway.

Placental amino acid transport

1995 ◽  
Vol 268 (6) ◽  
pp. C1321-C1331 ◽  
Author(s):  
A. J. Moe
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Human Placenta ◽  
Amino Acid Transport ◽  
Single Layer ◽  
Maternal Blood ◽  
Transport Systems ◽  
Amino Acid Transporters ◽  
Acid Transport ◽  
Principal Mechanism

Normal fetal growth and development depend on a continuous supply of amino acids from the mother to the fetus. The placenta is responsible for the transfer of amino acids between the two circulations. The human placenta is hemomonochorial, meaning that the maternal and fetal circulations are separated by a single layer of polarized epithelium called the syncytiotrophoblast, which is in direct contact with maternal blood. Transport proteins located in the microvillous and basal membranes of the syncytiotrophoblast are the principal mechanism for transfer from maternal blood to fetal blood. Knowledge of the function and regulation of syncytiotrophoblast amino acid transporters is of great importance in understanding the mechanism of placental transport and potentially improving fetal and newborn outcomes. The development of methods for the isolation of microvillous and basal membrane vesicles from human placenta over the past two decades has contributed greatly to this understanding. Now a primary cultured trophoblast model is available to study amino acid transport and regulation as the cells differentiate. The types of amino acid transporters and their distribution between the syncytiotrophoblast microvillous and basal membranes are somewhat unique compared with other polarized epithelia. These differences may reflect the unusual circumstance of this epithelium that is exposed to blood on both sides. The current state of knowledge as to the types of transport systems present in syncytiotrophoblast, their regulation, and the effects of maternal consumption of drugs on transport are discussed.

scholarly journals Rhizobium leguminosarum Has a Second General Amino Acid Permease with Unusually Broad Substrate Specificity and High Similarity to Branched-Chain Amino Acid Transporters (Bra/LIV) of the ABC Family

2002 ◽  
Vol 184 (15) ◽  
pp. 4071-4080 ◽  
Author(s):  
A. H. F. Hosie ◽  
D. Allaway ◽  
C. S. Galloway ◽  
H. A. Dunsby ◽  
P. S. Poole
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Rhizobium Leguminosarum ◽  
Binding Protein ◽  
Amino Acid Transporters ◽  
Acid Uptake ◽  
Amino Acid Permease ◽  
Branched Chain Amino Acid ◽  
General Amino Acid Permease ◽  
Branched Chain

ABSTRACT Amino acid uptake by Rhizobium leguminosarum is dominated by two ABC transporters, the general amino acid permease (Aap) and the branched-chain amino acid permease (BraRl). Characterization of the solute specificity of BraRl shows it to be the second general amino acid permease of R. leguminosarum. Although BraRl has high sequence identity to members of the family of hydrophobic amino acid transporters (HAAT), it transports a broad range of solutes, including acidic and basic polar amino acids (l-glutamate, l-arginine, and l-histidine), in addition to neutral amino acids (l-alanine and l-leucine). While amino and carboxyl groups are required for transport, solutes do not have to be α-amino acids. Consistent with this, BraRl is the first ABC transporter to be shown to transport γ-aminobutyric acid (GABA). All previously identified bacterial GABA transporters are secondary carriers of the amino acid-polyamine-organocation (APC) superfamily. Also, transport by BraRl does not appear to be stereospecific as d amino acids cause significant inhibition of uptake of l-glutamate and l-leucine. Unlike all other solutes tested, l-alanine uptake is not dependent on solute binding protein BraCRl. Therefore, a second, unidentified solute binding protein may interact with the BraDEFGRl membrane complex during l-alanine uptake. Overall, the data indicate that BraRl is a general amino acid permease of the HAAT family. Furthermore, BraRl has the broadest solute specificity of any characterized bacterial amino acid transporter.

Na(+)-independent transport (uniport) of amino acids and glucose in mammalian cells.

1994 ◽  
Vol 196 (1) ◽  
pp. 93-108
Author(s):  
D K Kakuda ◽  
C L MacLeod
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Mammalian Cells ◽  
Glucose Transporter ◽  
Sequence Similarity ◽  
Amino Acid Sequence Similarity ◽  
Amino Acid Transporters ◽  
Cationic Amino Acid ◽  
Transporter Family ◽  
Share Amino Acid Sequence

Recent advances have made possible the isolation of the genes and their cDNAs encoding Na(+)-independent amino acid transporters. Two classes of amino acid 'uniporters' have been isolated. One class contains the mCAT (murine cationic amino acid transporter) gene family that encodes proteins predicted to span the membrane 12-14 times and exhibits structural properties similar to the GLUT (glucose transporter) family and to other well-known transporters. The other class consists of two known genes, rBAT (related to B system amino acid transporters) and 4F2hc, that share amino acid sequence similarity with alpha-amylases and alpha-glucosidases. They are type II glycoproteins predicted to span the membrane only once, yet they mediate the Na(+)-independent transport of cationic and zwitterionic amino acids in Xenopus oocytes. Mutations in the human rBAT gene have been identified by Palacín and his co-workers in several families suffering from a heritable form of cystinuria. This important finding clearly establishes a key role for rBAT in cystine transport. The two classes of amino acid transporters are compared with the well-studied GLUT family of Na(+)-independent glucose transporters.

Amino-acid-dependent modulation of amino acid transport in Xenopus laevis oocytes.

1996 ◽  
Vol 199 (4) ◽  
pp. 923-931 ◽  
Author(s):  
P M Taylor ◽  
S Kaur ◽  
B Mackenzie ◽  
G J Peter
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Xenopus Laevis ◽  
Amino Acid Transport ◽  
Acid Mixture ◽  
Xenopus Laevis Oocytes ◽  
Amino Acid Transporters ◽  
Amino Acid Supplementation ◽  
Acid Transport ◽  
Acid Supplementation

We have measured rates of uptake of arginine, glutamine, glutamate, serine, phenylalanine and glycine in Xenopus laevis oocytes cultured for periods of up to 24h in saline in the presence or absence of a mixture of 20 amino acids at concentrations approximating those in Xenopus plasma. Amino acid supplementation increased the total intracellular amino acid concentration from 8.2 to 18.4 nmol per oocyte. Specific Na(+)-dependent amino acid transporters (systems B0,+, Xag-) exhibit 'adaptive regulation' (up-regulation during amino acid deprivation and down-regulation during amino acid supplementation). Na(+)-independent transporters of glutamate, glutamine and glycine (including system asc) display an opposite modulation in activity, which may help to combat amino-acid-induced oxidative stress by increasing the supply of glutathione precursors. Single amino acids at physiological plasma concentrations (0.47 mmol l-1 L-alanine, 0.08 mmol l-1 L-glutamate) mimicked at least some effects of the amino acid mixture. The mechanisms of transport modulation do not appear to include trans-amino acid or membrane potential effects and, in the case of Na(+)-independent transport, are independent of protein or mRNA synthesis. Furthermore, activation of protein kinase C by phorbol 12-myristate 13-acetate did not significantly affect endogenous glutamine and glutamate transport. The Xenopus oocyte appears to possess endogenous signalling mechanisms for selectively modulating the activity of amino acid transport proteins expressed in its surface membranes, a factor for consideration when using oocytes as an expression system for structure-function studies of cloned amino acid transporters.

scholarly journals Volta Phase Plate Cryo-EM Structure of the Human Heterodimeric Amino Acid Transporter 4F2hc-LAT2

2019 ◽  
Vol 20 (4) ◽  
pp. 931 ◽  
Author(s):  
Jean-Marc Jeckelmann ◽  
Dimitrios Fotiadis
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Drug Targets ◽  
Plasma Membranes ◽  
Protein Complexes ◽  
Methylotrophic Yeast ◽  
Disulfide Bridge ◽  
Phase Plate ◽  
Amino Acid Transporters ◽  
Loss Of Function

Heteromeric amino acid transporters (HATs) are protein complexes that catalyze the transport of amino acids across plasma membranes. HATs are composed of two subunits, a heavy and a light subunit, which belong to the solute carrier (SLC) families SLC3 and SLC7. The two subunits are linked by a conserved disulfide bridge. Several human diseases are associated with loss of function or overexpression of specific HATs making them drug targets. The human HAT 4F2hc-LAT2 (SLC3A2-SLC7A8) is specific for the transport of large neutral L-amino acids and specific amino acid-related compounds. Human 4F2hc-LAT2 can be functionally overexpressed in the methylotrophic yeast Pichia pastoris and pure recombinant protein purified. Here we present the first cryo-electron microscopy (cryo-EM) 3D-map of a HAT, i.e., of the human 4F2hc-LAT2 complex. The structure could be determined at ~13 Å resolution using direct electron detector and Volta phase plate technologies. The 3D-map displays two prominent densities of different sizes. The available X-ray structure of the 4F2hc ectodomain fitted nicely into the smaller density revealing the relative position of 4F2hc with respect to LAT2 and the membrane plane.

Chelating polymers. I. The synthesis and acid dissociation behavior of several N-(p-vinylbenzenesulfonyl)-substituted diaminopolyacetic acid monomers, monomeric analogues, and related intermediates

1970 ◽  
Vol 48 (1) ◽  
pp. 163-175 ◽  
Author(s):  
R. M. Genik-Sas-Berezowsky ◽  
I. H. Spinner
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Dissociation Constants ◽  
Acid Dissociation ◽  
Inductive Effects ◽  
Cyclic Amide ◽  
Amino Acid Analogues ◽  
Related Compounds ◽  
Chelating Polymers ◽  
Made In

Two new chelating monomers, N-(p-vinylbenzenesulfonyl)1,2-diaminoethane-N′,N′-diacetic (SS-EDDA) and -N,N′,N′-triacetic (SS-ED3A) acids, as well as several monomeric analogues and related intermediates have been prepared. In addition, 2-oxo-1-piperazine acetic (S-KP), 3-oxo-1-piperazine acetic (U-KP), and 2-oxo-1,4-piperazine diacetic (3-KP) acids have been synthesized and the interconvertibility between these cyclic amides and their unsubstituted linear amino acid analogues, ethylene-diamine-N,N′-diacetic (S-EDDA), -N,N-diacetic (U-EDDA), and -N,N,N′-triacetic (ED3A) acids respectively, was demonstrated.The acid dissociation constants of the various amino acids were determined potentiometrically at 25° and μ = 0.1 M(KNO3) and the results were compared with the hydrogen ion affinities of related compounds. Dissociation schemes were proposed for all the compounds based on these results. Rationalizations of the linear amino acid and the cyclic amide dissociation constants were made in terms of the effects of cyclization and the inductive effects of neighboring groups. These rationalizations were found to be helpful in clarifying the dissociation schemes previously proposed for several of the linear amino acids.

Formation and occurrence of N-malonylphenylalanine and related compounds in plants

1968 ◽  
Vol 46 (8) ◽  
pp. 797-806 ◽  
Author(s):  
N. Rosa ◽  
A. C. Neish
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Glutamic Acid ◽  
Plant Species ◽  
Isolation Procedure ◽  
Plant Kingdom ◽  
Feeding Experiments ◽  
Leucine Isomers ◽  
Related Compounds

Shoots of barley seedlings when fed D-phenylalanine convert the amino acid to N-malonylphenylalanine. Some N-acetylphenylalanine is obtained at the same time but this may be an artifact of the isolation procedure since it is readily formed by decarboxylation of the malonylphenylalanine. Feeding experiments with the D- and L-isomers of phenylalanine, valine, leucine, isoleucine, tyrosine, tryptophan, alanine, and glutamic acid showed that barley shoots form the malonyl derivative from all the D-isomers whereas little, if any, is formed from the L-isomers. Similar experiments with phenylalanine and leucine isomers, using seven different plant species, showed that the ability to conjugate the D-isomers (but not the L-isomers) was found in all of the plants tested. It was also observed that the ether-soluble acidic conjugates of a variety of amino acids, possibly malonyl derivatives, occur widely throughout the plant kingdom.

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