Abstract:
:In mammals, citric acid cycle intermediates play a key role in regulating various metabolic processes, such as fatty acid synthesis and glycolysis. Members of the sodium-dependent SLC13 transporter family mediate the transport of di- and tricarboxylates into cells. SLC13 family members have been implicated in lifespan extension and resistance to high-fat diets; thus, they are emerging drug targets for aging and metabolic disorders. We previously characterized key structural determinants of substrate and cation binding for the human NaDC3/SLC13A3 transporter using a homology model. Here, we combine computational modeling and virtual screening with functional and biochemical testing, to identify nine previously unknown inhibitors for multiple members of the SLC13 family from human and mouse. Our results reveal previously unknown substrate selectivity determinants for the SLC13 family, including key residues that mediate ligand binding and transport, as well as promiscuous and specific SLC13 small molecule ligands. The newly discovered ligands can serve as chemical tools for further characterization of the SLC13 family or as lead molecules for the future development of potent inhibitors for the treatment of metabolic diseases and aging. Our results improve our understanding of the structural components that are important for substrate specificity in this physiologically important family as well as in other structurally related transport systems.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Colas C,Pajor AM,Schlessinger Adoi
10.1021/acs.biochem.5b00388subject
Has Abstractpub_date
2015-08-11 00:00:00pages
4900-8issue
31eissn
0006-2960issn
1520-4995journal_volume
54pub_type
杂志文章相关文献
BIOCHEMISTRY文献大全abstract::The pyridoxal 5'-phosphate (PLP)-dependent cystathionine beta-lyase (CBL) was previously found to be inhibited by the natural toxins rhizobitoxine and l-aminoethoxyvinylglycine (AVG). The present study characterizes the interaction of Escherichia coli CBL with AVG and methoxyvinylglycine (MVG) by a combination of kine...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi970630m
更新日期:1997-10-14 00:00:00
abstract::We have used enzymic and chemical probes to search for altered DNA conformations in the 5' flanking region of the gene for a high mobility group protein (HMG-T) from trout. This search was conducted in order to identify potential genetic elements that might be involved in the transcriptional control of the HMG-T gene....
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00402a012
更新日期:1988-01-26 00:00:00
abstract::Two subfractions of low-density lipoproteins (LDL) were isolated from normal pig (Sus domesticus) serum by a combined method including precipitation, ultracentrifugation, and gel chromatography. The fractions recovered from the buoyant density ranges 1.020-1.050 and 1.050-1.090 g/mL, denoted as LDL1 and LDL2, respecti...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00514a038
更新日期:1981-05-26 00:00:00
abstract::The structure of MtrA, an essential gene product for the human pathogen Mycobacterium tuberculosis, has been solved to a resolution of 2.1 A. MtrA is a member of the OmpR/PhoB family of response regulators and represents the fourth family member for which a structure of the protein in its inactive state has been deter...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi602546q
更新日期:2007-06-12 00:00:00
abstract::The aminoacylation kinetics of 19 different variants of yeast tRNATyr with nucleotide substitutions in positions 33-35 were determined. Substitution of the conserved uridine-33 does not alter the rate of aminoacylation. However, substitution of the anticodon position 34 or position 35 reduces Km from 2- to 10-fold and...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00367a072
更新日期:1986-09-23 00:00:00
abstract::Seven mutant LH1 polypeptides of Rhodobactor sphaeroides have been isolated, and their behaviors in in vitro reconstitution of LH1 and its subunit complex have been characterized. Two mutants were selected to address the increased stability of the subunit complex of Rb. sphaeroides compared with that of Rhodobacter ca...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi962386p
更新日期:1997-03-25 00:00:00
abstract::Bacterial NO synthase (NOS)-like proteins such as that from Bacillus subtilis (bsNOS) share a high degree of structural homology with the oxygenase domain of mammalian NOSs (mNOSs), but biochemical studies have yet failed to establish that they are specifically capable of producing NO. To better understand the actual ...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi051710q
更新日期:2006-02-07 00:00:00
abstract::Two thiol-activated endopeptidases with pH optima near pH 7.5 were isolated from the supernatant fraction of rabbit brain homogenates by DEAE-cellulose chromatography, gel filtration and isoelectrofocusing. Peptide bond hydrolysis was measured quantitatively by ion-exchange chromatography with an amino acid analyzer. ...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00654a026
更新日期:1976-05-04 00:00:00
abstract::Deuterium quadrupole echo spectra and spin-lattice relaxation rates measured at 76.8 and 38.4 MHz as a function of relative humidity are reported for calf thymus DNA deuterated at positions A8 and G8. The amplitude of base pair motion is observed to increase slightly with increasing degree of hydration (up to approxim...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00371a069
更新日期:1986-11-18 00:00:00
abstract::Proline utilization A (PutA) from Escherichia coli is a multifunctional flavoprotein that is both a transcriptional repressor of the proline utilization (put) genes and a membrane-associated enzyme which catalyzes the 4-electron oxidation of proline to glutamate. Previously, proline was shown to induce PutA-membrane b...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi048596g
更新日期:2004-10-19 00:00:00
abstract::The stereochemical problem involving a pro-pro-prochiral phosphorus center, the hydrolysis of adenosine 5'-monophosphate to adenosine and inorganic phosphate catalyzed by the venom 5'-nucleotidase, has been studied by use of chiral [16O, 17O, 18O]thiophosphates (Psi). (Rp)- and (Sp)-[alpha-18O1]Adenosine 5'-thiophosph...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00564a025
更新日期:1980-11-11 00:00:00
abstract::We have used a photochemical method to map covalent binding sites of the carcinogen benzo[a]pyrenediol epoxide (BPDE) within DNA from the transcriptional control region of the chicken adult beta-globin gene. Our preliminary low-resolution mapping has demonstrated that this region contains highly preferred BPDE binding...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00358a045
更新日期:1986-05-20 00:00:00
abstract::The beta subunits of the 143-kDa alpha2beta2 tetrameric enzyme tryptophan synthase have been labeled by L-[ring-4-19F]phenylalanine and L-[phenol-4-13C]tyrosine in an effort to monitor the positions of these residues on ligand binding. Of the 13 phenylalanine and 11 tyrosine residues in the beta subunit, only three pa...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi9518297
更新日期:1996-03-12 00:00:00
abstract::For nonspecific binding of oligopeptides and other cationic ligands, including proteins, to nucleic acid oligomers, we develop a model capable of quantifying and predicting the salt concentration dependence of the binding free energy (deltaG(o)obs) by way of an analytic treatment of the Coulombic end effect (CEE). Lig...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi0520434
更新日期:2006-07-11 00:00:00
abstract::New analogues of 7-methylguanosine 5'-monophosphate (m7GMP) were synthesized with modified 5'-phosphate moieties by replacement of -O with -H, -CH3, or -NH2. Additional analogues were synthesized with 8-methyl- or 8-aminoguanine base substitutions or ring-opened ribose (2',3'-diol). These compounds were analyzed by 1H...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00388a028
更新日期:1987-07-14 00:00:00
abstract::Transcarboxylase is made up of a central hexameric subunit (S20,W similar 12 S), three peripheral dimeric metallo subunits (S20,W similar to 5 S), and six biotinyl carboxyl carrier subunits (S20,W similar to 1.3 S). The results presented here show that the carboxyl carrier subunit is required for assembly of the 12S a...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00679a010
更新日期:1975-04-22 00:00:00
abstract::Mouse fibroblasts contain a macromolecular binding component (receptor) which binds glucocorticoids specifically and with high affinity. This study shows that there are three different cellular forms of bound receptor and that it is experimentally possible to markedly alter the subcellular distribution of these three ...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00672a030
更新日期:1975-01-14 00:00:00
abstract::Since a major function of RNA polymerase must be to bring together substrates in the optimal configuration for internucleotide bond formation, studies have been undertaken to understand the geometrical relationship of the two substrates. A model has been constructed for the geometry of interaction of two ATP molecules...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00477a017
更新日期:1990-06-26 00:00:00
abstract::Pulmonary surfactant protein D (SP-D), a member of the collectin group of innate immune proteins, plays important roles in lipopolysaccharide (LPS) recognition. We have previously shown that surfactant protein A (SP-A), a homologous collectin, interacts with Toll-like receptor (TLR) 2, resulting in alteration of TLR2-...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi060176z
更新日期:2006-07-18 00:00:00
abstract::The iron-containing enzyme tyrosine hydroxylase catalyzes the hydroxylation of tyrosine to dihydroxyphenylalanine. A series of 4-X-substituted (X = H, F, Br, Cl, CH3, or CH3O) phenylalanines have been characterized as substrates to gain insight into the mechanism of hydroxylation. Multiple hydroxylated products were f...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi9606861
更新日期:1996-06-04 00:00:00
abstract::The binding properties of substrates and competitive inhibitors of Escherichia coli cytidine deaminase are compared with those of the fragments obtained by cutting these ligands at several positions including the glycosidic bond. In contrast with the normal substrate cytidine (kcat/Km = 2.6 x 10(6) M-1 s-1), cytosine ...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi980959n
更新日期:1998-08-25 00:00:00
abstract::The bacterial reaction center (RC) converts light into chemical energy through the reduction of an internal quinone molecule Q(B) to Q(B)H(2). In the native RC, proton transfer is coupled to electron transfer and is not rate-controlling. Consequently, proton transfer is not directly observable, and its rate was unknow...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi020419x
更新日期:2002-12-17 00:00:00
abstract::The protein product of the Methanococcus jannaschii MJ0768 gene has been expressed in Escherichia coli, purified to homogeneity, and shown to catalyze the GTP-dependent addition of two l-glutamates to the l-lactyl phosphodiester of 7,8-didemethyl-8-hydroxy-5-deazariboflavin (F(420)-0) to form F(420)-0-glutamyl-glutama...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi034779b
更新日期:2003-08-19 00:00:00
abstract::Raman difference spectroscopy is used to probe the properties of a 36-nt RNA molecule, "D5", which lies at the heart of the catalytic apparatus in group II introns. For D5 that has all of its adenine residues labeled with (13)C and (15)N and utilizing Raman difference spectroscopy, we identify the conformationally sen...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi902117w
更新日期:2010-04-27 00:00:00
abstract::In a previously determined minimal kinetic scheme for DNA polymerization catalyzed by the Klenow fragment (KF) of Escherichia coli DNA polymerase I, a nonchemical step that interconverted the KF'.DNAn+1.PPi and KF.DNAn+1PPi complexes was not observed in correct incorporation [Kuchta, R. D., Mizrahi, V., Benkovic, P.A....
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00234a002
更新日期:1991-05-21 00:00:00
abstract::Ultraviolet resonance Raman (UV RR) spectra are reported for ferricytochrome c from tuna and horse heart at pH 1.6, 7, 10, and 13, representing distinct conformational states of the protein (states II, III, IV, and V, respectively). The spectra were obtained with pulsed laser excitation at 200 and 218 nm, via H2 Raman...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi00339a035
更新日期:1985-08-27 00:00:00
abstract::The intracellular kinetic folding pathway of the human chorionic gonadotropin beta-subunit (hCG-beta) reveals the presence of a disulfide between Cys residues 38-57 that is not detected by X-ray analysis of secreted hCG-beta. This led us to propose that disulfide rearrangement is an essential feature of cystine knot f...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi049856x
更新日期:2004-05-04 00:00:00
abstract::Previous studies of the low molecular mass family 11 xylanase from Bacillus circulans show that the ionization state of the nucleophile (Glu78, pK(a) 4.6) and the acid/base catalyst (Glu172, pK(a) 6.7) gives rise to its pH-dependent activity profile. Inspection of the crystal structure of BCX reveals that Glu78 and Gl...
journal_title:Biochemistry
pub_type: 杂志文章
doi:
更新日期:2001-08-28 00:00:00
abstract::Detailed analysis of factors governing high affinity antibody-antigen interactions yields important insight into molecular recognition and facilitates the design of functional antibody libraries. Here we describe comprehensive mutagenesis of the light chain complementarity determining regions (CDRs) of HIV-1 antibody ...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi100293q
更新日期:2010-07-06 00:00:00
abstract::X-ray absorption spectroscopy at the Zn K-edge indicates that the active site of the marine diatom Thalassiosira weissflogii carbonic anhydrase is strikingly similar to that of mammalian alpha-carbonic anhydrase enzymes. The zinc has three histidine ligands and a single water at 1.98 A. This is quite different from th...
journal_title:Biochemistry
pub_type: 杂志文章
doi:10.1021/bi001416s
更新日期:2000-10-10 00:00:00