Identification of the amino acid residue responsible for the myricetin sensitivity of human proton-coupled folate transporter

AbstractHuman proton-coupled folate transporter (hPCFT/SLC46A1) has recently been found to be inhibited by myricetin by a sustained mechanism, raising a concern that the inhibition might lead to malabsorption of folates in the intestine, where hPCFT works for their epithelial uptake. However, rat PCFT (rPCFT) has more recently been found not to be inhibited by myricetin. Prompted by this finding, we attempted to determine the amino acid residue involved in that by analyses comparing between hPCFT and rPCFT. In the initial analysis, chimeric constructs prepared from hPCFT and rPCFT were examined for myricetin sensitivity to determine the hPCFT segment involved in the sensitivity. Focusing on the thereby determined segment from 83rd to 186th amino acid residue, hPCFT mutants having a designated amino acid residue replaced with its counterpart in rPCFT were prepared for the subsequent analysis. Among them, only G158N-substituted hPCFT was found to be transformed to be insensitive to myricetin and, accordingly, oppositely N158G-substituted rPCFT was transformed to be sensitive to myricetin. These results indicate the critical role of Gly158 in the myricetin sensitivity of hPCFT. This finding would help advance the elucidation of the mechanism of the myricetin-induced inhibition of hPCFT and manage the potential risk arising from that.

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Critical role of an amino acid residue in a T cell determinant is due to its interaction with a neighboring non-critical residue

European Journal of Immunology ◽

10.1002/eji.1830200939 ◽

1990 ◽

Vol 20 (9) ◽

pp. 2145-2148 ◽

Cited By ~ 4

Author(s):

Michel Boyer ◽

Zuzana Novak ◽

Arun Fotedar ◽

Ester Fraga ◽

Bhagirath Singh

Keyword(s):

Amino Acid ◽

T Cell ◽

Amino Acid Residue ◽

Critical Role ◽

Critical Residue

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Critical role of the A2 amino acid residue in the biological activity of insulin: [2-glycine-A]- and [2-alanine-A]insulins

Biochemistry ◽

10.1021/bi00302a011 ◽

1984 ◽

Vol 23 (7) ◽

pp. 1405-1413 ◽

Cited By ~ 40

Author(s):

Kouki Kitagawa ◽

Hiroshi Ogawa ◽

G. Thompson Burke ◽

Jacob D. Chanley ◽

Panayotis G. Katsoyannis

Keyword(s):

Biological Activity ◽

Amino Acid ◽

Amino Acid Residue ◽

Critical Role

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The critical role of amino acid residue at position 117 of mouse UDP-glucuronosyltransfererase 1a6a and 1a6b in resveratrol glucuronidation

The Journal of Biochemistry ◽

10.1093/jb/mvs078 ◽

2012 ◽

Vol 152 (4) ◽

pp. 331-340 ◽

Cited By ~ 3

Author(s):

S. Uchihashi ◽

M. Nishikawa ◽

T. Sakaki ◽

S.-i. Ikushiro

Keyword(s):

Amino Acid ◽

Amino Acid Residue ◽

Critical Role

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Ethambutol resistance in Mycobacterium tuberculosis: critical role of embB mutations.

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.41.8.1677 ◽

1997 ◽

Vol 41 (8) ◽

pp. 1677-1681 ◽

Cited By ~ 173

Author(s):

S Sreevatsan ◽

K E Stockbauer ◽

X Pan ◽

B N Kreiswirth ◽

S L Moghazeh ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Amino Acid ◽

Amino Acid Residue ◽

Critical Role ◽

Polymorphism Analysis ◽

Nucleotide Substitutions ◽

Automated Dna Sequencing ◽

Resistant Strains ◽

Conformation Polymorphism

Ethambutol [(S,S')-2,2'-(ethylenediimino)di-1-butanol; EMB], is a first-line drug used to treat tuberculosis. To gain insight into the molecular basis of EMB resistance, we characterized the 10-kb embCAB locus in 16 EMB-resistant and 3 EMB-susceptible genetically distinct Mycobacterium tuberculosis strains from diverse localities by automated DNA sequencing and single-stranded conformation polymorphism analysis. All 19 organisms had virtually identical sequences for the entire 10-kb region. Eight EMB-resistant organisms had mutations located in codon 306 of embB that resulted in the replacement of the wild-type Met residue with Ile or Val. Automated sequence analysis of the 5' region (1,892 bp) of embB in an additional 69 EMB-resistant and 30 EMB-susceptible M. tuberculosis isolates from diverse geographic localities and representing 70 distinct IS6110 fingerprints confirmed the unique association of substitutions in amino acid residue 306 of EmbB with EMB resistance. Six other embB nucleotide substitutions resulting in four amino acid replacements were uniquely found in resistant strains. Sixty-nine percent of epidemiologically unassociated EMB-resistant organisms had an amino acid substitution not found in susceptible strains, and most (89%) replacements occurred at amino acid residue 306 of EmbB. For strains with the Met306Leu or Met306Val replacements EMB MICs were generally higher (40 microg/ml) than those for organisms with Met306Ile substitutions (20 microg/ml). The data are consistent with the idea that amino acid substitutions in EmbB alter the drug-protein interaction and thereby cause EMB resistance.

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The Unusual Role of Pro in Cu(II) Binding by His2-Cyclopentapeptide

International Journal of Molecular Sciences ◽

10.3390/ijms22126628 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6628

Author(s):

Aleksandra Pieniężna ◽

Aleksandra Kotynia ◽

Justyna Brasuń

Keyword(s):

Amino Acid ◽

Potentiometric Titration ◽

Amino Acid Residue ◽

Strong Impact ◽

Mononuclear Complexes ◽

Study Results ◽

Metal Ratio ◽

Ph Range ◽

L1 And L2

In this paper, we present findings from studying the interaction of copper(II) ions with the His2-cyclopentapeptide and the role of proline used for the purpose of potentiometric titration and UV-Vis, CD and EPR spectroscopic measurements. Experiments of two homodetic peptides differing by one amino acid residue were conducted for a ligand to metal ratio of 1:1 in the pH range 2.5–11.0. The presented studies reveal that peptides form only mononuclear complexes, and the CuH2L complex appears in the system first (for both L1 and L2). Study results show that the presence of Pro influences the structure of formed complexes and their stabilities and has a strong impact on the efficiency of copper(II) coordination.

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