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1.
J Enzyme Inhib Med Chem ; 38(1): 2193866, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37013838

ABSTRACT

Inositol polyphosphates (IPs) are a group of inositol metabolites that act as secondary messengers for external signalling cues. They play various physiological roles such as insulin release, telomere length maintenance, cell metabolism, and aging. Inositol hexakisphosphate kinase 2 (IP6K2) is a key enzyme that produces 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (5-IP7), which influences the early stages of glucose-induced exocytosis. Therefore, regulation of IP6Ks may serve as a promising strategy for treating diseases such as diabetes and obesity. In this study, we designed, synthesised, and evaluated flavonoid-based compounds as new inhibitors of IP6K2. Structure-activity relationship studies identified compound 20s as the most potent IP6K2 inhibitor with an IC50 value of 0.55 µM, making it 5-fold more potent than quercetin, the reported flavonoid-based IP6K2 inhibitor. Compound 20s showed higher inhibitory potency against IP6K2 than IP6K1 and IP6K3. Compound 20s can be utilised as a hit compound for further structural modifications of IP6K2 inhibitors.


Subject(s)
Enzyme Inhibitors , Flavonoids , Insulin , Phosphotransferases (Phosphate Group Acceptor) , Flavonoids/pharmacology , Inositol , Signal Transduction , Phosphotransferases (Phosphate Group Acceptor)/antagonists & inhibitors , Enzyme Inhibitors/pharmacology
2.
J Enzyme Inhib Med Chem ; 37(1): 269-279, 2022 Dec.
Article in English | MEDLINE | ID: mdl-34894957

ABSTRACT

Inositol hexakisphosphate kinase (IP6K) is an important mammalian enzyme involved in various biological processes such as insulin signalling and blood clotting. Recent analyses on drug metabolism and pharmacokinetic properties on TNP (N2-(m-trifluorobenzyl), N6-(p-nitrobenzyl)purine), a pan-IP6K inhibitor, have suggested that it may inhibit cytochrome P450 (CYP450) enzymes and induce unwanted drug-drug interactions in the liver. In this study, we confirmed that TNP inhibits CYP3A4 in type I binding mode more selectively than the other CYP450 isoforms. In an effort to find novel purine-based IP6K inhibitors with minimal CYP3A4 inhibition, we designed and synthesised 15 TNP analogs. Structure-activity relationship and biochemical studies, including ADP-Glo kinase assay and quantification of cell-based IP7 production, showed that compound 9 dramatically reduced CYP3A4 inhibition while retaining IP6K-inhibitory activity. Compound 9 can be a tool molecule for structural optimisation of purine-based IP6K inhibitors.


Subject(s)
Cytochrome P-450 CYP3A/metabolism , Enzyme Inhibitors/pharmacology , Phosphotransferases (Phosphate Group Acceptor)/antagonists & inhibitors , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Phosphotransferases (Phosphate Group Acceptor)/metabolism , Structure-Activity Relationship
3.
Nucleic Acids Res ; 49(21): 12035-12047, 2021 12 02.
Article in English | MEDLINE | ID: mdl-34865121

ABSTRACT

Cisplatin is one of the most potent anti-cancer drugs developed so far. Recent studies highlighted several intriguing roles of histones in cisplatin's anti-cancer effect. Thus, the effect of nucleosome formation should be considered to give a better account of the anti-cancer effect of cisplatin. Here we investigated this important issue via single-molecule measurements. Surprisingly, the reduced activity of cisplatin under [NaCl] = 180 mM, corresponding to the total concentration of cellular ionic species, is still sufficient to impair the integrity of a nucleosome by retaining its condensed structure firmly, even against severe mechanical and chemical disturbances. Our finding suggests that such cisplatin-induced fastening of chromatin can inhibit nucleosome remodelling required for normal biological functions. The in vitro chromatin transcription assay indeed revealed that the transcription activity was effectively suppressed in the presence of cisplatin. Our direct physical measurements on cisplatin-nucleosome adducts suggest that the formation of such adducts be the key to the anti-cancer effect by cisplatin.


Subject(s)
Chromatin Assembly and Disassembly/drug effects , Cisplatin/pharmacology , Neoplasms/drug therapy , Histones/metabolism , Membrane Proteins/metabolism , Nucleosomes/metabolism
4.
Front Plant Sci ; 8: 1250, 2017.
Article in English | MEDLINE | ID: mdl-28775727

ABSTRACT

CYP21-4 is a novel Golgi-localized cyclophilin protein involved in oxidative stress tolerance. Here, we generated transgenic plants overexpressing AtCYP21-4 and OsCYP21-4 in potato and rice, respectively. The stems and roots of AtCYP21-4-overexpressing potato plants were longer than those of wild-type (WT) plants, which resulted in heavier tubers. In vitro tuberization in the transgenic potato also resulted in significantly greater tuber number and weight, as well as a shorter time to microtuber formation. Similarly, OsCYP21-4-overexpressing transgenic rice plants had higher biomass and productivity with longer early-stage internodes than the WT and higher seed weight. Immunoblot analysis with CYP21-4 antibody showed that these productivity-enhancing phenotypes were associated with high CYP21-4s protein expression. Anatomically, transgenic potato stems exhibited higher lignin content in xylem cells and thicker leaves. In addition, relative content of mannosidic glycoproteins per unit of total protein was above 20% in transgenic potato tubers and rice grains. Based on these findings, we propose that CYP21-4s are involved in the growth and development of plant vegetative and storage tissues via their effects on glycoprotein abundance or glycan processing in the Golgi apparatus. Thus, increasing CYP21-4s expression in crops could represent an alternative way to increase crop productivity and yield.

5.
J Microbiol Biotechnol ; 23(3): 297-303, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23462001

ABSTRACT

Phylogenetic analysis of the groEL1 and xynB1 gene sequences from Sorangium cellulosum strains isolated in Korea previously revealed the existence of at least 5 subgroups (A-E). In the present study, we used sequence analysis of polymerase chain reaction-amplified biosynthetic genes of strains from the 5 subgroups to indicate correlations between S. cellulosum subgroups and their secondary metabolic gene categories. We detected putative biosynthetic genes for disorazol, epothilone, ambruticin, and soraphen in group A, group C, group D, and group E strains, respectively. With the exception of KYC3204, culture extracts from group A, group B, and group C strains exhibited no noticeable antimicrobial inhibitory activities. By contrast, culture extracts from group D strains inhibited the growth of Candida albicans, whereas culture extracts from group E strains inhibited the growth of C. albicans and Staphylococcus aureus. High performance liquid chromatography analysis of the culture extracts from the strains of each subgroup revealed unique peak patterns. Our findings indicate the existence of at least 5 subgroups of S. cellulosum strains, each of which has the potential to produce a unique set of secondary metabolites.


Subject(s)
Biological Products/analysis , Myxococcales/classification , Myxococcales/metabolism , Anti-Infective Agents/analysis , Anti-Infective Agents/pharmacology , Biological Products/pharmacology , Biosynthetic Pathways/genetics , Candida albicans/drug effects , Candida albicans/growth & development , Chaperonin 60/genetics , Chromatography, High Pressure Liquid , Cluster Analysis , DNA, Bacterial/chemistry , DNA, Bacterial/genetics , Endo-1,4-beta Xylanases/genetics , Korea , Molecular Sequence Data , Myxococcales/genetics , Myxococcales/isolation & purification , Phylogeny , Polymerase Chain Reaction , Sequence Analysis, DNA , Staphylococcus aureus/drug effects , Staphylococcus aureus/growth & development , beta-Glucosidase/genetics
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