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Article: Crystal structures of FMN‐bound and FMN‐free forms of dihydroorotate dehydrogenase from Trypanosoma brucei

Kubota, Tomomi / Tani, Osamu / Yamaguchi, Tomohiko / Namatame, Ichiji / Sakashita, Hitoshi / Furukawa, Koji / Yamasaki, Kazuhiko

FEBS Open Bio. 2018 Apr., v. 8, no. 4

2018

Abstract: Dihydroorotate dehydrogenase (DHODH) is a flavin‐binding enzyme essential for pyrimidine biosynthesis, which converts dihydroorotate to orotate. Three‐dimensional structures of cytosolic DHODH of parasitic protozoa are of interest in drug discovery for ... ...

Abstract	Dihydroorotate dehydrogenase (DHODH) is a flavin‐binding enzyme essential for pyrimidine biosynthesis, which converts dihydroorotate to orotate. Three‐dimensional structures of cytosolic DHODH of parasitic protozoa are of interest in drug discovery for neglected tropical diseases, especially because these enzymes possess significantly different structural and functional properties from the membrane‐associated human enzyme. The existing crystal structures of the flavin mononucleotide (FMN)‐bound DHODHs reveal a number of interactions stabilizing FMN. However, to understand the binding mechanism correctly, it is necessary to compare the structures of the FMN‐bound and FMN‐free forms, because the protein moiety of the former is not necessarily the same as the latter. Here, we prepared the FMN‐free DHODH of Trypanosoma brucei using an Escherichia coli overexpression system. Although this apoform lacks enzymatic activity, simple incubation with FMN activated the enzyme. It was stable enough to be crystallized, enabling us to determine its structure by X‐ray crystallography at 1.6 Å resolution. We also determined the FMN‐bound form at 1.8 Å resolution. Although the two structures have essentially the same scaffold, we observed flipping of a peptide‐bond plane in the vicinity of the FMN‐binding site, accompanied by an alternative hydrogen‐bonding pattern. Comparisons of B factors of the protein main chain revealed that binding of FMN decreased flexibility of most of the residues at the FMN‐binding site, but increased flexibility of a lid‐like loop structure over the active center. This increase was ascribed to a conformational change in an FMN‐contacting residue, Asn195, which induced a rearrangement of a hydrogen‐bond network of the residues comprising the lid.
Keywords	Escherichia coli ; Trypanosoma brucei ; X-ray diffraction ; biosynthesis ; drugs ; enzyme activity ; humans ; hydrogen bonding ; moieties ; oxidoreductases
Language	English
Dates of publication	2018-04
Size	p. 680-691.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	JOURNAL ARTICLE
ZDB-ID	2651702-4
ISSN	2211-5463
ISSN	2211-5463
DOI	10.1002/2211-5463.12403
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Structures of complexes of type 5 17β-hydroxysteroid dehydrogenase with structurally diverse inhibitors: insights into the conformational changes upon inhibitor binding.

Amano, Yasushi / Yamaguchi, Tomohiko / Niimi, Tatsuya / Sakashita, Hitoshi

Acta crystallographica. Section D, Biological crystallography

2015 Volume 71, Issue Pt 4, Page(s) 918–927

Abstract: Type 5 17β-hydroxysteroid dehydrogenase (17β-HSD5) is an aldo-keto reductase expressed in the human prostate which catalyzes the conversion of androstenedione to testosterone. Testosterone is converted to 5α-dihydrotestosterone, which is present at high ... ...

Abstract	Type 5 17β-hydroxysteroid dehydrogenase (17β-HSD5) is an aldo-keto reductase expressed in the human prostate which catalyzes the conversion of androstenedione to testosterone. Testosterone is converted to 5α-dihydrotestosterone, which is present at high concentrations in patients with castration-resistant prostate cancer (CRPC). Inhibition of 17β-HSD5 is therefore considered to be a promising therapy for treating CRPC. In the present study, crystal structures of complexes of 17β-HSD5 with structurally diverse inhibitors derived from high-throughput screening were determined. In the structures of the complexes, various functional groups, including amide, nitro, pyrazole and hydroxyl groups, form hydrogen bonds to the catalytic residues His117 and Tyr55. In addition, major conformational changes of 17β-HSD5 were observed following the binding of the structurally diverse inhibitors. These results demonstrate interactions between 17β-HSD5 and inhibitors at the atomic level and enable structure-based drug design for anti-CRPC therapy.
MeSH term(s)	3-Hydroxysteroid Dehydrogenases/antagonists & inhibitors ; 3-Hydroxysteroid Dehydrogenases/chemistry ; 3-Hydroxysteroid Dehydrogenases/metabolism ; Aldo-Keto Reductase Family 1 Member C3 ; Crystallography, X-Ray ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Humans ; Hydroxyprostaglandin Dehydrogenases/antagonists & inhibitors ; Hydroxyprostaglandin Dehydrogenases/chemistry ; Hydroxyprostaglandin Dehydrogenases/metabolism ; Models, Molecular ; NADP/metabolism ; Protein Conformation/drug effects
Chemical Substances	Enzyme Inhibitors ; NADP (53-59-8) ; 3-Hydroxysteroid Dehydrogenases (EC 1.1.-) ; Hydroxyprostaglandin Dehydrogenases (EC 1.1.1.-) ; AKR1C3 protein, human (EC 1.1.1.357) ; Aldo-Keto Reductase Family 1 Member C3 (EC 1.1.1.357)
Language	English
Publishing date	2015-04
Publishing country	United States
Document type	Journal Article
ZDB-ID	2020492-9
ISSN	1399-0047 ; 2059-7983 ; 0907-4449
ISSN (online)	1399-0047 ; 2059-7983
ISSN	0907-4449
DOI	10.1107/S1399004715002175
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Article: Crystal structures of FMN-bound and FMN-free forms of dihydroorotate dehydrogenase from

Kubota, Tomomi / Tani, Osamu / Yamaguchi, Tomohiko / Namatame, Ichiji / Sakashita, Hitoshi / Furukawa, Koji / Yamasaki, Kazuhiko

FEBS open bio

2018 Volume 8, Issue 4, Page(s) 680–691

Abstract: Dihydroorotate dehydrogenase (DHODH) is a flavin-binding enzyme essential for pyrimidine biosynthesis, which converts dihydroorotate to orotate. Three-dimensional structures of cytosolic DHODH of parasitic protozoa are of interest in drug discovery for ... ...

Abstract	Dihydroorotate dehydrogenase (DHODH) is a flavin-binding enzyme essential for pyrimidine biosynthesis, which converts dihydroorotate to orotate. Three-dimensional structures of cytosolic DHODH of parasitic protozoa are of interest in drug discovery for neglected tropical diseases, especially because these enzymes possess significantly different structural and functional properties from the membrane-associated human enzyme. The existing crystal structures of the flavin mononucleotide (FMN)-bound DHODHs reveal a number of interactions stabilizing FMN. However, to understand the binding mechanism correctly, it is necessary to compare the structures of the FMN-bound and FMN-free forms, because the protein moiety of the former is not necessarily the same as the latter. Here, we prepared the FMN-free DHODH of
Language	English
Publishing date	2018
Publishing country	England
Document type	Journal Article
ISSN	2211-5463
ISSN	2211-5463
DOI	10.1002/2211-5463.12403
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Article ; Online: Structural insights into the novel inhibition mechanism of Trypanosoma cruzi spermidine synthase.

Amano, Yasushi / Namatame, Ichiji / Tateishi, Yukihiro / Honboh, Kazuya / Tanabe, Eiki / Niimi, Tatsuya / Sakashita, Hitoshi

Acta crystallographica. Section D, Biological crystallography

2015 Volume 71, Issue Pt 9, Page(s) 1879–1889

Abstract: Trypanosoma cruzi causes Chagas disease, a severe disease affecting 8-10 million people in Latin America. While nifurtimox and benznidazole are used to treat this disease, their efficacy is limited and adverse effects are observed. New therapeutic ... ...

Abstract	Trypanosoma cruzi causes Chagas disease, a severe disease affecting 8-10 million people in Latin America. While nifurtimox and benznidazole are used to treat this disease, their efficacy is limited and adverse effects are observed. New therapeutic targets and novel drugs are therefore urgently required. Enzymes in the polyamine-trypanothione pathway are promising targets for the treatment of Chagas disease. Spermidine synthase is a key enzyme in this pathway that catalyzes the transfer of an aminopropyl group from decarboxylated S-adenosylmethionine (dcSAM) to putrescine. Fragment-based drug discovery was therefore conducted to identify novel, potent inhibitors of spermidine synthase from T. cruzi (TcSpdSyn). Here, crystal structures of TcSpdSyn in complex with dcSAM, trans-4-methylcyclohexylamine and hit compounds from fragment screening are reported. The structure of dcSAM complexed with TcSpdSyn indicates that dcSAM stabilizes the conformation of the `gatekeeping' loop to form the putrescine-binding pocket. The structures of fragments bound to TcSpdSyn revealed two fragment-binding sites: the putrescine-binding pocket and the dimer interface. The putrescine-binding pocket was extended by an induced-fit mechanism. The crystal structures indicate that the conformation of the dimer interface is required to stabilize the gatekeeping loop and that fragments binding to this interface inhibit TcSpdSyn by disrupting its conformation. These results suggest that utilizing the dynamic structural changes in TcSpdSyn that occur upon inhibitor binding will facilitate the development of more selective and potent inhibitors.
MeSH term(s)	Allosteric Regulation ; Animals ; Binding Sites ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Hydrogen Bonding ; Models, Molecular ; Protein Conformation ; Spermidine Synthase/antagonists & inhibitors ; Spermidine Synthase/chemistry ; Trypanosoma cruzi/enzymology
Chemical Substances	Enzyme Inhibitors ; Spermidine Synthase (EC 2.5.1.16)
Language	English
Publishing date	2015-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	2020492-9
ISSN	1399-0047 ; 2059-7983 ; 0907-4449
ISSN (online)	1399-0047 ; 2059-7983
ISSN	0907-4449
DOI	10.1107/S1399004715013048
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Article ; Online: An NMR Biochemical Assay for Fragment-Based Drug Discovery: Evaluation of an Inhibitor Activity on Spermidine Synthase of Trypanosoma cruzi.

Yamasaki, Kazuhiko / Tani, Osamu / Tateishi, Yukihiro / Tanabe, Eiki / Namatame, Ichiji / Niimi, Tatsuya / Furukawa, Koji / Sakashita, Hitoshi

Journal of medicinal chemistry

2016 Volume 59, Issue 5, Page(s) 2261–2266

Abstract: Although NMR in fragment-based drug discovery is utilized almost exclusively to evaluate physical binding between molecules, it should be also a powerful tool for biochemical assay, evaluating inhibitory effect of compounds on enzymatic activity. Time- ... ...

Abstract	Although NMR in fragment-based drug discovery is utilized almost exclusively to evaluate physical binding between molecules, it should be also a powerful tool for biochemical assay, evaluating inhibitory effect of compounds on enzymatic activity. Time-dependent spectral change in real-time monitoring or inhibitor concentration-dependent spectral change after constant-time reaction was processed by factor analysis, by which reaction rate or IC50 value was obtained. Applications to spermidine synthase of Trypanosoma cruzi, which causes Chagas disease, are described.
MeSH term(s)	Chagas Disease/drug therapy ; Cyclohexylamines/chemical synthesis ; Cyclohexylamines/chemistry ; Cyclohexylamines/pharmacology ; Dose-Response Relationship, Drug ; Drug Discovery ; Enzyme Activation/drug effects ; Molecular Structure ; Nuclear Magnetic Resonance, Biomolecular ; Spermidine Synthase/antagonists & inhibitors ; Spermidine Synthase/metabolism ; Structure-Activity Relationship ; Time Factors ; Trypanosoma cruzi/enzymology
Chemical Substances	Cyclohexylamines ; 4-methylcyclohexylamine (6321-23-9) ; Spermidine Synthase (EC 2.5.1.16)
Language	English
Publishing date	2016-03-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.5b01769
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Article ; Online: Correction to NMR Biochemical Assay for Oxidosqualene Cyclase: Evaluation of Inhibitor Activities on Trypanosoma cruzi and Human Enzymes.

Tani, Osamu / Akutsu, Yukie / Ito, Shinji / Suzuki, Takayuki / Tateishi, Yukihiro / Yamaguchi, Tomohiko / Niimi, Tatsuya / Namatame, Ichiji / Chiba, Yasunori / Sakashita, Hitoshi / Kubota, Tomomi / Yanagi, Tetsuo / Mizukami, Shusaku / Hirayama, Kenji / Furukawa, Koji / Yamasaki, Kazuhiko

Journal of medicinal chemistry

2018 Volume 61, Issue 14, Page(s) 6399

Language	English
Publishing date	2018-07-13
Publishing country	United States
Document type	Journal Article ; Published Erratum
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.8b01017
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Article ; Online: NMR Biochemical Assay for Oxidosqualene Cyclase: Evaluation of Inhibitor Activities on Trypanosoma cruzi and Human Enzymes.

Journal of medicinal chemistry

2018 Volume 61, Issue 11, Page(s) 5047–5053

Abstract: Oxidosqualene cyclase (OSC), a membrane-associated protein, is a key enzyme of sterol biosynthesis. Here we report a novel assay for OSC, involving reaction in aqueous solution, NMR quantification in organic solvent, and factor analysis of spectra. We ... ...

Abstract	Oxidosqualene cyclase (OSC), a membrane-associated protein, is a key enzyme of sterol biosynthesis. Here we report a novel assay for OSC, involving reaction in aqueous solution, NMR quantification in organic solvent, and factor analysis of spectra. We evaluated one known and three novel inhibitors on OSC of Trypanosoma cruzi, a parasite causative of Chagas disease, and compared their effects on human OSC for selectivity. Among them, one novel inhibitor showed a significant parasiticidal activity.
MeSH term(s)	Drug Discovery ; Enzyme Inhibitors/pharmacology ; Humans ; Inhibitory Concentration 50 ; Intramolecular Transferases/antagonists & inhibitors ; Intramolecular Transferases/chemistry ; Nuclear Magnetic Resonance, Biomolecular ; Trypanosoma cruzi/drug effects ; Trypanosoma cruzi/enzymology
Chemical Substances	Enzyme Inhibitors ; Intramolecular Transferases (EC 5.4.-) ; lanosterol synthase (EC 5.4.99.7)
Language	English
Publishing date	2018-06-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.8b00484
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Article ; Online: Structural basis for telmisartan-mediated partial activation of PPAR gamma.

Amano, Yasushi / Yamaguchi, Tomohiko / Ohno, Kazuki / Niimi, Tatsuya / Orita, Masaya / Sakashita, Hitoshi / Takeuchi, Makoto

Hypertension research : official journal of the Japanese Society of Hypertension

2012 Volume 35, Issue 7, Page(s) 715–719

Abstract: Telmisartan, a selective angiotensin II type 1 receptor blocker, has recently been shown to act as a partial agonist for peroxisome proliferator-activated receptor gamma (PPARγ). To understand how telmisartan partially activates PPARγ, we determined the ... ...

Abstract	Telmisartan, a selective angiotensin II type 1 receptor blocker, has recently been shown to act as a partial agonist for peroxisome proliferator-activated receptor gamma (PPARγ). To understand how telmisartan partially activates PPARγ, we determined the ternary complex structure of PPARγ, telmisartan, and a coactivator peptide from steroid receptor coactivator-1 at a resolution of 2.18 Å. Crystallographic analysis revealed that telmisartan exhibits an unexpected binding mode in which the central benzimidazole ring is engaged in a non-canonical--and suboptimal--hydrogen-bonding network around helix 12 (H12). This network differs greatly from that observed when full-agonists bind with PPARγ and prompt high-coactivator recruitment through H12 stabilized by multiple hydrogen bonds. Binding with telmisartan results in a less stable H12 that in turn leads to attenuated coactivator binding, thus explaining the mechanism of partial activation.
MeSH term(s)	Angiotensin II Type 1 Receptor Blockers/chemistry ; Angiotensin II Type 1 Receptor Blockers/pharmacology ; Benzimidazoles/chemistry ; Benzimidazoles/pharmacology ; Benzoates/chemistry ; Benzoates/pharmacology ; Humans ; Hydrogen Bonding ; Nuclear Receptor Coactivator 1/chemistry ; PPAR gamma/agonists ; Structure-Activity Relationship
Chemical Substances	Angiotensin II Type 1 Receptor Blockers ; Benzimidazoles ; Benzoates ; PPAR gamma ; Nuclear Receptor Coactivator 1 (EC 2.3.1.48) ; telmisartan (U5SYW473RQ)
Language	English
Publishing date	2012-07
Publishing country	England
Document type	Journal Article
ZDB-ID	1175297-x
ISSN	1348-4214 ; 0916-9636
ISSN (online)	1348-4214
ISSN	0916-9636
DOI	10.1038/hr.2012.17
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Article ; Online: Fragment-based discovery of the first nonpeptidyl inhibitor of an S46 family peptidase.

Scientific reports

2019 Volume 9, Issue 1, Page(s) 13587

Abstract: Antimicrobial resistance is a global public threat and raises the need for development of new antibiotics with a novel mode of action. The dipeptidyl peptidase 11 from Porphyromonas gingivalis (PgDPP11) belongs to a new class of serine peptidases, family ...

Abstract	Antimicrobial resistance is a global public threat and raises the need for development of new antibiotics with a novel mode of action. The dipeptidyl peptidase 11 from Porphyromonas gingivalis (PgDPP11) belongs to a new class of serine peptidases, family S46. Because S46 peptidases are not found in mammals, these enzymes are attractive targets for novel antibiotics. However, potent and selective inhibitors of these peptidases have not been developed to date. In this study, a high-resolution crystal structure analysis of PgDPP11 using a space-grown crystal enabled us to identify the binding of citrate ion, which could be regarded as a lead fragment mimicking the binding of a substrate peptide with acidic amino acids, in the S1 subsite. The citrate-based pharmacophore was utilized for in silico inhibitor screening. The screening resulted in an active compound SH-5, the first nonpeptidyl inhibitor of S46 peptidases. SH-5 and a lipophilic analog of SH-5 showed a dose-dependent inhibitory effect against the growth of P. gingivalis. The binding mode of SH-5 was confirmed by crystal structure analysis. Thus, these compounds could be lead structures for the development of selective inhibitors of PgDPP11.
MeSH term(s)	Bacterial Proteins/antagonists & inhibitors ; Bacterial Proteins/chemistry ; Bacterial Proteins/metabolism ; Benzoates/chemistry ; Benzoates/pharmacology ; Binding Sites ; Catalytic Domain ; Citric Acid/metabolism ; Computer Simulation ; Crystallography, X-Ray ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/antagonists & inhibitors ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/chemistry ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/metabolism ; Drug Evaluation, Preclinical ; Inositol Phosphates ; Models, Molecular ; Porphyromonas gingivalis/enzymology ; Protein Conformation
Chemical Substances	1-((1-O-octadecyl-2-O-methylglycero)phospho)-3-deoxy-myo-inositol ; Bacterial Proteins ; Benzoates ; Inositol Phosphates ; Citric Acid (2968PHW8QP) ; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases (EC 3.4.14.-)
Language	English
Publishing date	2019-09-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-019-49984-3
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Article ; Online: 4-Hydroxypyridazin-3(2H)-one derivatives as novel D-amino acid oxidase inhibitors.

Hondo, Takeshi / Warizaya, Masaichi / Niimi, Tatsuya / Namatame, Ichiji / Yamaguchi, Tomohiko / Nakanishi, Keita / Hamajima, Toshihiro / Harada, Katsuya / Sakashita, Hitoshi / Matsumoto, Yuzo / Orita, Masaya / Takeuchi, Makoto

Journal of medicinal chemistry

2013 Volume 56, Issue 9, Page(s) 3582–3592

Abstract: D-Amino acid oxidase (DAAO) catalyzes the oxidation of d-amino acids including d-serine, a coagonist of the N-methyl-d-aspartate receptor. We identified a series of 4-hydroxypyridazin-3(2H)-one derivatives as novel DAAO inhibitors with high potency and ... ...

Abstract	D-Amino acid oxidase (DAAO) catalyzes the oxidation of d-amino acids including d-serine, a coagonist of the N-methyl-d-aspartate receptor. We identified a series of 4-hydroxypyridazin-3(2H)-one derivatives as novel DAAO inhibitors with high potency and substantial cell permeability using fragment-based drug design. Comparisons of complex structures deposited in the Protein Data Bank as well as those determined with in-house fragment hits revealed that a hydrophobic subpocket was formed perpendicular to the flavin ring by flipping Tyr224 in a ligand-dependent manner. We investigated the ability of the initial fragment hit, 3-hydroxy-pyridine-2(1H)-one, to fill this subpocket with the aid of complex structure information. 3-Hydroxy-5-(2-phenylethyl)pyridine-2(1H)-one exhibited the predicted binding mode and demonstrated high inhibitory activity for human DAAO in enzyme- and cell-based assays. We further designed and synthesized 4-hydroxypyridazin-3(2H)-one derivatives, which are equivalent to the 3-hydroxy-pyridine-2(1H)-one series but lack cell toxicity. 6-[2-(3,5-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one was found to be effective against MK-801-induced cognitive deficit in the Y-maze.
MeSH term(s)	Animals ; D-Amino-Acid Oxidase/antagonists & inhibitors ; D-Amino-Acid Oxidase/chemistry ; Dizocilpine Maleate/pharmacology ; Drug Evaluation, Preclinical ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/metabolism ; Enzyme Inhibitors/pharmacology ; HEK293 Cells ; Humans ; Male ; Maze Learning/drug effects ; Maze Learning/physiology ; Memory/drug effects ; Mice ; Models, Molecular ; Permeability ; Protein Conformation ; Pyridazines/chemical synthesis ; Pyridazines/chemistry ; Pyridazines/metabolism ; Pyridazines/pharmacology ; Structure-Activity Relationship
Chemical Substances	Enzyme Inhibitors ; Pyridazines ; pyridazine (449GLA0653) ; Dizocilpine Maleate (6LR8C1B66Q) ; D-Amino-Acid Oxidase (EC 1.4.3.3)
Language	English
Publishing date	2013-05-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/jm400095b
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