6 research outputs found
Lipocalin function of E.coli zinT (yodA) protein.
Get PDF重金属やアミトロール(AT)で発現誘導され、大腸菌ストレス応答タンパク質の一種であるzinT (yodA)は、一次構造比較やX線結晶構造解析による三次元立体構造などから、C末端領域に金属結合部位を持つこと、ABC transporter やlipocalinファミリーと一部相同なアミノ酸配列を持つことが明らかとなっているが、zinTの金属以外の低分子結合能については報告がない。そこで本研究では、大腸菌zinTタンパク質の種々の物質との結合能を、野生型zinTおよびN末端22残基欠損体(ΔN22)を用いて検討した。
まず、zinTの分子内TyrまたはTrp蛍光を指標として、種々の物質を添加に伴う蛍光強度の減少を測定した。低分子化合物としては、(1)ATおよびdNTP(2) 脂肪酸および脂質5種、(3) 複素式化合物3種、(4)芳香族化合物3種を検討し、zinTに対しそれぞれ添加し、30℃、10分間保温後、蛍光スペクトルを測定した。その結果、化合物添加によりzinTの最大蛍光強度は濃度依存的に減少し、特にdNTP, Qurcetinおよび8-ANSで顕著に見られた。また、野生型とΔN22において、蛍光減少の濃度依存性に顕著な差異は見られなかった。以上より、zinTは疎水性低分子化合物結合能(lipocalin活性)を有し、N末端領域のlipocalin活性に対する寄与は少ないことが明らかとなった
Discovery of Novel Pyrazole-Based Selective Aldosterone Synthase (CYP11B2) Inhibitors: A New Template to Coordinate the Heme-Iron Motif of CYP11B2
No full textIt
is necessary for aldosterone synthase (CYP11B2) inhibitors to
have both high potency and high selectivity over 11β-hydroxylase
(CYP11B1), a critical enzyme for cortisol synthesis. Previous studies
have reported a number of CYP11B2 inhibitors, most of which have an
imidazole or pyridine ring to coordinate the heme-iron motif of CYP11B2;
however, highly selective inhibitors of human CYP11B2 are still needed.
To expand the selectivity in humans, we explored alternative templates
and found that pyrazoles were suitable templates for CYP11B2 inhibitors.
Investigation of pyrazoles, especially <i>N-</i>alkyl pyrazoles,
as a new template to coordinate the heme-iron motif led to a potent
and highly selective CYP11B2 inhibitor <b>28</b> with an aldosterone-lowering
effect at 1 mg/kg dosing in cynomolgus monkeys
Discovery of Novel Pyrazole-Based Selective Aldosterone Synthase (CYP11B2) Inhibitors: A New Template to Coordinate the Heme-Iron Motif of CYP11B2
No full textIt
is necessary for aldosterone synthase (CYP11B2) inhibitors to
have both high potency and high selectivity over 11β-hydroxylase
(CYP11B1), a critical enzyme for cortisol synthesis. Previous studies
have reported a number of CYP11B2 inhibitors, most of which have an
imidazole or pyridine ring to coordinate the heme-iron motif of CYP11B2;
however, highly selective inhibitors of human CYP11B2 are still needed.
To expand the selectivity in humans, we explored alternative templates
and found that pyrazoles were suitable templates for CYP11B2 inhibitors.
Investigation of pyrazoles, especially <i>N-</i>alkyl pyrazoles,
as a new template to coordinate the heme-iron motif led to a potent
and highly selective CYP11B2 inhibitor <b>28</b> with an aldosterone-lowering
effect at 1 mg/kg dosing in cynomolgus monkeys
