4BHF

Three dimensional structure of human gamma-butyrobetaine hydroxylase in complex with 4-(Trimethylammonio)pentanoate

4BHF の概要

• エントリーDOI: 10.2210/pdb4bhf/pdb
• 関連するPDBエントリー: 4BG1 4BGK 4BGM 4BHI 4C5W
• 分子名称: GAMMA-BUTYROBETAINE DIOXYGENASE, N-OXALYLGLYCINE, 4-(Trimethylammonio)pentanoic acid, ... (6 entities in total)
• 機能のキーワード: oxidoreductase, inhibitor
• 由来する生物種: HOMO SAPIENS (HUMAN)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 45460.03

構造登録者

Tars, K.,Leitans, J.,Kazaks, A. (登録日: 2013-04-02, 公開日: 2014-03-12, 最終更新日: 2023-12-20)

主引用文献

Tars, K.,Leitans, J.,Kazaks, A.,Zelencova, D.,Liepinsh, E.,Kuka, J.,Makrecka, M.,Lola, D.,Andrianovs, V.,Gustina, D.,Grinberga, S.,Liepinsh, E.,Kalvinsh, I.,Dambrova, M.,Loza, E.,Pugovics, O.
Targeting Carnitine Biosynthesis: Discovery of New Inhibitors Against Gamma-Butyrobetaine Hydroxylase.
J.Med.Chem., 57:2213-, 2014

PubMed Abstract: γ-Butyrobetaine hydroxylase (BBOX) catalyzes the conversion of gamma butyrobetaine (GBB) to l-carnitine, which is involved in the generation of metabolic energy from long-chain fatty acids. BBOX inhibitor 3-(1,1,1-trimethylhydrazin-1-ium-2-yl)propanoate (mildronate), which is an approved, clinically used cardioprotective drug, is a relatively poor BBOX inhibitor and requires high daily doses. In this paper we describe the design, synthesis, and properties of 51 compounds, which include both GBB and mildronate analogues. We have discovered novel BBOX inhibitors with improved IC50 values; the best examples are in the nanomolar range and about 2 orders of magnitude better when compared to mildronate. For six inhibitors, crystal structures in complex with BBOX have been solved to explain their activities and pave the way for further inhibitor design.

PubMed: 24571165
DOI: 10.1021/JM401603E

実験手法

X-RAY DIFFRACTION (2.05 Å)