Document Detail

Natural product juglone targets three key enzymes from Helicobacter pylori: inhibition assay with crystal structure characterization.
MedLine Citation:
PMID:  18565285     Owner:  NLM     Status:  MEDLINE    
AIM: To investigate the inhibition features of the natural product juglone (5- hydroxy-1,4-naphthoquinone) against the three key enzymes from Helicobacter pylori (cystathionine gamma-synthase [HpCGS], malonyl-CoA:acyl carrier protein transacylase [HpFabD], and beta-hydroxyacyl-ACP dehydratase [HpFabZ]). METHODS: An enzyme inhibition assay against HpCGS was carried out by using a continuous coupled spectrophotometric assay approach. The inhibition assay of HpFabD was performed based on the alpha-ketoglutarate dehydrogenase-coupled system, while the inhibition assay for HpFabZ was monitored by detecting the decrease in absorbance at 260 nm with crotonoyl-CoA conversion to beta -hydroxybutyryl-CoA. The juglone/FabZ complex crystal was obtained by soaking juglone into the HpFabZ crystal, and the X-ray crystal structure of the complex was analyzed by molecular replacement approach. RESULTS: Juglone was shown to potently inhibit HpCGS, HpFabD, and HpFabZ with the half maximal inhibitory concentration IC50 values of 7.0 +/-0.7, 20 +/-1, and 30 +/-4 micromol/L, respectively. An inhibition-type study indicated that juglone was a non-competitive inhibitor of HpCGS against O-succinyl- L-homoserine (Ki=alphaKi=24 micromol/L), an uncompetitive inhibitor of HpFabD against malonyl-CoA (alphaKi=7.4 micromol/L), and a competitive inhibitor of HpFabZ against crotonoyl-CoA (Ki=6.8 micromol/L). Moreover, the crystal structure of the HpFabZ/juglone complex further revealed the essential binding pattern of juglone against HpFabZ at the atomic level. CONCLUSION: HpCGS, HpFabD, and HpFabZ are potential targets of juglone.
Yun-hua Kong; Liang Zhang; Zheng-yi Yang; Cong Han; Li-hong Hu; Hua-liang Jiang; Xu Shen
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Acta pharmacologica Sinica     Volume:  29     ISSN:  1745-7254     ISO Abbreviation:  Acta Pharmacol. Sin.     Publication Date:  2008 Jul 
Date Detail:
Created Date:  2008-06-20     Completed Date:  2009-05-15     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100956087     Medline TA:  Acta Pharmacol Sin     Country:  China    
Other Details:
Languages:  eng     Pagination:  870-6     Citation Subset:  IM    
Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
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MeSH Terms
Enzyme Inhibitors / chemistry,  pharmacology*
Helicobacter pylori / drug effects,  enzymology*
Naphthoquinones / chemistry,  pharmacology*
Protein Conformation
X-Ray Diffraction
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Naphthoquinones; 481-39-0/juglone

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