| Evidence for inhibition of HIF-1α prolyl hydroxylase 3 activity by four biologically active tetraazamacrocycles. | |
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MedLine Citation:
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PMID: 22481471 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Hypoxia inducible factor 1 (HIF-1) is central to the hypoxic response in mammals. HIF-1α prolyl hydroxylase 3 (PHD3) degrades HIF through the hydroxylation of HIF-1α. Inhibition of PHD3 activity is crucial for up-regulating HIF-1α levels, thereby acting as HIF-dependent diseases therapy. Macrocyclic polyamines which display high stability on iron-chelating may well inhibit the enzyme activity. Thus inhibition and interaction on catalytic PHD3 by four biologically active tetraazamacrocycles (), which have two types of parent rings to chelate iron(ii) dissimilarly, were studied. The apparent IC(50) values of 2.56, 1.91, 5.29 and 2.44 μM, respectively, showed good inhibition potency of the four compounds. K(I) values were 7.86, 3.69, 1.59 and 2.92 μM for , respectively. Different inhibition actions of the two groups of compounds were identified. Circular dichroism (CD) and fluorescence spectrometries proved that one type of compound has significant effects on protein conformation while another type does not. Computational methodology was constructed to employ the equilibrium geometry of enzyme active site with the presence of substrate competitive inhibitor. Iron(ii) coordination in the active site by inhibitors of this kind induces conformational change of the enzyme and blocks substrate binding. |
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Authors:
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Jing Cao; Zhirong Geng; Xiaoyan Ma; Jinghan Wen; Yuxin Yin; Zhilin Wang |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-4-5 |
Journal Detail:
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Title: Organic & biomolecular chemistry Volume: - ISSN: 1477-0539 ISO Abbreviation: - Publication Date: 2012 Apr |
Date Detail:
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Created Date: 2012-4-6 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101154995 Medline TA: Org Biomol Chem Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, P. R. China. wangzl@nju.edu.cn. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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