2h5l

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(New page: 200px<br /><applet load="2h5l" size="450" color="white" frame="true" align="right" spinBox="true" caption="2h5l, resolution 2.8&Aring;" /> '''S-Adenosylhomocystein...)
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Revision as of 09:25, 21 November 2007


2h5l, resolution 2.8Å

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S-Adenosylhomocysteine hydrolase containing NAD and 3-deaza-D-eritadenine

Overview

d-Eritadenine (DEA) is a potent inhibitor of S-adenosyl-l-homocysteine, hydrolase (SAHH) and has hypocholesterolemic activity. We have, hypothesized that 3-deaza-DEA (C3-DEA) and its analogues retain high level, of SAHH inhibitory activity and have resistance to deamination and, glycosidic bond hydrolysis in vivo. Such C3-DEA analogues would have much, higher hypocholesterolemic activity. C3-DEA, and its methyl ester, (C3-OMeDEA) and its methyl amido (C3-NMeDEA) were synthesized to examine, their SAHH inhibitory and hypocholesterolemic activities. A crystal, structure of SAHH containing C3-DEA was determined and confirmed that DEA, and C3-DEA bound to the same site of SAHH with the same binding mode. The, SAHH inhibitory activities of C3-DEA (K(I)=1.5 microM) and C3-OMeDEA, (K(I)=1.5 microM) are significantly lower than that of DEA (K(I)=30 nM), while rats fed by C3-DEA and C3-OMeDEA decrease the total plasma, cholesterol and phospholipids by 36-40% and 23%, respectively, which is, similar to the level of reductions (42% and 27%) by DEA. C3-NMeDEA lost, most of the SAHH inhibitory activity (K(I)=30 microM) and dietary, C3-NMeDEA does not decrease cholesterol and phospholipid in plasma but, decreases the triacylglycerol level by 16%. DEA and C3-DEA analogues are, neither substrates nor inhibitors of adenosine deaminase.

About this Structure

2H5L is a Single protein structure of sequence from Rattus norvegicus with NAD and 3DD as ligands. Active as Adenosylhomocysteinase, with EC number 3.3.1.1 Full crystallographic information is available from OCA.

Reference

Structure and function of eritadenine and its 3-deaza analogues: potent inhibitors of S-adenosylhomocysteine hydrolase and hypocholesterolemic agents., Yamada T, Komoto J, Lou K, Ueki A, Hua DH, Sugiyama K, Takata Y, Ogawa H, Takusagawa F, Biochem Pharmacol. 2007 Apr 1;73(7):981-9. Epub 2006 Dec 14. PMID:17214973

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