2H5L

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

Summary for 2H5L

• Entry DOI: 10.2210/pdb2h5l/pdb
• Descriptor: Adenosylhomocysteinase, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, (2R,3R)-4-(4-AMINO-1H-IMIDAZO[4,5-C]PYRIDIN-1-YL)-2,3-DIHYDROXYBUTANOIC ACID, ... (4 entities in total)
• Functional Keywords: s-adenosylhomocysteine, hydrolase, inhibitor, hypocholesterolemic activity
• Biological source: Rattus norvegicus (Norway rat)
• Cellular location: Cytoplasm: P10760
• Total number of polymer chains: 8
• Total formula weight: 387050.90

Authors

Yamada, T.,Komoto, J.,Takusagawa, F. (deposition date: 2006-05-26, release date: 2007-04-10, Last modification date: 2024-02-14)

Primary citation

Yamada, T.,Komoto, J.,Lou, K.,Ueki, A.,Hua, D.H.,Sugiyama, K.,Takata, Y.,Ogawa, H.,Takusagawa, F.
Structure and function of eritadenine and its 3-deaza analogues: Potent inhibitors of S-adenosylhomocysteine hydrolase and hypocholesterolemic agents.
Biochem.Pharm., 73:981-989, 2007

PubMed Abstract: 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.

PubMed: 17214973
DOI: 10.1016/j.bcp.2006.12.014

Experimental method

X-RAY DIFFRACTION (2.8 Å)