Structure and function of eritadenine and its 3-deaza analogues: Potent inhibitors of S-adenosylhomocysteine hydrolase and hypocholesterolemic agents

Taro Yamada; Junichi Komoto; Kaiyan Lou; Akiharu Ueki; Duy H Hua; Kimio Sugiyama; Yoshimi Takata; Hirofumi Ogawa; Fusao Takusagawa

doi:10.1016/j.bcp.2006.12.014

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Structure and function of eritadenine and its 3-deaza analogues: Potent inhibitors of S-adenosylhomocysteine hydrolase and hypocholesterolemic agents

Journal article

Peer reviewed

Structure and function of eritadenine and its 3-deaza analogues: Potent inhibitors of S-adenosylhomocysteine hydrolase and hypocholesterolemic agents

Taro Yamada, Junichi Komoto, Kaiyan Lou, Akiharu Ueki, Duy H Hua, Kimio Sugiyama, Yoshimi Takata, Hirofumi Ogawa and Fusao Takusagawa

Biochemical pharmacology, Vol.73(7), pp.981-989

04/01/2007

DOI: 10.1016/j.bcp.2006.12.014

PMID: 17214973

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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 (KI=1.5μM) and C3-OMeDEA (KI=1.5μM) are significantly lower than that of DEA (KI=30nM), 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 (KI=30μM) 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.

Chemical Synthesis

Enzyme inhibition

Cholesterol reduction

Eritadenine

S-Adenosylhomocysteine hydrolase

3-Deaza analogue

Details

Title: Subtitle: Structure and function of eritadenine and its 3-deaza analogues: Potent inhibitors of S-adenosylhomocysteine hydrolase and hypocholesterolemic agents
Creators: Taro Yamada - Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Avenue, Lawrence, KS 66045, USA
Junichi Komoto - Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Avenue, Lawrence, KS 66045, USA
Kaiyan Lou - Department of Chemistry, Kansas State University, 111 Willard Hall, Manhattan, KS 66506-3701, USA
Akiharu Ueki - Department of Chemistry, Kansas State University, 111 Willard Hall, Manhattan, KS 66506-3701, USA
Duy H Hua - Department of Chemistry, Kansas State University, 111 Willard Hall, Manhattan, KS 66506-3701, USA
Kimio Sugiyama - Department of Applied Biological Chemistry, Faculty of Agriculture, Shizuoka University, Shizuoka 422-8529, Japan
Yoshimi Takata - Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Avenue, Lawrence, KS 66045, USA
Hirofumi Ogawa - Department of Molecular Neuroscience, Graduate School of Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan
Fusao Takusagawa - Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Avenue, Lawrence, KS 66045, USA
Resource Type: Journal article
Publication Details: Biochemical pharmacology, Vol.73(7), pp.981-989
Publisher: Elsevier Inc
DOI: 10.1016/j.bcp.2006.12.014
PMID: 17214973
ISSN: 0006-2952
eISSN: 1873-2968
Language: English
Date published: 04/01/2007
Academic Unit: Neurology
Record Identifier: 9984020724802771

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