X-ray crystal structure and binding mode analysis of human S-adenosylhomocysteine hydrolase complexed with novel mechanism-based inhibitors, haloneplanocin A analogues

Kang Man Lee, Won Jun Choi, Yoonji Lee, Hyun Joo Lee, Long Xuan Zhao, Hyuk Woo Lee, Jae Gyu Park, Hea Ok Kim, Kwang Yeon Hwang, Yong Seok Heo, Sun Choi, Lak Shin Jeong

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

The X-ray crystal structure of human S-adenosylhomocysteine (AdoHcy) hydrolase was first determined as a tetrameric form bound with the novel mechanism-based inhibitor fluoroneplanocin A (4b). The crystallized enzyme complex showed the closed conformation and turned out to be the intermediate of mechanism-based inhibition. It confirmed that the cofactor depletion by 3′-oxidation of fluoroneplanocin A contributes to the enzyme inhibition along with the irreversible covalent modification of AdoHcy hydrolase. In addition, a series of haloneplanocin A analogues (4b-e and 5b-e) were designed and synthesized to characterize the binding role and reactivity of the halogen substituents and the 4′-CH2OH group. The biological evaluation and molecular modeling studies identified the key pharmacophores and structural requirements for the inhibitor binding of AdoHcy hydrolase. The inhibitory activity was decreased as the size of the halogen atom increased and/or if the 4′-CH2OH group was absent. These results could be utilized to design new therapeutic agents operating via AdoHcy hydrolase inhibition.

Original languageEnglish (US)
Pages (from-to)930-938
Number of pages9
JournalJournal of Medicinal Chemistry
Volume54
Issue number4
DOIs
StatePublished - Feb 24 2011
Externally publishedYes

Fingerprint

Adenosylhomocysteinase
Hydrolases
Halogens
X-Rays
Enzymes
fluoroneplanocin A
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

X-ray crystal structure and binding mode analysis of human S-adenosylhomocysteine hydrolase complexed with novel mechanism-based inhibitors, haloneplanocin A analogues. / Lee, Kang Man; Choi, Won Jun; Lee, Yoonji; Lee, Hyun Joo; Zhao, Long Xuan; Lee, Hyuk Woo; Park, Jae Gyu; Kim, Hea Ok; Hwang, Kwang Yeon; Heo, Yong Seok; Choi, Sun; Jeong, Lak Shin.

In: Journal of Medicinal Chemistry, Vol. 54, No. 4, 24.02.2011, p. 930-938.

Research output: Contribution to journalArticle

Lee, Kang Man ; Choi, Won Jun ; Lee, Yoonji ; Lee, Hyun Joo ; Zhao, Long Xuan ; Lee, Hyuk Woo ; Park, Jae Gyu ; Kim, Hea Ok ; Hwang, Kwang Yeon ; Heo, Yong Seok ; Choi, Sun ; Jeong, Lak Shin. / X-ray crystal structure and binding mode analysis of human S-adenosylhomocysteine hydrolase complexed with novel mechanism-based inhibitors, haloneplanocin A analogues. In: Journal of Medicinal Chemistry. 2011 ; Vol. 54, No. 4. pp. 930-938.
@article{a7b5469511e0405ab9758fe7356e7475,
title = "X-ray crystal structure and binding mode analysis of human S-adenosylhomocysteine hydrolase complexed with novel mechanism-based inhibitors, haloneplanocin A analogues",
abstract = "The X-ray crystal structure of human S-adenosylhomocysteine (AdoHcy) hydrolase was first determined as a tetrameric form bound with the novel mechanism-based inhibitor fluoroneplanocin A (4b). The crystallized enzyme complex showed the closed conformation and turned out to be the intermediate of mechanism-based inhibition. It confirmed that the cofactor depletion by 3′-oxidation of fluoroneplanocin A contributes to the enzyme inhibition along with the irreversible covalent modification of AdoHcy hydrolase. In addition, a series of haloneplanocin A analogues (4b-e and 5b-e) were designed and synthesized to characterize the binding role and reactivity of the halogen substituents and the 4′-CH2OH group. The biological evaluation and molecular modeling studies identified the key pharmacophores and structural requirements for the inhibitor binding of AdoHcy hydrolase. The inhibitory activity was decreased as the size of the halogen atom increased and/or if the 4′-CH2OH group was absent. These results could be utilized to design new therapeutic agents operating via AdoHcy hydrolase inhibition.",
author = "Lee, {Kang Man} and Choi, {Won Jun} and Yoonji Lee and Lee, {Hyun Joo} and Zhao, {Long Xuan} and Lee, {Hyuk Woo} and Park, {Jae Gyu} and Kim, {Hea Ok} and Hwang, {Kwang Yeon} and Heo, {Yong Seok} and Sun Choi and Jeong, {Lak Shin}",
year = "2011",
month = "2",
day = "24",
doi = "10.1021/jm1010836",
language = "English (US)",
volume = "54",
pages = "930--938",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "4",

}

TY - JOUR

T1 - X-ray crystal structure and binding mode analysis of human S-adenosylhomocysteine hydrolase complexed with novel mechanism-based inhibitors, haloneplanocin A analogues

AU - Lee, Kang Man

AU - Choi, Won Jun

AU - Lee, Yoonji

AU - Lee, Hyun Joo

AU - Zhao, Long Xuan

AU - Lee, Hyuk Woo

AU - Park, Jae Gyu

AU - Kim, Hea Ok

AU - Hwang, Kwang Yeon

AU - Heo, Yong Seok

AU - Choi, Sun

AU - Jeong, Lak Shin

PY - 2011/2/24

Y1 - 2011/2/24

N2 - The X-ray crystal structure of human S-adenosylhomocysteine (AdoHcy) hydrolase was first determined as a tetrameric form bound with the novel mechanism-based inhibitor fluoroneplanocin A (4b). The crystallized enzyme complex showed the closed conformation and turned out to be the intermediate of mechanism-based inhibition. It confirmed that the cofactor depletion by 3′-oxidation of fluoroneplanocin A contributes to the enzyme inhibition along with the irreversible covalent modification of AdoHcy hydrolase. In addition, a series of haloneplanocin A analogues (4b-e and 5b-e) were designed and synthesized to characterize the binding role and reactivity of the halogen substituents and the 4′-CH2OH group. The biological evaluation and molecular modeling studies identified the key pharmacophores and structural requirements for the inhibitor binding of AdoHcy hydrolase. The inhibitory activity was decreased as the size of the halogen atom increased and/or if the 4′-CH2OH group was absent. These results could be utilized to design new therapeutic agents operating via AdoHcy hydrolase inhibition.

AB - The X-ray crystal structure of human S-adenosylhomocysteine (AdoHcy) hydrolase was first determined as a tetrameric form bound with the novel mechanism-based inhibitor fluoroneplanocin A (4b). The crystallized enzyme complex showed the closed conformation and turned out to be the intermediate of mechanism-based inhibition. It confirmed that the cofactor depletion by 3′-oxidation of fluoroneplanocin A contributes to the enzyme inhibition along with the irreversible covalent modification of AdoHcy hydrolase. In addition, a series of haloneplanocin A analogues (4b-e and 5b-e) were designed and synthesized to characterize the binding role and reactivity of the halogen substituents and the 4′-CH2OH group. The biological evaluation and molecular modeling studies identified the key pharmacophores and structural requirements for the inhibitor binding of AdoHcy hydrolase. The inhibitory activity was decreased as the size of the halogen atom increased and/or if the 4′-CH2OH group was absent. These results could be utilized to design new therapeutic agents operating via AdoHcy hydrolase inhibition.

UR - http://www.scopus.com/inward/record.url?scp=79951844831&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79951844831&partnerID=8YFLogxK

U2 - 10.1021/jm1010836

DO - 10.1021/jm1010836

M3 - Article

C2 - 21226494

AN - SCOPUS:79951844831

VL - 54

SP - 930

EP - 938

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 4

ER -