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M94B0800.TXT
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1994-11-11
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Document 0800
DOCN M94B0800
TI Effects of novel anti-viral adenosine analogues on the activity of
S-adenosylhomocysteine hydrolase from human liver.
DT 9412
AU Fabianowska-Majewska K; Duley JA; Simmonds HA; Purine Research
Laboratory, UMDS Guy's Hospital, London, U.K.
SO Biochem Pharmacol. 1994 Aug 30;48(5):897-903. Unique Identifier :
AIDSLINE MED/94380105
AB Some adenosine analogues have been found previously to inhibit
S-adenosylhomocysteine (SAH)-hydrolase activity in erythrocyte lysates.
In this study, the enzyme was purified 500-fold from human liver and its
M(r) found to be 190,000. Its kinetics in the synthase direction were
studied, the Km for adenosine being determined as 32 microM. Several
purine nucleoside analogues currently used in antitumour and antiviral
therapy were tested for their influence on SAH-hydrolase activity. The
results confirmed our previous findings for the unpurified human
erythrocyte enzyme, and demonstrated that the most potent inhibitors of
human liver SAH-hydrolase were neplanocin A, 7-deaza-adenosine
(tubercidin), 2'-deoxyadenosine, and 9-beta-D-arabino-furanosyladenine.
Analogues showing intermediate inhibition were 2'3'-dideoxyadenosine
(2'3'-ddAdo), 5'-deoxy-5'-methyl-thioadenosine, 3'-deoxy-adenosine,
2-chloroadenosine, 1,2,4-triazole-3-carboxamide riboside (ribavirin),
delta-adenosylornithine (sinefungin), S-adenosylmethionine,
5-amino-4-imidazole carboxamide riboside (AICAR), and
5'-iodo-5'-deoxyadenosine (5'I,5'-dAdo). Weak or no inhibition was noted
with 5'-deoxyadenosine, 5-hydroxyimidazole-4-carboxamideriboside
(bredinin), inosine and its deoxy analogues, and acyclovir. Our results
show that drugs such as 2'3'-dideoxyadenosine (used in HIV therapy) and
ribavirin (an inhibitor of inosinate dehydrogenase), in addition to
their other known mechanisms of action, have an inhibitory effect on
SAH-hydrolase activity, which may be of significance in their antiviral
action.
DE Adenosine/*ANALOGS & DERIVATIVES/PHARMACOLOGY Antiviral
Agents/*PHARMACOLOGY Human Hydrolases/*ANTAGONISTS & INHIB/ISOLATION &
PURIF Liver/*ENZYMOLOGY Structure-Activity Relationship Support,
Non-U.S. Gov't JOURNAL ARTICLE
SOURCE: National Library of Medicine. NOTICE: This material may be
protected by Copyright Law (Title 17, U.S.Code).