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J. Biol. Chem., Vol. 277, Issue 15, 12632-12641, April 12, 2002
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From the Silent information regulator 2 (Sir2) family of
enzymes has been implicated in many cellular processes that include
histone deacetylation, gene silencing, chromosomal stability, and
aging. Yeast Sir2 and several homologues have been shown to be
NAD+-dependent histone/protein
deacetylases. Previously, it was demonstrated that the yeast enzymes
catalyze a unique reaction mechanism in which the cleavage of
NAD+ and the deacetylation of substrate are coupled with
the formation of O-acetyl-ADP-ribose, a novel metabolite.
We demonstrate that the production of O-acetyl-ADP-ribose
is evolutionarily conserved among Sir2-like enzymes from yeast,
Drosophila, and human. Also, endogenous yeast Sir2 complex
from telomeres was shown to generate O-acetyl-ADP-ribose.
By using a quantitative microinjection assay to examine the possible
biological function(s) of this newly discovered metabolite, we
demonstrate that O-acetyl-ADP-ribose causes a delay/block in oocyte maturation and results in a delay/block in embryo cell division in blastomeres. This effect was mimicked by injection of low
nanomolar levels of active enzyme but not with a catalytically impaired
mutant, indicating that the enzymatic activity is essential for the
observed effects. In cell-free oocyte extracts, we demonstrate the
existence of cellular enzymes that can efficiently utilize O-acetyl-ADP-ribose.
Conserved Enzymatic Production and Biological Effect
of O-Acetyl-ADP-ribose by Silent Information Regulator
2-like NAD+-dependent Deacetylases*
,,
,,**
Department of Biochemistry and Molecular
Biology, Oregon Health and Sciences University,
Portland, Oregon 97201-3098, the § Department of
Molecular, Cellular, and Developmental Biology and the Marine
Science Institute, University of California,
Santa Barbara, California 93106, and the Gladstone
Institute of Virology and Immunology, University of California,
San Francisco, California 94141-9100
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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