John Denu:
The Importance of
Reversible Protein
Acetylation
BY NICK ZAGORSKI
Protein phosphorylation is
unquestionably a critical cellular process, but the focus given
to the attachment and removal of
phosphate groups from proteins
sometimes leaves the impression that
it’s the be-all and end-all method
of regulating proteins. However, an
abundance of reversible chemical
modifications for proteins exist, each
serving their own purpose in carefully controlling the countless activities occurring inside cells.
One such emerging modification might be reversible acetylation
(not to be confused with irreversible
N-terminal acetylation that caps many
proteins during translation). True,
most researchers consider acetylation
an important event, but typically only
in relation to histones, the protein
spools that compact our DNA thread
into form-fitting chromatin. Altering the pattern of acetyl groups can
change which portions of chromatin are exposed to DNA-binding
proteins, making them essential for
proper gene expression, replication,
and repair.
“But there’s so much more to
acetylation than one protein class,”
says John Denu, Professor of Biomo-lecular Chemistry at the University
of Wisconsin-Madison School of
Medicine and Public Health. “And
only recently have we gained a greater
appreciation for this modification.” A
goodly amount of credit for this new
appreciation stems
from the work of
Denu, who switched
over from the bustling phosphorylation
field to work on this
“other” modification.
Through his studies, we’ve found
that proteins throughout a cell—
nucleus, cytoplasm, even mitochondria—can be modified by acetylation
and learned more about the sirtuins,
proteins whose deacetylation of
metabolic enzymes might hold the
key to a longer life span. He’s also
begun to branch out to other modifications, examining how all of them
come together to form the enigmatic
“histone code.”
Denu
Here’s Looking
at You, Kid
Denu has always been interested
in the living world; a large part of
that stemmed from his upbringing
in the southern Wisconsin town of
Beloit. His house backed along a
wooded creek, which, better than any
large screen TV, gave Denu a firsthand glimpse into the wonders of
nature. “I spent a lot of time as a kid
in my backyard, just observing the
creatures and other natural events.”
As he grew a bit older, he shifted
his wonder to a deeper level, trying
to understand what elements were
behind all these natural things he had
been enamored by in his youth.
In high school and later college at Wisconsin, that reasoning
would lead Denu toward biochemistry,
and particularly enzymology. “I figured, to really satisfy my desire about
how biology works at the molecular
level, why not try and understand the
enzymes that carry out biology. To this
day the minute details about enzymatic processes still fascinate me.”
After completing his undergraduate biochemistry degree in 1988,
Denu moved on to Texas A&M
University for his doctorate. And if
you’re wondering what convinced a
small town Wisconsin boy to relocate
to Texas, he quotes one of his all-time
favorite movies, Casablanca: “I went
there for the waters,” Denu says in an
impressive Bogart tone. “I was misinformed.”
In all seriousness, Denu sought
to take advantage of his Ph.D. years.
“This was a prime opportunity for
me to get away, find a warm place to
study, and experience life in a different culture. And Texas certainly fit
that bill.” He notes that Texas A&M
also contained a large and strong
biochemistry department, giving him
plenty of options for his graduate
