Clearer views of the cell’s
movers and shakers
threaten a century-old
mainstay of biology
By Lisa Grossman
In some ways, cells are a lot like cities. Maps of a cell’s innards depict thor- oughfares linking factories that build large molecules to post offices
where those molecules are packaged
up and shipped out, for example. The
cell’s denizens—proteins and other
molecules— shuttle around busy cellular byways like people on the street,
meeting up, interacting and keeping the
whole enterprise going.
But anyone who has ever been delayed
on the way to an important meeting
knows something about cities that biochemists are just beginning to learn
about cells: Maps don’t capture a lot of
details — traffic, closed roads, a downed
tree — that can drastically slow a journey.
FACING PAGE: PHOTO: PEDRO SALAVERRÍA/SHUTTERSTOCK; MOLECULE: M. ALVARO-BENITO ET AL./J. BIOL. CHEM. 2010;
PHOTO ILLUSTRATION: T. DUBÉ; THIS PAGE, FROM TOP: K. BLANK, PYMOL; T. DUBÉ
For almost a century, biologists trying
to describe cells’ inner workings have
assumed that the differences between
map and street didn’t matter. That has
been especially true for studies of the
cell’s go-to, workhorse proteins called
enzymes, which orchestrate the majority of the chemical reactions necessary
for life. A revered textbook formula that
describes how these crucial molecular catalysts speed up reactions, the
Michaelis-Menten equation, assumes
that enzymes don’t usually get stuck in
traffic. Enzymes are supposed to meet
other molecules at regular intervals and
do their transactions at a constant speed,
more like workers on an assembly line
than urban pedestrians.
In most laboratory experiments,
researchers make sure that molecules
can move freely and interact often, so
the classic formula seems to work well.
But lab experiments don’t reflect the
inner lives of cells. And the differences
could dethrone the venerable equation.
Because of the crowds, in a cell it’s
more difficult for enzymes to find their
partner molecules
than it is in a test
tube, biophysicist
Ramon Grima of the
University of Edinburgh
recently showed. Another
study noted that individual
cells can have different numbers
of enzymes — even when the cells
are otherwise identical. Combined,
the new results could mean models of
enzyme kinetics based on the Michaelis-Menten equation are wrong.
“It’s a system that people thought
they had understood for 100 years,” says
enzymologist Kerstin Blank of Radboud
University in Nijmegen, the Netherlands.
“Now we get some new information that,
a little bit, turns everything upside down.”
When scientists model the chemistry
in a cell, Michaelis-Menten is the default
equation for enzymes. “It has a broad
impact,” Grima says. “Given any biochem-
ical pathway, you’ll always find that at the
backbone of the pathway you will have
a few enzymes. When you’re modeling
that enzyme, you will naturally assume a
Michaelis-Menten equation for it.”
By zooming in to the street view, sci-
entists hope that they can draw a more
accurate map of the cellular city. Experi-
mental methods for watching enzymes
in cells aren’t yet good enough to see how
important variations in these chemical
reaction speeds actually are. But if it
turns out that the Michaelis-Menten
equation doesn’t accurately predict
how fast enzymes work in living cells, it
could change everything from introduc-
tory biochemistry classes to strategies
for cancer treatments.
Shape-shifting
enzymes like CalB
are revealing the
role of form in
reaction speeds.
Far from being discouraged about having to rewrite their textbooks, though,
scientists are now dreaming about how
to use this newfound knowledge to engineer new drugs or biofuels. “Ultimately,”
says Nathan Price of the University of
Illinois at Urbana-Champaign, “you want
to understand those processes so you can
control them.”
Shape-shifting enzymes
Enzymes make the cellular city run on
time. Reactions that would take more
than 300 years unassisted can take about
a second when an enzyme steps in. By
embracing a specific partner molecule,
called the substrate, and morphing it
into something new, enzymes enable
everything from transcribing DNA to
digesting food to generating light in
fireflies. So understanding how enzymes
work is crucial for understanding how
cells work — and for manipulating them.
When Leonor Michaelis and Maud
Menten published their now-famous
paper in Biochemische Zeitschrift in 1913,
watching an individual enzyme at work
was impossible. To figure out how quickly
enzymes help transform neighboring
molecules from one form to another, the
duo had to make do with analyzing test
tubes full of billions of molecules.
Michaelis and Menten focused on the
enzyme invertase, which helps break
down sucrose, ordinary table sugar. If
Substrate Products of reaction
Lowering the energy Enzymes make reactions in the body go, and go fast, by permitting them
to proceed with less energy input than would otherwise be needed. The substrate molecule is held
by weak forces, such as hydrogen bonds, in a suitably shaped active pocket in the enzyme. This facilitates the conversion of substrate into products, which are then released without using up the enzyme.
