1 Background

When one inhibits glycolysis enzymes (say, LDH) with drugs (say, FX11), the
drugs usually do not have 100% specicity and may have unintended inhibition
on some other enzymes in the cell. The dierence between the glycolysis enzymes
and other enzymes is usually their concentration scales (glycolysis enzymes are
usually much more abundant other enzymes), but not their anities to the
drugs (we do not assume glycolysis enzymes attract drugs greater than other
enzymes).
2 Question
Given two enzymes E
1
, E
2
and one inhibitor I which would reversibly inhibit
E
1
and E
2
(forming complexes X
1
and X
2
, respectively), do the concentration
scales of the three chemical species aect the inhibition eects?
3 Notation
E
1
: concentration of free E
1
E
2
: concentration of free E
2
E
T
1
: total concentration of E
1
E
T
2
: total concentration of E
2
I: concentration of free I
I
T
: total concentration of I
X
1
: concentration of X
1
X
2
: concentration of X
2
4 Answer
If we quantify the inhibition eect of an enzyme by the proportion of the
inhibitor-bound enzyme copies out of the total enzyme copies, p
i
=
X
i
E
i
+ X
i
(i =
1, 2), then without any assumption on the concentration scales of the relevant
species, p
1
=
I
I + K
1
and p
2
=
I
I + K
2
, where K
i
=
E
i
I
X
i
are the dissociation
constants and I is the unique positive root of the cubic equation:
I
3
+(K
1
+K
2
+E
T
1
+E
T
2
I
T
)I
2
+(K
1
K
2
+E
T
1
K
2
+E
T
2
K
1
I
T
(K
1
+K
2
))II
T
K
1
K
2
= 0.
(1)
1
5 Derivations
5.1 Derivation of the boxed equations
K
i
=
E
i
I
X
i
X
i
=
E
i
I
K
i
.
So, p
i
=
X
i
E
i
+ X
i
=
Ei I
Ki
E
i
+
Ei I
Ki
=
I
I + K
i
.
5.2 Derivation of equation (1)
K
i
=
E
i
I
X
i
E
i
=
K
i
X
i
I
,
which, plugged into E
i
+ X
i
= E
T
i
, gets X
i
=
E
T
i
1 +
Ki
I
.
Finally, plugging X
i
s into X
1
+ X
2
+ I = I
T
one gets equation (1).
6 Discussions
1. The key reason why the derivation of the boxed equations holds: The de-
nition of dissociation constant K
i
=
E
i
I
X
i
is independent of the environment,
that is, no matter whether there are other chemical species that might re-
act with E
i
, X
i
or I in the system, when the system settles to equilibrium,
the concentration quotient
E
i
I
X
i
is always constant K
i
.
2. The boxed equations say that as long as K
1
and K
2
are similar in magni-
tude, p
1
and p
2
are going to be similar in magnitude; the comparison of
p
1
and p
2
would not depend on E
T
1
, E
T
2
and I
T
. E
T
1
, E
T
2
and I
T
might
aect the magnitudes of p
1
and p
2
through aecting I via equation (1),
but in the same way.
3. All the derivations and conclusions are conrmed by many simulations.
4. How E
T
1
, E
T
2
and I
T
aects I via equation (1) can be seen by the attached
images (K
1
= K
2
= I
T
= 1 used in the simulation).
7 Plots
2
Figure 1: Dependence of p
i
on E
T
1
and E
T
2
3
Figure 2: Dependence of q
1
on E
T
1
and E
T
2
(q
1
: the proportion of E
1
-bound I)
4
Figure 3: Dependence of q
2
on E
T
1
and E
T
2
(q
2
: the proportion of E
2
-bound I)
5