94
chapter 6
Enzymes I: General Properties, Kinetics, and inhibition
TA B LE 6-2
Effects of Competitive Inhibitors on Km and Vmax (Michaelis-Menten Kinetic
Parameters)
Inhibitor Type
Vmax
Km
Competitive
None
(V
= V
)
v
maxann
max/
K mapp
K m( 1
+ K; y
Noncompetitive
1
+-
K:
None
<Km
= Km)
Uncompetitive
V
V„
1
+-
K;
K
K
=
niapp
1
+-
Note:
[E][I]
[ES][I]
[El]
°r
[ESI] '
In uncompetitive inhibition, the inhibitor binds equally well to E and ES.
reductase is competitively inhibited by methotrexate.
Since FH
4
is needed for the synthesis of DNA precur-
sors, a deficiency causes most harm to those cells which
synthesize DNA rapidly. Certain types of cancers (e.g.,
the leukemias) exhibit an extremely high rate of cell divi-
sion and are particularly susceptible to folate antagonists.
The reactions of one-carbon metabolism are discussed in
Chapter 27.
h
2
n-
N r
N p—h
fO -
0
COOH
^ C -C H 2-
Il
h
1
—C— N—C—CH
2
CH2COOH
1
MU
CH
3
Methotrexate
(4-amino-W'°-methyl folic acid)
OH
OH
Hypoxanthine
Allopurinol
Allopurinol inhibits the formation of xanthine and of uric
acid, catalyzed by xanthine oxidase, and is itself trans-
formed into alloxanthine by the enzyme. Alloxanthine
bears the same structural relationship to xanthine that al-
lopurinol does to hypoxanthine:
o h
o h
Inhibition of Xanthine Oxidase
Uric acid, the end
product of purine catabolism in humans, is formed by
the serial oxidation of hypoxanthine and of xanthine,
catalyzed by xanthine oxidase.
xanthine
xanthine
oxidase
oxidase
Hypoxanthine
— y
xanthine
— y
uric acid
Allopurinol, a structural analogue of hypoxanthine, is a
competitive inhibitor as well as a substrate for xanthine
oxidase:
Xanthine
Alloxanthine
Alloxanthine, however, remains tightly bound to the ac-
tive site of the enzyme by chelation with Mo4+. Since xan-
thine oxidase is a molybdenum-dependent enzyme whose
catalytic cycle requires the reversible oxidation and re-
duction of Mo4+ to Mo6+ (Chapter 27), the reoxidation
of Mo4+ to Mo6+ in the presence of alloxanthine is very
