100
chapter
6
Enzymes I: General Properties, Kinetics, and Inhibition
A nionic
.H istidine S erin e.
site
E steratic site
A cety lch o lin estera se
A cetylch olin e
C holin e
HaC
.CH,
n
JCT
'CH2
'C,
CH,
H3C
CH,
'CH3
v y
ft— H
E n zy m e-su b stra te
in term ed iate
A cety la ted
e n z y m e
A cetic acid
HO—C"
CH3
+HjO
R eg en er a ted
e n z y m e
FIGURE 6-9
Hydrolysis of acetylcholine by acetylcholinesterase.
cause tissue hypoxia by binding to the trivalent iron of
cytochrome oxidase, a terminal component of the mito-
chondrial electron transport chain. This chain consists of
electron-transferring proteins and other carriers arranged
sequentially in the inner mitochondrial membrane. The
reducing equivalents, obtained from a variety of sub-
strates, are passed through the electron transport system to
molecular oxygen with the formation of water and energy
(Chapter 14). Thus, cyanide severely impairs the normal
energy-generating functions of mitochondria by inhibition
of mitochondrial respiration, leading to cell death, partic-
ularly affecting the central nervous system. Death in acute
cyanide poisoning is due to respiratory failure.
Cytochrome oxidase is a multienzyme complex that
contains oxidation-reduction centers of iron-porphyrin
prosthetic groups as well as centers of copper ion. Cyanide
has a higher affinity for the oxidized form of cytochrome
oxidase than for the reduced form. CN“ probably forms
a loose complex with Fe2+ of porphyrin. When Fe2+ is
oxidized to Fe3+, the latter forms a stable complex with
CN“ . This complex cannot be reduced, thus preventing
electron flow and uptake of O
2
.
Cyanide and cyanide precursors occur widely in nature.
Foods that contain moderate to high levels of cyanogenic
glycosides include cassava (a dietary staple in several re-
gions of Africa), kernels of some fruits (peach, cherry,
plum, and apricot), lima beans, sorghum, linseed, sweet
potato, maize, millet, and bamboo shoots.
Amygdalin
(Figure 6-11) is one of the principal cyanogenic glyco-
sides of dietary origin. Hydrogen cyanide is released when
amygdalin undergoes enzymatic hydrolysis in the gas-
trointestinal tract:
C 2o H 27N O n + 2 H 2
2 C 6H , 20 6 + C 6H 5C H O
Amygdalin
Glucose
Benzaldehyde
+
H C N
Hydrogen cyanide
The toxicity of amygdalin is directly related to the re-
lease of hydrogen cyanide. The enzymes that catalyze
the hydrolysis of amygdalin are supplied by the micro-
bial flora of the intestine, which probably explains why
amygdalin is many times more toxic when taken by mouth
than when given intravenously. Amygdalin and the related
compound
laetrile
have been at the center of a controversy
regarding their efficacy as anticancer agents. Their anti-
cancer activity is claimed to depend on selective hydroly-
sis at the tumor site by ^-glucuronidase or /3-glucosidase,
with local release of HCN to cause cell death. Presumably
