Supplemental Readings and References
305
of biological molecules and inactivates
a
\-antitrypsin and
other protease inhibitors.
In the presence of metals, such as iron, hydrogen per-
oxide reacts with superoxide anion to produce hydroxyl
radicals (OH’) and singlet oxygen ('
0 2
) by the reaction
shown below:
0 2 + H 20 2 ^
‘0 2 + 0H “ + 0 H ’
Hydroxyl radicals are highly reactive, oxidizing a vari-
ety of biological molecules. Singlet oxygen, which has an
excited (high-energy) electronic configuration, can decay
spontaneously to 0 2 or interact with and oxidize some
other molecule. In either case, part of the energy of the
singlet state is emitted as light. This chemiluminescence,
like the respiratory burst, is characteristic of actively
phagocytic cells capable of killing microorganisms; it has
been used for evaluating the functional capacity of these
cells.
Persons with
chronic granulomatous disease
(CGD)
suffer from recurrent bacterial and fungal infections.
About 300 cases have been reported, of which about 80%
were inherited as an X-linked, and 20% as an autosomal,
recessive trait. CGD is actually a group of diseases caused
by lack of activation of NADPH oxidase due to an ab-
normality in the enzyme itself or in the activating sys-
tem. Phagocytes from CGD patients fail to show either
a respiratory burst or chemiluminescence. Chemotaxis,
recognition, engulfment, degranulation, and the presence
of enzymes of the pentose phosphate pathway are nor-
mal in the phagocytes from CGD patients. Many infec-
tions are caused by bacteria that make catalase. The small
amounts of hydrogen peroxide made in these organisms
are destroyed by this endogenous catalase. Bacteria that
lack catalase release small amounts of H20 2 into the
phagolysosome, where myeloperoxidase, the presence of
which is normal, can use it as a substrate to generate bacte-
ricidal products. Therapy of CGD involves prevention of
infections (e.g., by antibiotic prophylaxis) and treatment
of infections and their complications. A promising new
prophylactic agent is
y-interferon,
which is synthesized
by recombinant DNA technology. This agent, a cytokine,
alters the development of very early neutrophil precur-
sors and eventually leads to improvement in neutrophil
function.
Severe G6PD deficiency (<5% of normal; class I) may
cause a disease with symptoms similar to those of CGD,
together with nonspherocytic hemolytic anemia. This dis-
order occurs only rarely, however, because leukocytes have
a large excess of G6PD activity. In common G6PD de-
ficiency (G6PD A- ) the enzyme is produced in normal
amounts and is functionally normal. Although unstable,
the enzyme retains adequate activity during the lifetime
of the phagocyte to provide NADPH to support bacterici-
dal activity.
The oxidative intermediates produced in phagocytes
(O j, H20 2, '0 2, and OH’) are bactericidal
in vitro,
re-
acting readily with many biological molecules, including
DNA and membrane lipids. However, hypohalide ions and
hence the myeloperoxidase pathway are thought to be the
major source of bactericidal activity in phagocytes. All
of these highly reactive substances are potentially cyto-
toxic to phagocytes themselves and to surrounding tis-
sue, if leakage occurs. Protection against such an eventu-
ality is provided by glutathione, glutathione peroxidase,
and superoxide dismutase. Cytoplasmic (Cu/Zn) superox-
ide dismutase (SOD-1) and catalase can together convert
superoxide ion to oxygen and increase the bactericidal ca-
pacity of phagocytes under conditions in which oxygen
supply is limited. Disorders of cellular adhesion, chemo-
taxis, ingestion, and degranulation of phagocytes are also
known.
Supplemental Readings and References
M . Bollen, S. Keppens, and W. Stalm ans: Specific features o f glycogen
m etabolism in the liver.
B io ch e m ic a l J o u rn a l
336,
19 (1998).
X. C hen, N. Iqbal, and G. Boden: The effects o f free fatty acids on gluconeo-
genesis and glycogenolysis in norm al subjects.
T he J o u rn a l o f C lin ica l
In vestig a tio n
103,
365 (1999).
M . Denborough: M alignant hypertherm ia.
L a n c e t
352, 1131 (1998).
L. J. Elsas, S. Langley, E. Steele, et al.: G alactosem ia: A strategy to identify
new biochem ical phenotypes and m olecular genotypes.
A m e rica n Jo u rn a l
o f H u m a n G en etics
56,
630 (1995).
R. H alse, J. J. R ochford, J. G. M cCorm ack, et ah: C ontrol o f glycogen
synthesis in cultured hum an m uscle cells.
J o u rn a l o f B io lo g ica l C h em istry
274,
776(1999).
M . B. H am pton, A. J. Keftle, and C. C. W interbourn: Inside the N eutrophil
phagosom e: O xidants, m yeloperoxidase and bacterial killing.
B lo o d
92,
3007 (1998).
J. C. Law rence, Jr. and R J. Roach: N ew insights into the role and m echanism
o f G lycogen Synthase activation by insulin.
D ia b e te s
46,
541 (1997).
C. G. Proud and R. M . D enton: M olecular M echanism s for the control of
translation o f insulin.
B io ch e m ic a l J o u rn a l
328, 329 (1997).
L. R agolia and N. Begum : Protein phosphatase-1 and insulin action.
M o le c -
u la r a n d C ellu la r B io ch e m istry
182,
49 (1998).
A. K. Srivastava and S. K. Pandey: Potential m echanism (s) involved in the
regulation o f glycogen synthesis by insulin.
M o le c u la r a n d C ellu la r B io -
ch em istry
182,
135 (1998).
C. V illar-Palasi and J. J. Guinovart: The role o f glucose-6-phosphate in the
control o f glycogen synthase.
F A SE B J o u rn a l
11,
544 (1997).
