Introduction to Human Nutrition

(Sean Pound) #1

182 Introduction to Human Nutrition


substrate is linked to decarboxylation of 2-
oxoglutarate. Many of these enzymes are involved in
the modifi cation of precursor proteins to yield the
fi nal, mature, protein. This is a process of postsyn-
thetic modifi cation of an amino acid residue after it
has been incorporated into the protein during synthe-
sis on the ribosome.


● Proline and lysine hydroxylases are required for the
postsynthetic modifi cation of procollagen in the
formation of mature, insoluble, collagen, and
proline hydroxylase is also required for the post-
synthetic modifi cation of the precursor proteins
of osteocalcin and the C1q component of
complement.
● Aspartate β-hydroxylase is required for the postsyn-
thetic modifi cation of the precursor of protein C,
the vitamin K-dependent protease that hydrolyzes
activated factor V in the blood-clotting cascade.
● Trimethyl-lysine and γ-butyrobetaine hydroxylases
are required for the synthesis of carnitine.
Ascorbate is oxidized during the reaction of these
enzymes, but not stoichiometrically with the decar-
boxylation of 2-oxoglutarate and hydroxylation of the
substrate. The purifi ed enzyme is active in the absence
of ascorbate, but after some 5–10 s (about 15–30 cycles
of enzyme action) the rate of reaction begins to fall. At
this stage the iron in the catalytic site has been oxi-
dized to Fe^3 +, which is catalytically inactive; activity is
restored only by ascorbate, which reduces it back to
Fe^2 +. The oxidation of Fe^2 + is the consequence of a
side-reaction rather than the main reaction of the
enzyme, which explains how 15–30 cycles of enzyme
activity can occur before there is signifi cant loss of
activity in the absence of ascorbate, and why the con-
sumption of ascorbate is not stoichiometric.


Pro-oxidant and antioxidant roles of ascorbate
Ascorbate can act as a radical-trapping antioxidant,
reacting with superoxide and a proton to yield hydro-
gen peroxide, or with the hydroxy radical to yield
water. In each instance the product is the monodehy-
droascorbate radical. Thus, as well as reducing the
tocopheroxyl radical formed by interaction of
α-tocopherol in membranes with lipid peroxides,
ascorbate acts to trap the oxygen radicals that would
otherwise react to form lipid peroxides.
At high concentrations, ascorbate can reduce
molecular oxygen to superoxide, being oxidized to


monodehydroascorbate. At physiological concentra-
tions of ascorbate, both Fe^3 + and Cu^2 + ions are reduced
by ascorbate, yielding monodehydroascorbate. Fe^2 +
and Cu+ are readily reoxidized by reaction with hydro-
gen peroxide to yield hydroxide ions and hydroxyl
radicals. Cu+ also reacts with molecular oxygen to
yield superoxide. Thus, as well as its antioxidant role,
ascorbate has potential pro-oxidant activity. However,
because at high levels of intake the vitamin is excreted
quantitatively, is it unlikely that tissue concentrations
will rise high enough for there to be signifi cant for-
mation of oxygen radicals.

Vitamin C defi ciency: scurvy
The vitamin C defi ciency disease scurvy was formerly
a common problem at the end of winter, when there
had been no fresh fruit and vegetables for many
months.
Although there is no specifi c organ for storage of
vitamin C in the body, signs of defi ciency do not
develop in previously adequately nourished subjects
until they have been deprived of the vitamin for 4–6
months, by which time plasma and tissue concentra-
tions have fallen considerably. The earliest signs of
scurvy in volunteers maintained on a vitamin C-free
diet are skin changes, beginning with plugging of hair
follicles by horny material, followed by enlargement
of the hyperkeratotic follicles, and petechial hemor-
rhage with signifi cant extravasation of red cells, pre-
sumably as a result of the increased fragility of blood
capillaries.
At a later stage there is also hemorrhage of the
gums, beginning in the interdental papillae and pro-
gressing to generalized sponginess and bleeding. This
is frequently accompanied by secondary bacterial
infection and considerable withdrawal of the gum
from the necks of the teeth. As the condition pro-
gresses, there is loss of dental cement, and the teeth
become loose in the alveolar bone and may be lost.
Wounds show only superfi cial healing in scurvy,
with little or no formation of (collagen-rich) scar
tissue, so that healing is delayed and wounds can
readily be reopened. The scorbutic scar tissue has only
about half the tensile strength of that normally
formed.
Advanced scurvy is accompanied by intense pain in
the bones, which can be attributed to changes in bone
mineralization as a result of abnormal collagen syn-
thesis. Bone formation ceases and the existing bone
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