Tuesday, July 3, 2007

Thyroid hormone regulation of flavocoenzyme biosynthesis

The tight binding of FMN or FAD to their respective
apoenzymes confers stability to the holoenzyme and
an insuffi ciency of coenzyme leads to loss of enzyme
activity through proteolysis. There is evidence (Rivlin
& Langdon, 1966; Rivlin, 1970; Lee & McCormick,
1985) that thyroid hormone regulates the conversion
of ribofl avin to its functional coenzyme forms.
The mechanism of regulation is on biosynthetic
rather than degradative steps. Hepatic fl avokinase
activity was diminished in hypothyroid rats, causing
decreased FMN and FAD synthesis and consequent
decreases in the activities of a number of FMN- and
FAD-dependent enzymes. FAD synthetase activity
was also diminished, but to a lesser degree than fl avokinase.
Furthermore, ribofl avin levels were reduced
in the livers of hypothyroid rats. Treatment of the
hypothyroid rats with thyroid hormone restored
coenzyme levels and enzyme activities to normal. In
the case of hyperthyroid rats, hepatic levels of FMN
and FAD were not increased above normal despite a
two-fold increase in the activity of fl avokinase. Even
when supplemental ribofl avin was administered,
coenzymes levels were not increased above normal.
Cimino et al. (1987) reported that in hypothyroid
adult humans, the activity of the FAD-containing enzyme
erythrocyte glutathione reductase was reduced
to levels observed during ribofl avin defi ciency. After
2 weeks of therapy with thyroxine and without supplementation
with ribofl avin, the enzyme activity
reverted to normal.
It is well established that thyroid hormone increases
the synthesis of protein at the transcriptional and
translational levels. Yet the restoration of fl avoprotein
enzyme activity produced by thyroid hormone
treatment in hypothyroidism was not prevented by
inhibiting protein synthesis with actinomycin-D
(Rivlin & Langdon, 1966). Apparently, therefore,
thyroid hormone does not induce the synthesis of
fl avokinase apoenzyme; rather it appears to stimulate
the conversion of an inactive precursor form of fl avokinase
to the active form or, alternatively, decrease
the proteolytic conversion of active to inactive form
(Lee & McCormick (1985). The reduced levels of substrate
(ribofl avin) could explain the reduced activity
of fl avokinase in hypothyroidism.
Rivlin & Langdon (1966) offered a plausible explanation
for the apparent upper limit in the hepatic
concentration of FMN and FAD in hyperthyroidism.
The concentration of FMN/FAD remaining in the
liver cells is restricted by the quantity of apoenzyme
to which it can be stably bound. Excess free coenzyme
would not be stored but would be destroyed enzymatically.
Thus the elevated fl avokinase activity seen in
hyperthyroidism is not accompanied by abnormally
high levels of coenzyme.
From these data it appears that thyroid hormone
regulates FMN and FAD synthesis by altering the
activity of fl avokinase. Excessive concentrations of
FMN/FAD are prevented by the enzymatic destruction
of coenzyme that is not stably bound to the limited
amounts of apoenzyme.

1 comment:

Violeta Corona said...

I have been using bovine supplements for almost 4 months now and I can't believe how good I feel. I have more vitality than I had in my twenties, and I am in my 50's now. I sleep well and wake up rested and prepared to start my day.