Chemistry Reference
In-Depth Information
(
http://www.rcsb.org/pdb/home/home.do
). Queries can be targeted to individual
enzymes or to entire pathways.
10.3 MEDICAL ASPECTS
10.3.1 Genetic Deficiency of Coenzyme Biosynthesis
Genetic defects have been reported for the biosynthesis of several coenzymes in
humans. Typically, these rare anomalies cause severe neurological deficits that
become apparent at birth or in early childhood.
Specifically, the deficiency of certain enzymes of tetrahydrobiopterin biosyn-
thesis (GTP cyclohydrolase I, pyruvoyltetrahydrobiopterin synthase, Fig. 10.3)
result in severe neurological and developmental deficit designated as atypical
phenylketonuria caused by the ensuing deficiency in catecholamine type neu-
rotransmitter biosynthesis. The condition can be treated with some success by
the oral application of synthetic tetrahydrobiopterin in large amounts. Tetrahy-
drobiopterin therapy has also been advocated for certain patients with classic
phenylketonuria that results from mutations of phenylalanine hydroxylase (71).
This therapeutic approach is based on the concept that the function of certain
defective phenylalanine hydroxylases can be bolstered by increased amounts of
the cognate coenzyme tetrahydrobiopterin. In fact, the relatively large number
of patients with classic phenylketonuria may provide an economic incentive for
the development of a biotechnological process for the bulk production of the
coenzyme.
Deficiencies of enzymes involved in the transformation of the vitamin pan-
tothenic acid (
64
) into the cognate coenzyme forms (
66
, Fig. 10.7) result in
severe developmental and neurological deficits that affect few human patients
(34, 72). Therapy with megadoses of pantothenic acid has been advocated, but
their efficiency has yet to be demonstrated by stringent clinical studies (73).
Genetic defects of molybdopterin biosynthesis (Fig. 10.3) also result in severe
neurologic and developmental deficits (74). Genetic defects in the biosynthesis
of the quinine-type coenzyme Q10 (
97
, Fig. 10.11) can result in encephalopathy,
myopathy, and renal disease (53).
Inherited defects or porphyrine biosynthetic enzymes can cause the accumula-
tion of pathway intermediates that cannot be converted anymore with sufficient
velocity. Various genetic forms of porphyria have been reported and result in
liver toxicity, neurological damage and photosensitivity (75). Acquired forms of
porphyria can be caused by a variety of toxic and pharmacologic agents.
The absorption of vitamin B
12
(
20
) requires a glycoprotein-designated intrin-
sic factor that is secreted by the gastric mucosa (7, 76). The factor binds the
vitamin and enables its subsequent transport across the ileal mucosa. Acquired
failure to produce the intrinsic factor results in a complex disease that can present
with hematological (macrocytotic anemia and pernicious anemia), neurological,
or psychiatric symptoms or a combination thereof. Prior to the discovery of
vitamin B
12
, pernicious anemia was lethal. Initial treatment was based on the
