viernes, 10 de agosto de 2012

megadosis para frenar SNP

Cystathionine -synthase: homocystinuria


-synthase (CBS) of the transsulfuration pathway

catalyzes the PLP-dependent condensation of homocysteine
and serine to form cystathionine. Individuals carrying a defective
form of this enzyme (

see OMIM 236200) accumulate homocysteine

in the blood and urine and display a wide range of symptoms
that appear to be due to homocysteine toxicity, including
mental retardation, vascular and skeletal problems, and optic
lens dislocation. Barber and Spaeth (40) were the first to report
pyridoxine-responsiveness with a complete return to normal of
the patient’s methionine and homocysteine concentrations in
plasma and urine. They speculated that “if the deficient enzymatic
activity were due to decreased affinity of a defective
apoenzyme for its cofactor, activity might be restored by increasing
the intracellular concentration of pyridoxal phosphate” (40).
Kim and Rosenberg (41) showed that CBS activity was 5% of
that of control subjects in pyridoxine-responsive homocystinuric
patients, who had markedly elevated plasma and urinary concentrations
of methionine and homocystine. The mutant synthases
had a 20-fold lower affinity for PLP. A 2- to 3-fold increase in

Km for homocysteine and serine was found in one vitamin

B-6-responsive patient, although the

Km for PLP was not measured.

The maximum reaction rate (

Vmax) was also reduced. It

was suggested that pharmacologic doses of pyridoxine led to
increased cellular concentrations of PLP and increased enzymatic
activity (41).
One group showed cell lines from pyridoxine-responsive
patients to have higher

Km values for PLP (155, 145, 195, and

200 mol/L) than control values (52, 52, and 85 mol/L),
whereas nonresponsive patients had the highest values (990 and
4000 mol/L). It was noted that, in general, about one-half of
CBS-deficient patients respond to pyridoxine with a lowering
of homocysteine and serine concentrations to normal (42). A
21-y-old pyridoxine-responsive individual had a 3- to 4-fold
elevated apparent

Km of CBS for PLP as measured in fibroblast

extracts (43). An Ala114

Val substitution was present in this individual,

which is only 5 residues away from the lysine residue, Lys119,
that binds PLP. These investigators concluded that in vivo
responsiveness in individuals with some residual CBS activity is
related both to the affinity of the mutant aposynthase for PLP
and to the capacity of cells to accumulate PLP (43).
In one report (44), a G-to-A substitution at nucleotide 797
A; amino acid substitution: Arg266Lys) was found in
most pyridoxine-responsive patients. Seven of 12 patients were
responsive to pyridoxine (40–900 mg/d), which greatly decreased
total plasma homocysteine.
Pyridoxine (50–1000 mg/d) markedly reduced homocysteine
excretion in a group of pyridoxine-responsive patients: patient 1,
867 to 10 mol/d; patient 2, 1021 to 79 mol/d; patient 3,
15 mol/L (blood concentration) to undetectable concentrations;
and patient 4, plasma amino acids reverted to normal (45). It
appears that a missense mutation (Ile278
Thr) is common (41%)
in pyridoxine-responsive patients and that patients who are
responsive to pyridoxine usually have a milder clinical phenotype
than do nonresponsive patients.
The idea that pyridoxine-responsive patients have an increased

m was supported in a review of the mechanism of pyridoxineresponsive
disorders (46). A review of the CBS deficiencies (2)
found 629 patients in the literature: 231 (37%) were vitamin
B-6–responsive, 231 (37%) were vitamin B-6–nonresponsive,
67 (11%) were intermediate in response, and 100 (16%) had not
been classified. A decade later, the field was reviewed again and it
was suggested that dosages of pyridoxine of 500 mg/d for 2 y
appear to be safe, but that 1000 mg/d should not be exceeded (47).
A database of mutations in CBS (48) lists and maps >100 pathogenic
mutations (including >70 missense mutations) that span all 7
exons of the
CBS gene. Although the Schiff-base forming lysine has
been assigned to nucleotide 119 in exon 3, it is difficult to say which
domains are responsible for PLP binding. Serine should be tested
clinically in addition to pyridoxine for treating patients, with the use
of homocysteine concentrations as a measure of efficacy, because the

m of CBS for serine was shown to be increased in several cases
(41). Oral serine administration (500 mg·kg
1·d 1) raises serine
concentrations in plasma and cerebrospinal fluid (49), although very
high doses (1400 mg·kg
1·d 1) can result in adverse effects (50).
Vitamin B-6-therapy may be valuable in more than just severe
homozygous CBS-deficient cases: heterozygous parents of CBSdeficient
patients also have significantly increased homocysteine
concentrations (51). Increased homocysteine is a risk factor for
cardiovascular disease (52). Heterozygosity for CBS deficiency
may be present in 1% or 2% of the population.

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