Cystathionine ▀ - Synthase
| Gene | Enzyme | Deficiency |
THE SULFUR AMINO ACID METABOLISM
In eukaryotes, the sulfur atom of cysteine is derived from methionine while the carbon
chain and the amino group originate from serine. An intermediate metabolite in this
synthesis is homocysteine. Homocysteine
occupies a branch point in methionine, cysteine, and AdoMet metabolism. About half of the
homocysteine formed is conserved by remethylation to methionine in the "methionine
cycle" [Finkelstein, 1984a]. The other
half is irreversibly converted by cystathionine b-synthase
(L-serine hydrolyase (adding homocysteine), EC 188.8.131.52) (CBS) and cystathionine g-lyase to cysteine. Thus, CBS is directly involved in the removal of
homocysteine from the cycle and in the biosynthesis of cysteine, a precursor of
glutathione, the major redox regulating metabolite of the cell.
In vitro studies have indicated that AdoMet functions as a switch between the
methionine cycle and the transsulfuration pathway [Finkelstein,
1984b]. At low AdoMet concentrations its resynthesis is unimpaired. High
concentrations of AdoMet, however, limit homocysteine remethylation by inhibiting
5,10-methylenetetrahydrofolate reductase [Daubner and
Matthews 1982] and betaine methyltransferase [Finkelstein,
1984b]. Transsulfuration, on the other hand, is enhanced by the stimulatory effect of
AdoMet on CBS activity [Finkelstein et al. 1975;
Koracevic and Djordjevic 1977].
THE HUMAN CBS GENE
The locus for human CBS was mapped to chromosome 21 by study of Chinese hamster-human
cell hybrids [Skovby et al. 1984a]. This assignment
was corroborated by in situ hybridization studies using a cDNA probe for CBS [Kraus et al. 1986]. The gene has subsequently been
localized more precisely to the subtelomeric region of band 21q22.3 of chromosome 21 [MŘnke et al. 1988] where the gene for a-A-crystallin, a major structural protein of the ocular lens, is
also found. Synteny of these two loci is conserved in the mouse on chromosome 17 [Stubbs et al. 1990], in the rat on chromosome 20 [Locker et al. 1990], and in the cow in the syntenic
group U10 [Kraus 1990]. The entire human CBS gene was
cloned and sequenced in 1998 [Kraus et al. 1998]. A
total of 28,046 nucleotides
were reported spanning the entire CBS gene and an additional 5 kbp of 5' -flanking
Alternative splicing of CBS pre-mRNA.
The human CBS gene contains 23 exons; the CBS polypeptide of 551 amino acids is encoded by
exons 1-14 and 16. Exon 15, the human homolog of rat exon 16, is alternatively spliced. It
encodes 14 amino acids and is incorporated in relatively few mature human CBS mRNA
molecules. The CBS polypeptide containing exon 15 has not been detected in any of the
various human tissues that have been examined so far. Consequently, the biological
significance, if any, of exon 15 remains obscure [Kraus et
al. 1998]. The 5'-UTR of human CBS mRNA is formed by one of five alternatively
used exons, designated -1a to -1e, and one invariably present, exon 0, while the 3'-UTR is
encoded by exons 16 and 17 [Bao et al. 1998; ChassÚ et al. 1995; ChassÚ
et al. 1997]. Interestingly, intron 16 appears to be retained in the 3'-UTR of most of
the fibroblast and liver mRNA of every individual tested [Kraus
et al. 1993].
There are at least two alternatively used promoters in the human gene. These are located
upstream of exons -1a and -1b. They are GC rich (~ 80%) and contain numerous
putative binding sites for Sp1, Ap1, Ap2 and c-myb, but lack the classical TATA box.
The CBS locus contains a number of DNA sequence repeats and single
base variations that are polymorphic in Caucasians
[Kraus et al. 1999, Kraus
et al. 1998]. One variation deserves a special mention because
of its relatively high incidence in the normal population. Sebastio
et al. described an insertion of 68 bp in exon 8 (844ins68) in
an allele from a CBS-deficient patient that also contained the frequent
I278T mutation. Subsequently, the 844ins68
was shown to be a frequent polymorphism occurring in about 5% of Caucasian
alleles [Kluijtmans et al. 1997;
Sperandeo et al. 1996; Tsai
et al. 1996].
The insertion duplicates the intron 7 acceptor splice site and may
lead to two alternatively spliced transcripts. The most abundant
transcript, and the only one that has been detected in the cytosol
of patient derived fibroblasts, contains the wild type mRNA sequence.
The other transcript carrying the I278T mutation and a premature termination
codon may be unstable and was detected in very low amounts only in
the nucleus [Sperandeo et al.
THE CBS ENZYME
CBS has been purified from several vertebrate livers [Kraus
et al. 1978]. The primary translational product of both the human and the rat CBS gene
is a polypeptide with a molecular weight of 63 kDa [Skovby
et al. 1984c] that forms tetramers or higher oligomers. Limited proteolysis of the
full-lenght enzyme yields the "active core" of CBS (amino acid residues
40-413). The reduction in size is accompanied by a significant increase in the
specific activity of the enzyme and change from a tetramer to a dimer [Kraus and Rosenberg 1983; Skovby at al. 1984c]. The purified enzyme contains
firmly bound pyridoxal 5'-phosphate (PLP), on which it depends for activity [Brown and Gordon 1971; Kimura
and Nakagawa 1971; Kraus et al. 1978].
Expression of recombinant human CBS.
The CBS cDNA has been used in various vectors to express the human recombinant enzyme in
E. coli [Bukovska et al. 1994], in yeast [Kruger and Cox 1994], and in Chinese hamster ovary
cells [Kraus et al. 1993]. Significant amounts
of the recombinant human CBS were purified from E. coli and characterized [Bukovska et al. 1994; Kery
et al. 1994; Taoka et al. 1998]. Each subunit of
551 amino acid residues binds, in addition to the two substrates, three additional
ligands: PLP, AdoMet (an allosteric activator), and, surprisingly, heme.
The PLP binding site.
Each mole of CBS subunit binds one mole of PLP [Kery et al.
1994]. Kery et al. 1999 demonstrated that Lys119
is the PLP binding residue in human CBS.
As outlined above, the homocysteine branch point in the methyl cycle appears to be
controlled by AdoMet [Finkelstein, 1984b; Selhub, 1992]. CBS in crude extracts is activated by
AdoMet 2-4-fold with an apparent Kact of 15 mM [Kozich and Kraus 1992]. A human mutation, D444N, has
been described that appears to interfere with the activation process [Kluijtmans et al. 1996]. In addition, AdoMet does
not activate CBS that has been truncated at W409 or R413, and is thus missing ~140
residues from the COOH terminus but exhibits increased activity [Kery et al. 1998; Shan and
Kruger 1998]. TOP
The role of heme in CBS.
Heme binding was first assigned to protein "H-450" [Ishihara, 1990; Omura,
1984]. Later, comparison of the cDNA sequences revealed that H-450 and CBS were
identical. The visible spectrum of CBS is mostly due to heme rather than PLP. CBS
exhibits the characteristic features of a heme protein: a sharp Soret peak at 428 nm with
a shoulder at 363 nm and a broad band at 550 nm. The presence of heme in CBS is
striking because the mechanism of the b-replacement reactions
catalyzed by the enzyme can be explained solely by PLP mediated catalysis [Borcsok and Abeles 1982; Braunstein and Goryachenkova 1984]. The role of heme
in this PLP enzyme is unclear at present.
Active core of CBS.
The active core, extending from Glu 37 to Arg 413, forms a dimer of 45 kDa subunits. The
45 kDa active core is the portion of CBS most homologous with the evolutionarily related enzymes
isolated from plants or bacteria. The dimer is about twice as active as the
tetramer. It binds both PLP and heme co-factors, but is no longer activated by
AdoMet [Kery et al., 1998].
Other b- replacement reactions and evolutionary conservation
CBS can catalyze alternative b-replacement reactions in which
sulfide is a substrate or a product [Braunstein and
Goryachenkova 1984] according to the general scheme:
| XCH2CH(NH2)COOH + YH >
XH + YCH2CH(NH2)COOH
where, X = OH or SH and Y = SH
The amino acid sequence of the active core of human CBS shares a high degree of structural similarity (52% if
conservative replacements are counted) with the related O-acetylserine sulfhydrases
(cysteine synthases) from plants and bacteria [Kraus 1994;
Swaroop et al. 1992]. These enzymes catalyze the
synthesis of cysteine from sulfide and acetylserine. Exon 3 is the most highly conserved
region with about 50% identity to the bacterial enzymes. This highly conserved
region contains lysine 119, the PLP binding residue [Kery
et al. 1999].
The second class of enzymes that are structurally related to CBS includes
hydroxylaminoacid deaminases (dehydratases) from E. coli, yeast, rat and human liver [Ogawa et al. 1989]. There are 118 identical
residues between CBS and threonine deaminase (21% identity) and 33% similarity between
them including conservative replacements.
A third class of CBS related proteins can be represented by the tryptophan synthase beta
chain encoded by the trpB gene of E. coli [Yanofsky,
1981]. The CBS and tryptophan synthase share 113 residues (28.5%) identity and
their overall similarity is nearly 36%. Here, again as in all the other comparisons,
the most conserved regions are located in their amino-terminal regions corresponding to
residues 102-169 of CBS.
Recently, "CBS protein
domains ", comprising CBS residues 416-469, were identified in a wide range of
otherwise unrelated proteins including inosine-monophosphate dehydrogenase, glycine
betaine ABC transporters, numerous chloride channels and many other proteins. Although the
role of the "CBS domain" is unclear, it may be involved in cytoplasmic
targeting, protein-protein interaction and/or protein regulation [Bateman 1997].
THE CBS DEFICIENCY
Clinical Picture of CBS Deficiency
The most complete clinical description of CBS deficiency in 629 patients with proven or
presumed enzymatic defect was published in 1985 [Mudd et
al. 1985]. Some of the most important clinical aspects of CBS deficiency are discussed
Eye. Lens dislocation is one of the typical features of CBS deficiency, and
the most common sign leading to diagnosis. Lens dislocation has been instrumental in
the diagnosis in more than 80% of symptomatic unrelated patients in the studies of
Mudd et al [Mudd et al. 1985] and Cruysberg [Cruysberg et al. 1996]. Although lens ectopia was
detected in one patient by 4 weeks of age [Mudd et al.
1989], it is rarely seen before 2 years of age.
Skeleton. In patients with CBS deficiency numerous skeletal abnormalities may
be observed [Mudd et al. 1989], both by clinical and
X-ray examinations. The most remarkable abnormalities resembling the Marfan syndrome
include scoliosis/kyphosis, dolichostenomelia (long and thin extremities), decreased
upper/lower segment ratio and arachnodactyly [Skovby
Vasculature. Vascular disorders are another peculiar feature of this
disease. Generally, they can be characterized as a thrombotic diathesis that
may manifest in the venous or arterial system and/or as accelerated atherosclerosis.
Central nervous system. Mental retardation is a frequent finding in CBS
deficient patients. In an international survey, quantitative data from 284 patients
showed a median IQ of 78 and 56 for the pyridoxine responders and non-responders,
respectively [Mudd et al. 1985].
The clinical and biochemical consequences of CBS deficiency are profoundly influenced by
pyridoxine responsiveness. Pyridoxine responsiveness is an ability to enhance
transsulfuration of homocysteine upon pyridoxine administration. It was originally
defined as elimination of homocystine from plasma and urine and decrease of plasma
methionine into the normal range as summarized by Mudd et al et al. [Mudd et al. 1999]. Although this term is widely used, no
unified definition of pyridoxine responsiveness is available. Various doses ranging
between 25 and 1200 mg/day have been shown to elicit the biochemical response, although
occasionally, a response was reported after a 2-mg dose of pyridoxine [Mudd et al. 1999]. The confusion about responsiveness is
further complicated by the change in analytical procedures. The older methods for
homocystine determination by amino acid analyzer have been almost universally replaced by
the analysis of total homocysteine in plasma. In the previous definition of responsiveness
as "virtual elimination of homocystine from plasma and urine" [Brenton and Cusworth 1971], the limit for detecting
any plasma homocystine corresponds to a currently detectable total plasma
homocysteine concentration of ╗ 50-60 mmol/l.
Consequently, we propose to classify pyridoxine responsiveness as a decrease of total
homocysteine below 50 mmol/l, and non-responsiveness as no
change in plasma total homocysteine after a dose of up to 10 mg/kg of pyridoxine per day
administered for at least 2 weeks.
Most of the mutations found in CBS deficient patients are missense mutations and the
vast majority of them are private mutations. To date, more than 158 mutations have been found on
more than 803 CBS alleles.
There are about 10 known nonsense mutations and
the remainder are various deletions, insertions, and splicing mutations. About half of all
point substitutions in the coding region of the CBS gene originate from deaminations of
methylcytosines in CpG dinucleotides[Kraus et al., 1999].
There have been 158 missense mutations found in CBS patients. Nearly a third of these have
been expressed in E. coli and all of them have been found to significantly decrease the
level of CBS activity [Kraus et al., 1999]. Nearly a
quarter of the missense mutations are found in exon 3, the most evolutionarily conserved
part of the CBS polypeptide. The two most frequent mutations, I278T and G307S are found in
exon 8. The I278T mutation is panethnic, and overall it accounts for close to a quarter of
all homocystinuric alleles. However, in some countries, e.g. the Netherlands [Kluijtmans et al., 1999], it accounts for more than
a half of the affected alleles. Interestingly, a DNA- based screening of newborns in
Denmark showed 1.4% of them to be heterozygous for the I278T mutation [Gaustadnes M 1999]. This value corresponds to a
homozygote frequency of ~ 1: 20 000, a significantly higher incidence than the often
quoted figure of 1:335,000 [Mudd et al. 1995].
The G307S mutation is undoubtedly the leading cause of homocystinuria in Ireland (71% of
affected alleles) [Gallagher et al. 1995].
It has also been detected frequently in U.S. and Australian patients of 'Celtic' origin,
including families with Irish, Scottish, English, French, and Portuguese ancestry.
In contrast, the G307S mutation has not been detected in a large number of tested alleles
in Italy, the Netherlands, Germany and the Czech Republic.
The third most frequent alteration is a splice mutation in intron 11, 1224-2 A>C (IVS
11-2 A>C), which results in the skipping of all of exon 12. Surprisingly,
although it was found in Germany in about 20% of affected chromosomes of German and
Turkish origin [Koch et al. 1994], it has never been
detected in Italy and the Netherlands in nearly 70 alleles studied. It is, together
with the I278T mutation, the most prevalent mutation in patients of Czech and Slovak
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