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Cystathionine ▀ - Synthase (CBS):

| Metabolism | Gene | Enzyme | Deficiency |


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. MetabolismHomocysteine 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 (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 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 sequence.


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].

CBS promoters.
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. 1996].


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.

AdoMet activation.
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 of CBS.
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:


where, X = OH or SH and Y = SH or S-alkyl

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].



Clinical Picture of CBS Deficiency

Organ involvement.
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 below.
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 1999].
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].



Pyridoxine responsiveness.
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 origin [Kozich, 1999].


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