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 18.104.22.168) (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
origin [Kozich, 1999].
Abe K, Kimura H (1996) The possible role of hydrogen sulfide as an
endogenous neuromodulator. J.Neurosci. 16: 1066-1071
Bao L, Vlcek C, Paces V, Kraus JP (1998) Identification and
tissue distribution of human cystathionine beta-synthase messenger-RNA isoforms.
Arch.Biochem.Biophys. 350: 95-103
Bateman A (1997) The structure of a domain common to
archaebacteria and the homocystinuria protein. Trends Biochem.Sci. 22: 12-13
Borcsok E, Abeles RH (1982) Mechanism of action of
cystathionine synthase. Arch.Biochem.Biophys. 213: 695-707
Braunstein AE, Goryachenkova EV (1984) The b-replacement-specific pyridoxal-P-dependent lyases.
Adv.Enzymol. 56: 1-89
Brenton DP, Cusworth DC (1971) The response of patients with
cystathionine synthase deficiency to pyridoxine. In: Carson NAJ, Raine DN (eds) Inherited
Disorders of Sulphur Metabolism. Churchill Livingstone, Ltd., London, pp 264-274
Brown FC, Gordon PH (1971) Cystathionine synthase from rat
liver: Partial purification and properties. Can.J.Biochem. 49: 484-491 TOP
Bukovska G, Kery V, Kraus JP (1994) Expression of human
cystathionine ▀-synthase in Escherichia coli: purification and characterization. Protein
Expr.Purif. 5: 442-448
ChassÚ JF, Paly E, Paris D, Paul V, Sinet PM, Kamoun P,
London J (1995) Genomic organization of the human cystathionine ▀-synthase gene: evidence
for various cDNAs. Biochem.Biophys.Res.Commun. 211: 826-832
ChassÚ JF, Paul V, Esca˝ez R, Kamoun P, London J (1997)
Human cystathionine ▀-synthase: gene organization and expression of different 5'
alternative splicing. Mammalian Genome 8: 917-921
Cruysberg JRM, Boers GHJ, Trijbels JMF, Deutman AF (1996)
Delay in dignosis of homocystinuria: retrospective study of consecutive patients.
Br.Med.J. 313: 1037-1040
Daubner SC, Matthews RG (1982) Purification and properties
of methylenetetrahydrofolate reductase from pig liver. J.Biol.Chem. 257: 140-145
Finkelstein JD, Kyle WE, Martin JJ, Pick A-M (1975)
Activation of cystathionine synthase by adenosylmethionine and adenosylethionine.
Biochem.Biophys.Res.Commun. 66: 81-87
Martin JJ (1984a) Methionine metabolism in mammals. Distribution of homocysteine between
competing pathways. J Biol Chem 259: 9508-13TOP
Martin JJ (1984b) Inactivation of betaine-homocysteine methyltransferase by
adenosylmethionine and adenosylethionine. Biochem.Biophys.Res.Commun. 118: 14-19
Gallagher PM, Ward P, Tan S, Naughten E, Kraus JP, Sellar
GC, McConnell DJ, Graham I, Whitehead AS (1995) High frequency (71%) of cystathionine
▀-synthase mutation G307S in Irish homocystinuria patients. Hum.Mutation 6: 177-180
Gaustadnes M IJ, RŘdiger N (1999) Prevalence of
congenital homocystinuria in Denmark [letter]. N Engl J Med 340:1513.
Ishihara S, Morohashi K, Sadano H, Kawabata S, Gotoh O,
Omura T (1990) Molecular cloning and sequence
analysis of cDNA coding for rat liver hemoprotein H-450. J Biochem (Tokyo) 108:
Kery V, Bukovska G, Kraus JP (1994) Transsulfuration depends on
heme in addition to pyridoxal 5'-phosphate. Cystathionine ▀-synthase is a heme protein.
J.Biol.Chem. 269: 25283-25288
Kery V, Poneleit L, Kraus JP (1998) Trypsin cleavage of human
cystathionine ▀-synthase into an evolutionary conserved active core: Structural and
functional consequences. Arch.Biochem.Biophys. 355: 222-232
Kery V, Poneleit L, Meyer J, Manning M, Kraus JP (1999)
Binding of pyridoxal 5'-phosphate to the hemeprotein - human cystathionine ▀-synthase.
Biochemistry 38: 2716-2724 TOP
Kim CE, Gallagher PM, Guttormsen AB, Refsum H, Ueland PM, Ose L,
Folling I, Whitehead AS, Tsai MY, Kruger WD (1997) Functional modeling of vitamin
responsiveness in yeast: a common pyridoxine-responsive cystathionine ▀-synthase mutation
in homocystinuria. Hum.Mol.Genet. 6: 2213-2221
Kimura H, Nakagawa H (1971) Studies on cystathionine
synthetase: Characteristics of purified rat liver enzyme. J.Biochem.(Tokyo) 69:
Kluijtmans LAJ, Boers GHJ, Stevens EMB, Renier WO, Kraus
JP, Trijbels FJM, van den Heuvel LPWJ, Blom HJ (1996) Defective cystathionine ▀-synthase
regulation by S-adenosylmethionine in a partially pyridoxine responsive homocystinuria
patient. J.Clin.Invest. 98: 285-289
Kluijtmans LAJ, Boers GHJ, Trijbels FJM, van Lith-Zanders
HMA, van den Heuvel LPWJ, Blom HJ (1997) A common 844INS68 insertion variant in the
cystathionine ▀-synthase gene. Biochem.Mol.Med. 62: 23-25
Kluijtmans LA, Boers GH, Kraus JP, van den Heuvel LP,
Cruysberg JR, Trijbels FJ, Blom HJ (1999) The Molecular
Basis of Cystathionine beta-Synthase Deficiency in Dutch Patients with Homocystinuria:
Effect of CBS Genotype on
Biochemical and Clinical Phenotype and on Response to Treatment. Am J Hum Genet 65:
Koch HG, Ullrich K, Deufel T, Harms E (1994) High prevalence of
a splice site mutation in the cystathionine ▀-synthase gene causing pyridoxine
nonresponsive homocystinuria. Sixth International Congress, Inborn Errors of Metabolism,
Milan, May 27-31
Koracevic D, Djordjevic V (1977) Effect of trypsin,
S-adenosylmethionine and ethionine on serine sulfhydrase activity. Experientia 33:
Kozich V, Kraus JP (1992) Screening for mutations by
expressing patient cDNA segments in E. coli - homocystinuria due to cystathionine
▀-synthase deficiency. Hum.Mutation 1: 113-123
Kozich V (1999) unpublished observations.
Kraus JP, Packman S, Fowler B, Rosenberg LE (1978)
Purification and properties of cystathionine ▀-synthase from human liver. J.Biol.Chem.
Kraus JP, Rosenberg LE (1983) Cystathionine ▀-synthase
from human liver: Improved purification scheme and additional characterization of the
enzyme in crude and pure form. Arch.Biochem.Biophys. 222: 44-52
Kraus JP, Williamson CL, Firgaira FA, Yang-Feng TL, MŘnke M,
Francke U, Rosenberg LE (1986) Cloning and screening with nanogram amounts of
immunopurified mRNAs: cDNA cloning and chromosomal mapping of cystathionine ▀-synthase
and the b subunit of propionyl-CoA carboxylase.
Proc.Natl.Acad.Sci.USA 83: 2047-2051
Kraus JP (1990) Molecular analysis of cystathionine
▀-synthase - a gene on chromosome 21. Prog.Clin.Biol.Res. 360: 201-214
Kraus JP, Le K, Swaroop M, Ohura T, Tahara T, Rosenberg LE,
Roper MD, Kozich V (1993) Human cystathionine ▀-synthase cDNA: sequence, alternative
splicing and expression in cultured cells. Hum.Mol.Genet. 2: 1633-1638
Kraus JP (1994) Molecular basis of phenotype expression in
homocystinuria. J.Inher.Metab.Dis. 17: 383-390 TOP
Kraus JP, Oliveriusova J, Sokolova J, Kraus E, Vlcek C, de
Franchis R, Maclean KN, Bao L, Bukovska G, Patterson D, Paces V, Ansorge W, Kozich V
(1998) The human cystathionine ▀-synthase (CBS) gene: complete sequence, alternative
splicing and polymorphisms. Genomics 52: 312-324
Kraus JP, Janosik M, Kozich V, Mandell R, Shih V, Sperandeo
MP, Sebastio G, de Franchis R, Andria G,
Kluijtmans LA, Blom H, Boers GH, Gordon RB, Kamoun P, Tsai MY, Kruger WD, Koch HG, Ohura
T, Gaustadnes M (1999) Cystathionine beta-synthase mutations in homocystinuria. Hum Mutat
Kruger WD, Cox DR (1994) A yeast system for expression of
human cystathionine ▀-synthase: Structural and functional conservation of the human and
yeast genes. Proc.Natl.Acad.Sci.USA 91: 6614-6618
Locker J, Gill TJ, III, Kraus JP, Ohura T, Swarop M, RiviŔre
M, Islam MQ, Levan G, Szpirer J, Szpirer C (1990) The rat MHC and cystathionine
▀-synthase gene are syntenic on chromosome 20. Immunogenetics 31: 271-274
Mudd SH, Edwards WA, Loeb PM, Brown MS, Laster L (1970)
Homocystinuria due to cystathionine synthase deficiency: The effect of pyridoxine.
J.Clin.Invest. 49: 1762-1773
Mudd SH, Levy HL, Kraus JP (1999) Disorders of
transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Vogelstein B
(eds) The Metabolic and Molecular Bases of Inherited Disease, 8 edn. McGraw-Hill, New
York, pp in press
Mudd SH, Levy HL, Skovby F (1989) Disorders of
transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The Metabolic Basis of
Inherited Disease, 6 edn. McGraw-Hill, Inc., New York, pp 693-734
Mudd SH, Levy HL, Skovby F (1995) Disorders of
transsulfuration. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The Metabolic and
Molecular Bases of Inherited Disease, 7 edn. McGraw-Hill, Inc., pp 1279-1327
Mudd SH, Skovby F, Levy HL, Pettigrew KD, Wilcken B, Pyeritz
RE, Andria G, Boers GHJ, Bromberg IL, Cerone R, Fowler B, Grobe H, Schmidt H, Schweitzer L
(1985) The natural history of homocystinuria due to cystathionine ▀-synthase deficiency.
Am.J.Hum.Genet. 37: 1-31
MŘnke M, Kraus JP, Ohura T, Francke U (1988) The gene for
cystathionine ▀-synthase (CBS) maps to the subtelomeric region on human chromosome 21q
and to proximal mouse chromosome 17. Am.J.Hum.Genet. 42: 550-559
Ogawa H, Gomi T, Konishi K, Date T, Nakashima H, Nose K,
Matsuda Y, Peraino C, Pitot HC, Fujioka M (1989) Human liver serine dehydratase. cDNA
cloning and sequence homology with hydroxyamino acid dehydratases from other sources.
J.Biol.Chem. 264: 15818-15823
Omura T, Sadano H, Hasegawa T, Yoshida Y, Kominami S (1984)
Hemoprotein H-450 identified as a form of
cytochrome P-450 having an endogenous ligand at the 6th coordination position of the heme.
J Biochem (Tokyo) 96:
Sebastio G, Sperandeo MP, Panico M, de Franchis R, Kraus J,
Andria G (1995) The molecular basis of homocystinuria due to cystathionine ▀-synthase
deficiency in Italian families, and report of four novel mutations. Am.J.Hum.Genet. 56:
Selhub J, Miller JW (1992) The pathogenesis of
homocysteinemia: Interruption of the coordinate regulation by
S-adenosylmethionine of the remethylation and transsulfuration of homocysteine.
Am.J.Clin.Nutr. 55: 131-138
Shan X, Kruger WD (1998) Correction of disease-causing CBS
mutations in yeast. Nature Genet. 19: 91-93
Skovby F, Krassikoff N, Francke U (1984a) Assignment of the
gene for cystathionine ▀-synthase to human chromosome 21 in somatic cell hybrids.
Hum.Genet. 65: 291-294
Skovby F, Kraus JP, Rosenberg LE (1984b) Biosynthesis and
proteolytic activation of cystathionine ▀-synthase in rat liver. J.Biol.Chem. 259:
Skovby F, Kraus JP, Rosenberg LE (1984c) Biosynthesis of
human cystathionine ▀-synthase in cultured fibroblasts. J.Biol.Chem. 259: 583-587
Skovby F, Kraus, J.P. (1999) The homocystinurias. In: Royce
PM, Steinmann B (eds) Connective Tissue and its Heritable Disorders: Molecular, Genetic,
and Medical Aspects, vol in press. Wiley-Liss, New York
Sperandeo MP, de Franchis R, Andria G, Sebastio G (1996) A
68-bp insertion found in a homocystinuric patient is a common variant and is skipped by
alternative splicing of the cystathionine ▀-synthase mRNA. Am.J.Hum.Genet. 59:
Stubbs L, Kraus J, Lehrach H (1990) The a-A-crystallin and
cystathionine ▀-synthase genes are physically very closely linked in proximal mouse
chromosome 17. Genomics 7: 284-288
Swaroop M, Bradley K, Ohura T, Tahara T, Roper MD, Rosenberg
LE, Kraus JP (1992) Rat cystathionine ▀-synthase. Gene organization and alternative
splicing. J.Biol.Chem. 267: 11455-11461
Taoka S, Ohja S, Shan X, Kruger WD, Banerjee R (1998) Evidence
for heme-mediated redox regulation of human cystathionine ▀-synthase activity.
J.Biol.Chem. 273: 25179-25184
Taoka S, West M, Banerjee R (1999) Characterization of the
heme and pyridoxal phosphate cofactors of human cystathionine beta-synthase reveals
nonequivalent active sites [In Process Citation]. Biochemistry 38: 2738-44
Tsai MY, Bignell M, Schwichtenberg K, Hanson NQ (1996) High
prevalence of a mutation in the cystathionine ▀-synthase gene. Am.J.Hum.Genet. 59:
Yanofsky C, Platt T, Crawford IP, Nichols BP, Christie GE,
Horowitz H, VanCleemput M, Wu AM (1981) The
complete nucleotide sequence of the tryptophan operon of Escherichia coli. Nucleic Acids
Res 9: 6647-68