View source for Cystathionine beta synthase

{{Short description|Mammalian protein found in humans}}
{{Infobox_gene}}
'''Cystathionine-β-synthase''', also known as '''CBS''', is an [[enzyme]] ({{EnzExplorer|4.2.1.22}}) that in humans is encoded by the ''CBS'' [[gene]]. It catalyzes the first step of the [[transsulfuration pathway]], from [[homocysteine]] to [[cystathionine]]:<ref>{{cite web | title = Entrez Gene: CBS cystathionine-beta-synthase| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=875}}</ref>

:[[Serine|<small>L</small>-serine]] + [[homocysteine|<small>L</small>-homocysteine]] <math>\rightleftharpoons</math> [[cystathionine|<small>L</small>-cystathionine]] + [[water (molecule)|H<sub>2</sub>O]]

CBS uses the [[Cofactor (biochemistry)|cofactor]] [[pyridoxal-phosphate]] (PLP) and can be [[allosterically]] regulated by effectors such as the ubiquitous cofactor [[S-adenosyl-L-methionine|''S''-adenosyl-<small>L</small>-methionine]] (adoMet). This enzyme belongs to the family of [[lyase]]s, to be specific, the hydro-lyases, which cleave carbon-oxygen bonds.

CBS is a multidomain enzyme composed of an N-terminal enzymatic domain and two [[CBS domain]]s. The ''CBS'' gene is the most common locus for mutations associated with [[homocystinuria]].<ref name="janosik">{{cite journal | vauthors = Janosík M, Kery V, Gaustadnes M, Maclean KN, Kraus JP | title = Regulation of human cystathionine beta-synthase by S-adenosyl-L-methionine: evidence for two catalytically active conformations involving an autoinhibitory domain in the C-terminal region | journal = Biochemistry | volume = 40 | issue = 35 | pages = 10625–33 |date=September 2001 | pmid = 11524006 | doi = 10.1021/bi010711p }}</ref>

== Nomenclature ==

The [[List of enzymes|systematic name]] of this enzyme class is <small>L</small>-serine hydro-lyase (adding homocysteine; <small>L</small>-cystathionine-forming). Other names in common use include:
* β-thionase,
* cysteine synthase,
* <small>L</small>-serine hydro-lyase (adding homocysteine),
* methylcysteine synthase,
* serine sulfhydrase, and
* serine sulfhydrylase.

'''Methylcysteine synthase''' was assigned the [[Enzyme Commission number|EC number]] EC 4.2.1.23 in 1961. A side-reaction of CBS caused this. The EC number EC 4.2.1.23 was deleted in 1972.<ref>[http://www.chem.qmul.ac.uk/iubmb/enzyme/EC4/2/1/23.html EC 4.2.1.23<!-- Bot generated title -->]</ref>

== Structure ==

[[Image:CBSsequence.png|thumb|left|400px|Sequence and secondary structure of the CBS enzyme.<ref name="pmid11483494">{{PDB|1JBQ}}; {{cite journal | vauthors = Meier M, Janosik M, Kery V, Kraus JP, Burkhard P | title = Structure of human cystathionine beta-synthase: a unique pyridoxal 5'-phosphate-dependent heme protein | journal = The EMBO Journal | volume = 20 | issue = 15 | pages = 3910–6 | date = August 2001  | pmid = 11483494 | pmc = 149156 | doi = 10.1093/emboj/20.15.3910 }}</ref>]]
The human enzyme cystathionine β-synthase is a [[tetrameric protein|tetramer]] and comprises 551 [[amino acid]]s with a subunit molecular weight of 61 kDa. It displays a modular organization of three modules with the N-terminal heme domain followed by a core that contains the [[pyridoxal-phosphate|PLP]] cofactor.<ref name="Ruma">{{cite journal | vauthors = Banerjee R, Zou CG | title = Redox regulation and reaction mechanism of human cystathionine-beta-synthase: a PLP-dependent hemesensor protein | journal = Archives of Biochemistry and Biophysics | volume = 433 | issue = 1 | pages = 144–56 |date=January 2005 | pmid = 15581573 | doi = 10.1016/j.abb.2004.08.037 }}</ref> The cofactor is deep in the heme domain and is linked by a Schiff base.<ref name="Mamoru">{{cite journal | vauthors = Yamanishi M, Kabil O, Sen S, Banerjee R | title = Structural insights into pathogenic mutations in heme-dependent cystathionine-beta-synthase | journal = Journal of Inorganic Biochemistry | volume = 100 | issue = 12 | pages = 1988–95 |date=December 2006 | pmid = 17069888 | doi = 10.1016/j.jinorgbio.2006.08.020 }}</ref> A [[Schiff base]] is a [[functional group]] containing a C=N bond with the nitrogen atom connected to an [[aryl]] or [[alkyl]] group. The heme domain is composed of 70 amino acids and it appears that the heme only exists in [[mammal]]ian CBS and is absent in yeast and [[protozoan]] CBS.  At the C-terminus, the regulatory domain of CBS contains a tandem repeat of two CBS domains of β-α-β-β-α, a secondary structure motif found in other proteins.<ref name=Ruma />  CBS has a C-terminal inhibitory domain. The C-terminal domain of cystathionine β-synthase regulates its activity via both intrasteric and allosteric effects and is important for maintaining the tetrameric state of the protein.<ref name=Ruma /> This inhibition is alleviated by binding of the [[allosteric]] effector, [[S-Adenosyl methionine|adoMet]], or by deletion of the regulatory domain; however, the magnitude of the effects differ.<ref name=Ruma /> Mutations in this domain are correlated with [[hereditary disease]]s.<ref name="pmid17087506">{{cite journal | vauthors = Kabil O, Zhou Y, Banerjee R | title = Human cystathionine beta-synthase is a target for sumoylation | journal = Biochemistry | volume = 45 | issue = 45 | pages = 13528–36 |date=November 2006 | pmid = 17087506 | doi = 10.1021/bi0615644 }}</ref>

The heme domain contains an N-terminal loop that binds heme and provides the axial [[ligand]]s C52 and H65.  The distance of heme from the [[pyridoxal-phosphate|PLP]] binding site suggests its non-role in catalysis, however deletion of the heme domain causes loss of [[redox]] sensitivity, therefore it is hypothesized that heme is a redox sensor.<ref name=Mamoru /> The presence of protoporphyrin IX in CBS is a unique PLP-dependent enzyme and is only found in the mammalian CBS.  [[Drosophila melanogaster|''D. melanogaster'']] and [[Dictyostelium discoides|''D. discoides'']] have truncated [[N-terminus|N-terminal]] extensions and therefore prevent the conserved [[histidine]] and [[cysteine]] heme ligand [[residue (chemistry)|residue]]s.  However, the ''[[Anopheles gambiae]]'' sequence has a longer N-terminal extension than the human enzyme and contains the conserved [[histidine]] and [[cysteine]] [[heme]] ligand residues like the human [[heme]].  Therefore, it is possible that CBS in slime molds and insects are hemeproteins that suggest that the [[heme]] domain is an early evolutionary innovation that arose before the separation of animals and the slime molds.<ref name=Ruma /> The [[pyridoxal-phosphate|PLP]] is an internal [[aldimine]] and forms a [[Schiff base]] with K119 in the active site.   Between the catalytic and regulatory domains exists a hypersensitive site that causes proteolytic cleavage and produces a truncated [[protein dimer|dimer]]ic enzyme that is more active than the original enzyme.  Both truncated enzyme and the enzyme found in yeast are not regulated by adoMet. The yeast enzyme is also activated by the deletion of the C-terminal to produce the dimeric enzyme.<ref name=Ruma />

As of late 2007, two [[tertiary structure|structures]] have been solved for this class of enzymes, with [[Protein Data Bank|PDB]] accession codes {{PDB link|1JBQ}} and {{PDB link|1M54}}.

{{Clear}}

== Enzymatic activity ==
{{infobox enzyme
| Name       = cystathionine beta-synthase
| EC_number  = 4.2.1.22
| CAS_number = 9023-99-8
| GO_code    = 0004122
| image      = 1jbq.jpg
| width      = 270
| caption    = Cystathionine beta synthase homodimer, Human
}}
[[File:Cysteine biosynthesis.svg|thumb|150px|Cysteine metabolism. Cystathionine beta synthase catalyzes the upper reaction and [[cystathionine gamma-lyase]] catalyzes the lower reaction.]]

Transsulfuration, catalyzed by CBS, converts [[homocysteine]] to [[cystathionine]], which cystathione gamma lyase converts to  [[cysteine]].<ref name="pmid11106665">{{cite journal | vauthors = Nozaki T, Shigeta Y, Saito-Nakano Y, Imada M, Kruger WD | title = Characterization of transsulfuration and cysteine biosynthetic pathways in the protozoan hemoflagellate, Trypanosoma cruzi. Isolation and molecular characterization of cystathionine beta-synthase and serine acetyltransferase from Trypanosoma | journal = The Journal of Biological Chemistry | volume = 276 | issue = 9 | pages = 6516–23 |date=March 2001 | pmid = 11106665 | doi = 10.1074/jbc.M009774200 | doi-access = free }}</ref>

CBS occupies a pivotal position in mammalian sulfur metabolism at the [[homocysteine]] junction where the decision to conserve [[methionine]] or to convert it to cysteine via the [[transsulfuration pathway]], is made. Moreover, the transsulfuration pathway is the only pathway capable of removing sulfur-containing [[amino acids]] under conditions of excess.<ref name=Ruma />

In analogy with other β-replacement enzymes, the reaction catalyzed by CBS is predicted to involve a series of [[S-adenosyl-L-methionine|adoMet]]-bound intermediates. Addition of [[serine]] results in a [[Schiff base|transchiffization]] reaction, which forms of an external [[aldimine]]. The [[aldimine]] undergoes proton abstraction at the α-carbon followed by elimination to generate an amino-[[acrylate]] intermediate. Nucleophilic attack by the thiolate of homocysteine on the aminoacrylate and reprotonation at Cα generate the external aldimine of [[cystathionine]]. A final [[transaldimination]] reaction releases the final product, cystathionine.<ref name=Ruma /> The final product, <small>L</small>-cystathionine can also form an aminoacrylate intermediate, indicating that the entire reaction of CBS is reversible.<ref name="Jhee">{{cite journal | vauthors = Jhee KH, Kruger WD | title = The role of cystathionine beta-synthase in homocysteine metabolism | journal = Antioxidants & Redox Signaling | volume = 7 | issue = 5–6 | pages = 813–22 | year = 2005 | pmid = 15890029 | doi = 10.1089/ars.2005.7.813 }}</ref>

The measured V<sub>0</sub> of an enzyme-catalyzed reaction, in general, reflects the steady state (where [ES] is constant), even though V<sub>0</sub> is limited to the early part of a reaction, and analysis of these initial rates is referred to as steady-state kinetics. Steady-state kinetic analysis of yeast CBS yields parallel lines. These results agree with the proposed ping-pong mechanism in which serine binding and release of water are followed by homocysteine binding and release of cystathionine. In contrast, the steady-state [[enzyme kinetics]] of rat CBS yields intersecting lines, indicating that the β-substituent of serine is not released from the enzyme prior to binding of homocysteine.<ref name=Ruma />

One of the alternate reactions involving CBS is the condensation of [[cysteine]] with homocysteine to form cystathionine and [[hydrogen sulfide]] (H<sub>2</sub>S).<ref name=Jhee /> H<sub>2</sub>S in the brain is produced from <small>L</small>-cysteine by CBS. This alternative metabolic pathway is also dependent on [[S-adenosyl-L-methionine|adoMet]].<ref name="pmid12213817">{{cite journal | vauthors = Eto K, Kimura H | title = A novel enhancing mechanism for hydrogen sulfide-producing activity of cystathionine beta-synthase | journal = The Journal of Biological Chemistry | volume = 277 | issue = 45 | pages = 42680–5 |date=November 2002 | pmid = 12213817 | doi = 10.1074/jbc.M205835200 | doi-access = free }}</ref>

CBS enzyme activity is not found in all tissues and cells. It is absent from heart, lung, testes, adrenal, and spleen in rats. In humans, it has been shown to be absent in heart muscle and primary cultures of human aortic [[endothelial]] cells. The lack of CBS in these tissues implies that these tissues are unable to synthesize cysteine and that cysteine must be supplied from extracellular sources. It also suggests that these tissues might have increased sensitivity to homocysteine toxicity because they cannot catabolize excess homocysteine via transsulfuration.<ref name=Jhee />

== Regulation ==

[[allosteric regulation|Allosteric activation]] of CBS by [[S-adenosyl-L-methionine|adoMet]] determines the metabolic fate of [[homocysteine]]. Mammalian CBS is activated 2.5-5-fold by AdoMet with a [[dissociation constant]] of 15 μM.<ref name=janosik /> [[S-adenosyl-L-methionine|AdoMet]] is an allosteric activator that increases the [[Michaelis–Menten kinetics|V<sub>max</sub>]] of the CBS reaction but does not affect the [[Michaelis–Menten kinetics|K<sub>m</sub>]] for the substrates.  In other words, AdoMet stimulates CBS activity by increasing the turnover rate rather than the binding of substrates to the enzyme.<ref name=Ruma /> This protein may use the [[morpheein]] model of [[allosteric regulation]].<ref name=pmid22182754>{{cite journal | author = T. Selwood | author2 = E. K. Jaffe | name-list-style = amp | title = Dynamic dissociating homo-oligomers and the control of protein function | journal =  Arch. Biochem. Biophys. | volume =  519| issue =  2| pages =  131–43| year = 2011 | pmid = 22182754 | doi=10.1016/j.abb.2011.11.020 | pmc=3298769}}</ref>

Human CBS performs a crucial step in the [[Cysteine#Biosynthesis|biosynthetic pathway of cysteine]] by providing a regulatory control point for AdoMet. Homocysteine, after being methylated to [[methionine]], can be converted to AdoMet, which donates [[methyl]] groups to a variety of substrates, e.g., [[neurotransmitters]], [[proteins]], and [[nucleic acids]]. AdoMet functions as an allosteric activator of CBS and exerts control on its biosynthesis: low concentrations of AdoMet  result in low CBS activity, thereby funneling homocysteine into the [[transmethylation|transmethylation cycle]] toward AdoMet  formation. In contrast, high adoMet  concentrations funnel homocysteine into the [[transsulfuration pathway]] toward [[Cysteine#Biosynthesis|cysteine biosynthesis]].<ref name="Ignoul">{{cite journal | vauthors = Ignoul S, Eggermont J | title = CBS domains: structure, function, and pathology in human proteins | journal = American Journal of Physiology. Cell Physiology | volume = 289 | issue = 6 | pages = C1369–78 |date=December 2005 | pmid = 16275737 | doi = 10.1152/ajpcell.00282.2005 | url = http://ajpcell.physiology.org/cgi/pmidlookup?view=long&pmid=16275737 }}</ref>

In mammals, CBS is a highly regulated enzyme, which contains a [[heme]] cofactor that functions as a redox sensor,<ref name="pmid17087506"/> that can modulate its activity in response to changes in the redox potential. If the resting form of CBS in the cell has [[ferrous]] (Fe<sup>2+</sup>) heme, the potential exists for activating the enzyme under oxidizing conditions by conversion to the [[ferric]] (Fe<sup>3+</sup>) state.<ref name=Ruma /> The Fe<sup>2+</sup> form of the enzyme is inhibited upon binding CO or nitric oxide, whereas enzyme activity is doubled when the Fe<sup>2+</sup> is oxidized to Fe<sup>3+</sup>. The redox state of the [[heme]] is pH dependent, with oxidation of Fe<sup>2+</sup>–CBS to Fe<sup>3+</sup>–CBS being favored at low pH conditions.<ref name="pmid16505479">{{cite journal | vauthors = Puranik M, Weeks CL, Lahaye D, Kabil O, Taoka S, Nielsen SB, Groves JT, Banerjee R, Spiro TG | title = Dynamics of carbon monoxide binding to cystathionine beta-synthase | journal = The Journal of Biological Chemistry | volume = 281 | issue = 19 | pages = 13433–8 |date=May 2006 | pmid = 16505479 | doi = 10.1074/jbc.M600246200| pmc = 2745537 | doi-access = free }}</ref>

Since mammalian CBS contains a heme cofactor, whereas yeast and protozoan enzyme from ''[[Trypanosoma cruzi]]'' do not have heme cofactors, researchers have speculated that heme is not required for CBS activity.<ref name=Ruma />

CBS is regulated at the transcriptional level by [[NFYA|NF-Y]], [[Sp1 transcription factor|SP-1]], and [[Sp3 transcription factor|SP-3]].  In addition it is upregulated transcriptionally by [[glucocorticoid]]s and [[glycogen]], and downregulated by [[insulin]].  Methionine upregulates CBS at the post-transcriptional level.

== Human disease ==

[[Down syndrome]] is a medical condition characterized by an overexpression of cystathionine beta synthase (CBS) and a low level of homocysteine in the blood.
It has been speculated that cystathionine beta synthase overexpression could be the major culprit in this disease (along with dysfunctioning of GabaA and Dyrk1a). The phenotype of Down syndrome is the opposite of hyperhomocysteinemia (described below). Pharmacologicals inhibitors of CBS have been patented by the Jerome Lejeune Foundation (November 2011) and trials (animals and humans are planned).

[[Hyperhomocysteinemia]] is a medical condition characterized by an abnormally large level of [[homocysteine]] in the blood. Mutations in CBS are the single most common cause of hereditary hyperhomocysteinemia. Genetic defects that affect the [[MTHFR]], [[5-Methyltetrahydrofolate-homocysteine methyltransferase|MTR]], and [[Methionine synthase|MTRR/MS]] enzyme pathways can also contribute to high homocysteine levels. Inborn errors in CBS result in hyperhomocysteinemia with complications in the cardiovascular system leading to early and aggressive arterial disease. Hyperhomocysteinemia also affects three other major organ systems including the ocular, central nervous, and skeletal.<ref name=Ruma />

[[Homocystinuria]] due to CBS deficiency is a special type of hyperhomocysteinemia. It is a rare, hereditary recessive autosomal disease, in general diagnosed during childhood. A total of 131 different homocystinuria-causing mutations have been identified. A common functional feature of the mutations in the CBS domains is that the mutations abolish or strongly reduce activation by [[S-adenosyl-L-methionine|adoMet]].<ref name=Ignoul /> No specific cure has been discovered for homocystinuria; however, many people are treated using high doses of [[vitamin B6|vitamin B<sub>6</sub>]], which is a cofactor of CBS.

== Bioengineering ==

Cystathionine beta synthase (CBS) is involved in [[oocyte]] development. However, little is known about the regional and cellular expression patterns of CBS in the ovary and research is now focused on determining the location and expression during follicle development in the ovaries.<ref name="pmid17134586">{{cite journal | vauthors = Liang R, Yu WD, Du JB, Yang LJ, Shang M, Guo JZ | title = Localization of cystathionine beta synthase in mice ovaries and its expression profile during follicular development | journal = Chinese Medical Journal | volume = 119 | issue = 22 | pages = 1877–83 | date = November 2006 | doi = 10.1097/00029330-200611020-00006 | pmid = 17134586 | s2cid = 23891500 | doi-access = free }}</ref>

Absence of Cystathionine beta synthase in mice provokes infertility due to the loss of uterine protein expression.<ref name="Guzmán_2006">{{cite journal | vauthors = Guzmán MA, Navarro MA, Carnicer R, Sarría AJ, Acín S, Arnal C, Muniesa P, Surra JC, Arbonés-Mainar JM, Maeda N, Osada J | title = Cystathionine beta-synthase is essential for female reproductive function | journal = Human Molecular Genetics | volume = 15 | issue = 21 | pages = 3168–76 | date = November 2006 | pmid = 16984962 | doi = 10.1093/hmg/ddl393 | doi-access = free }}</ref>

== Mutations ==

The genes that control CBS enzyme expression may not operate at 100% efficiency in individuals who have one of the SNPs ([[single-nucleotide polymorphisms]], a type of [[mutations]]) that affect this gene. Known variants include the A360A, C699T, I278T, N212N, and T42N SNPs (among others). These SNPs, which have varied effects on the effectiveness of the enzyme, can be detected with standard DNA testing methods.

== See also ==
* [[Homocystinuria]]
* [[Cysteine]]
* [[DNA methylation]]
* [[Metabolism]]
* [[Amino acid]]
* [[S-Adenosyl-L-methionine]]
* [[Heme]]

==References==
{{Reflist}}

==Further reading==
{{refbegin | 2}}
*{{cite journal  | author=Kraus JP |title=Komrower Lecture. Molecular basis of phenotype expression in homocystinuria |journal=J. Inherit. Metab. Dis. |volume=17 |issue= 4 |pages= 383–90 |year= 1994 |pmid= 7967489 |doi=10.1007/BF00711354  |s2cid=42317828 }}
*{{cite journal  | vauthors=Kraus JP, Janosík M, Kozich V |title=Cystathionine beta-synthase mutations in homocystinuria |journal=Hum. Mutat. |volume=13 |issue= 5 |pages= 362–75 |year= 1999 |pmid= 10338090 |doi= 10.1002/(SICI)1098-1004(1999)13:5<362::AID-HUMU4>3.0.CO;2-K |s2cid=86447340 |display-authors=etal}}
*{{cite journal  | author=Jones AL |title=The localization and interactions of huntingtin |journal=Philos. Trans. R. Soc. Lond. B Biol. Sci. |volume=354 |issue= 1386 |pages= 1021–7 |year= 1999 |pmid= 10434301 |doi= 10.1098/rstb.1999.0454  | pmc=1692601 }}
*{{cite journal  | vauthors=Griffiths R, Tudball N |title=The molecular defect in a case of (cystathionine beta-synthase)-deficient homocystinuria |journal=Eur. J. Biochem. |volume=74 |issue= 2 |pages= 269–73 |year= 1977 |pmid= 404147 |doi=10.1111/j.1432-1033.1977.tb11390.x  |doi-access=free }}
*{{cite journal  | vauthors=Kraus J, Packman S, Fowler B, Rosenberg LE |title=Purification and properties of cystathionine beta-synthase from human liver. Evidence for identical subunits |journal=J. Biol. Chem. |volume=253 |issue= 18 |pages= 6523–8 |year= 1978 |doi=10.1016/S0021-9258(19)46963-9 |pmid= 681363 |doi-access=free }}
*{{cite journal  | vauthors=Longhi RC, Fleisher LD, Tallan HH, Gaull GE |title=Cystathionine beta-synthase deficiency: a qualitative abnormality of the deficient enzyme modified by vitamin B<sub>6</sub> therapy |journal=Pediatr. Res. |volume=11 |issue= 2 |pages= 100–3 |year= 1977 |pmid= 840498 |doi=10.1203/00006450-197702000-00003  |doi-access=free }}
*{{cite journal  | vauthors=Kozich V, Kraus JP |title=Screening for mutations by expressing patient cDNA segments in E. coli: homocystinuria due to cystathionine beta-synthase deficiency |journal=Hum. Mutat. |volume=1 |issue= 2 |pages= 113–23 |year= 1993 |pmid= 1301198 |doi= 10.1002/humu.1380010206 |s2cid=36663527 |doi-access=free }}
*{{cite journal  | vauthors=Münke M, Kraus JP, Ohura T, Francke U |title=The gene for cystathionine beta-synthase (CBS) maps to the subtelomeric region on human chromosome 21q and to proximal mouse chromosome 17 |journal=Am. J. Hum. Genet. |volume=42 |issue= 4 |pages= 550–9 |year= 1988 |pmid= 2894761 | pmc=1715237  }}
*{{cite journal  | vauthors=Hu FL, Gu Z, Kozich V |title=Molecular basis of cystathionine beta-synthase deficiency in pyridoxine responsive and nonresponsive homocystinuria |journal=Hum. Mol. Genet. |volume=2 |issue= 11 |pages= 1857–60 |year= 1994 |pmid= 7506602 |doi=10.1093/hmg/2.11.1857  |display-authors=etal}}
*{{cite journal  | vauthors=Sperandeo MP, Panico M, Pepe A |title=Molecular analysis of patients affected by homocystinuria due to cystathionine beta-synthase deficiency: report of a new mutation in exon 8 and a deletion in intron 11 |journal=J. Inherit. Metab. Dis. |volume=18 |issue= 2 |pages= 211–4 |year= 1995 |pmid= 7564249 |doi=10.1007/BF00711769  |s2cid=40407615 |display-authors=etal}}
*{{cite journal  | vauthors=Chassé JF, Paly E, Paris D |title=Genomic organization of the human cystathionine beta-synthase gene: evidence for various cDNAs |journal=Biochem. Biophys. Res. Commun. |volume=211 |issue= 3 |pages= 826–32 |year= 1995 |pmid= 7598711 |doi= 10.1006/bbrc.1995.1886 |display-authors=etal}}
*{{cite journal  | vauthors=Shih VE, Fringer JM, Mandell R |title=A missense mutation (I278T) in the cystathionine beta-synthase gene prevalent in pyridoxine-responsive homocystinuria and associated with mild clinical phenotype |journal=Am. J. Hum. Genet. |volume=57 |issue= 1 |pages= 34–9 |year= 1995 |pmid= 7611293 | pmc=1801250  |display-authors=etal}}
*{{cite journal  | vauthors=Kluijtmans LA, Blom HJ, Boers GH |title=Two novel missense mutations in the cystathionine beta-synthase gene in homocystinuric patients |journal=Hum. Genet. |volume=96 |issue= 2 |pages= 249–50 |year= 1995 |pmid= 7635485 |doi=10.1007/BF00207394  |s2cid=6642338 |display-authors=etal}}
*{{cite journal  | vauthors=Sebastio G, Sperandeo MP, Panico M |title=The molecular basis of homocystinuria due to cystathionine beta-synthase deficiency in Italian families, and report of four novel mutations |journal=Am. J. Hum. Genet. |volume=56 |issue= 6 |pages= 1324–33 |year= 1995 |pmid= 7762555 | pmc=1801112  |display-authors=etal}}
*{{cite journal  | vauthors=Marble M, Geraghty MT, de Franchis R |title=Characterization of a cystathionine beta-synthase allele with three mutations in cis in a patient with B<sub>6</sub> nonresponsive homocystinuria |journal=Hum. Mol. Genet. |volume=3 |issue= 10 |pages= 1883–6 |year= 1995 |pmid= 7849717 |doi=10.1093/hmg/3.10.1883  |display-authors=etal}}
*{{cite journal  | vauthors=Kraus JP, Le K, Swaroop M |title=Human cystathionine beta-synthase cDNA: sequence, alternative splicing and expression in cultured cells |journal=Hum. Mol. Genet. |volume=2 |issue= 10 |pages= 1633–8 |year= 1994 |pmid= 7903580 |doi=10.1093/hmg/2.10.1633  |display-authors=etal}}
*{{cite journal  | vauthors=de Franchis R, Kozich V, McInnes RR, Kraus JP |title=Identical genotypes in siblings with different homocystinuric phenotypes: identification of three mutations in cystathionine beta-synthase using an improved bacterial expression system |journal=Hum. Mol. Genet. |volume=3 |issue= 7 |pages= 1103–8 |year= 1995 |pmid= 7981678 |doi=10.1093/hmg/3.7.1103  }}
*{{cite journal  | vauthors=Kruger WD, Cox DR |title=A yeast system for expression of human cystathionine beta-synthase: structural and functional conservation of the human and yeast genes |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=91 |issue= 14 |pages= 6614–8 |year= 1994 |pmid= 8022826 |doi=  10.1073/pnas.91.14.6614| pmc=44253  |bibcode=1994PNAS...91.6614K |doi-access=free }}
*{{cite journal  | vauthors=Kozich V, de Franchis R, Kraus JP |title=Molecular defect in a patient with pyridoxine-responsive homocystinuria |journal=Hum. Mol. Genet. |volume=2 |issue= 6 |pages= 815–6 |year= 1993 |pmid= 8353501 |doi=10.1093/hmg/2.6.815  }}
{{refend}}

== External links ==
* [https://archive.today/20070928010229/http://www.uchsc.edu/cbs/cbsdata/cbs_02.htm CBS Main Page at University of Colorado Health Sciences Center]
* [http://www.brenda.uni-koeln.de/index.php4?page=information/all_enzymes.php4?ecno=4.2.1.22 Cystathionine beta-synthase in BRENDA: The Comprehensive Enzyme Information System]{{dead link|date=August 2017 |bot=InternetArchiveBot |fix-attempted=yes }}
* [http://www.rcsb.org/pdb/explore.do?structureId=1JBQ Cystathionine beta-Synthase: Protein Data Bank Entry]

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{{DEFAULTSORT:Cystathionine Beta Synthase}}
[[Category:EC 4.2.1]]
[[Category:Pyridoxal phosphate enzymes]]
[[Category:Enzymes of known structure]]