cystathionine synthase

シスタチオニンβ-シンターゼ

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2016/07/24 14:55:10」(JST)

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CBS
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 1JBQ, 1M54, 4COO, 4L0D, 4L27, 4L28, 4L3V, 4PCU, 4UUU
Identifiers
Aliases	CBS, HIP4, cystathionine-beta-synthase
External IDs	OMIM: 613381 MGI: 88285 HomoloGene: 37258 GeneCards: 875
Genetically Related Diseases
Disease Name		References
obesity		[1]
Gene ontology Molecular function • oxygen binding • protein homodimerization activity • cystathionine beta-synthase activity • metal ion binding • nitric oxide binding • catalytic activity • protein binding • heme binding • modified amino acid binding • S-adenosyl-L-methionine binding • lyase activity • identical protein binding • enzyme binding • pyridoxal phosphate binding • cysteine synthase activity • nitrite reductase (NO-forming) activity • ubiquitin protein ligase binding • carbon monoxide binding Cellular component • cytoplasm • cytosol • nucleus Biological process • transsulfuration • cysteine biosynthetic process via cystathionine • L-serine metabolic process • DNA protection • cellular amino acid biosynthetic process • L-serine catabolic process • selenium compound metabolic process • cysteine biosynthetic process • homocysteine catabolic process • sulfur amino acid metabolic process • cellular nitrogen compound metabolic process • small molecule metabolic process • hydrogen sulfide biosynthetic process • metabolic process • homocysteine metabolic process • oxidation-reduction process • cysteine biosynthetic process from serine • L-cysteine catabolic process Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	875	12411
Ensembl	ENSG00000160200	ENSMUSG00000024039
UniProt	P35520	Q91WT9
RefSeq (mRNA)	NM_000071 NM_001178008 NM_001178009 NM_001320298 NM_001321072	NM_001271353 NM_144855 NM_178224
RefSeq (protein)	NP_000062.1 NP_001171479.1 NP_001171480.1	NP_001258282.1 NP_659104.1 NP_835742.1
Location (UCSC)	Chr 21: 43.05 – 43.08 Mb	Chr 17: 31.61 – 31.64 Mb
PubMed search	[2]	[3]
Wikidata
View/Edit Human		View/Edit Mouse

Cystathionine-β-synthase, also known as CBS, is an enzyme (EC 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:

L-serine + L-homocysteine $\rightleftharpoons$ L-cystathionine + H₂O

CBS uses the cofactor pyridoxal-phosphate (PLP) and can be allosterically regulated by effectors such as the ubiquitous cofactor S-adenosyl-L-methionine (adoMet). This enzyme belongs to the family of lyases, 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 domains. The CBS gene is the most common locus for mutations associated with homocystinuria.

Nomenclature

The systematic name of this enzyme class is L-serine hydro-lyase (adding homocysteine; L-cystathionine-forming). Other names in common use include:

• beta-thionase,
• cysteine synthase,
• L-serine hydro-lyase (adding homocysteine),
• methylcysteine synthase,
• serine sulfhydrase, and
• serine sulfhydrylase.

Methylcysteine synthase was assigned the 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.

Structure

Sequence and secondary structure of the CBS enzyme.

The human enzyme cystathionine β-synthase is a tetramer and comprises 551 amino acids 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 PLP cofactor. The cofactor is deep in the heme domain and is linked by a Schiff base. 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 mammalian 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. 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. This inhibition is alleviated by binding of the allosteric effector, adoMet, or by deletion of the regulatory domain; however, the magnitude of the effects differ. Mutations in this domain are correlated with hereditary diseases.

The heme domain contains an N-terminal loop that binds heme and provides the axial ligands C52 and H65. The distance of heme from the 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. The presence of protoporphyrin IX in CBS is a unique PLP-dependent enzyme and is only found in the mammalian CBS. D. melanogaster and D. discoides have truncated N-terminal extensions and therefore prevent the conserved histidine and cysteine heme ligand residues. 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. The 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 dimeric 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.

As of late 2007, two structures have been solved for this class of enzymes, with PDB accession codes 1JBQ and 1M54.

Enzymatic activity

cystathionine beta-synthase
Identifiers
EC number	4.2.1.22
CAS number	9023-99-8
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / EGO
Search PMC articles PubMed articles NCBI proteins

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.

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.

In analogy with other β-replacement enzymes, the reaction catalyzed by CBS is predicted to involve a series of adoMet-bound intermediates. Addition of serine results in a 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. The final product, L-cystathionine can also form an aminoacrylate intermediate, indicating that the entire reaction of CBS is reversible.

The measured V₀ of an enzyme-catalyzed reaction, in general, reflects the steady state (where [ES] is constant), even though V₀ 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-substitutent of serine is not released from the enzyme prior to binding of homocysteine.

One of the alternate reactions involving CBS is the condensation of cysteine with homocysteine to form cystathionine and hydrogen sulfide (H₂S). H₂S in the brain is produced from L-cysteine by CBS. This alternative metabolic pathway is also dependent on adoMet.

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.

Regulation

Allosteric activation of CBS by adoMet determines the metabolic fate of homocysteine. Mammalian CBS is activated 2.5-5-fold by AdoMet with a dissociation constant of 15 µM. AdoMet is an allosteric activator that increases the V_max of the CBS reaction but does not affect the K_m for the substrates. In other words, AdoMet stimulates CBS activity by increasing the turnover rate rather than the binding of substrates to the enzyme. This protein may use the morpheein model of allosteric regulation.

Human CBS performs a crucial step in the 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 cycle toward AdoMet formation. In contrast, high adoMet concentrations funnel homocysteine into the transsulfuration pathway toward cysteine biosynthesis.

In mammals, CBS is a highly regulated enzyme, which contains a heme cofactor that functions as a redox sensor, that can modulate its activity in response to changes in the redox potential. If the resting form of CBS in the cell has ferrous (Fe²⁺) heme, the potential exists for activating the enzyme under oxidizing conditions by conversion to the ferric (Fe³⁺) state. The Fe²⁺ form of the enzyme is inhibited upon binding CO or nitric oxide, whereas enzyme activity is doubled when the Fe²⁺ is oxidized to Fe³⁺. The redox state of the heme is pH dependent, with oxidation of Fe²⁺–CBS to Fe³⁺–CBS being favored at low pH conditions.

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.

CBS is regulated at the transcriptional level by NF-Y, SP-1, and SP-3. In addition it is upregulated transcriptionally by glucocorticoids 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. 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.

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 adoMet. No specific cure has been discovered for homocystinuria; however, many people are treated using high doses of vitamin B₆, 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.

See also

• Homocystinuria
• Cysteine
• Metabolism
• Amino Acids
• S-Adenosyl-L-methionine
• Heme

References

Further reading

• Kraus JP (1994). "Komrower Lecture. Molecular basis of phenotype expression in homocystinuria". J. Inherit. Metab. Dis. 17 (4): 383–90. doi:10.1007/BF00711354. PMID 7967489. 
• Kraus JP, Janosík M, Kozich V, et al. (1999). "Cystathionine beta-synthase mutations in homocystinuria". Hum. Mutat. 13 (5): 362–75. doi:10.1002/(SICI)1098-1004(1999)13:5<362::AID-HUMU4>3.0.CO;2-K. PMID 10338090. 
• Jones AL (1999). "The localization and interactions of huntingtin". Philos. Trans. R. Soc. Lond., B, Biol. Sci. 354 (1386): 1021–7. doi:10.1098/rstb.1999.0454. PMC 1692601. PMID 10434301. 
• Griffiths R, Tudball N (1977). "The molecular defect in a case of (cystathionine beta-synthase)-deficient homocystinuria". Eur. J. Biochem. 74 (2): 269–73. doi:10.1111/j.1432-1033.1977.tb11390.x. PMID 404147. 
• Kraus J, Packman S, Fowler B, Rosenberg LE (1978). "Purification and properties of cystathionine beta-synthase from human liver. Evidence for identical subunits". J. Biol. Chem. 253 (18): 6523–8. PMID 681363. 
• Longhi RC, Fleisher LD, Tallan HH, Gaull GE (1977). "Cystathionine beta-synthase deficiency: a qualitative abnormality of the deficient enzyme modified by vitamin B₆ therapy". Pediatr. Res. 11 (2): 100–3. doi:10.1203/00006450-197702000-00003. PMID 840498. 
• Kozich V, Kraus JP (1993). "Screening for mutations by expressing patient cDNA segments in E. coli: homocystinuria due to cystathionine beta-synthase deficiency". Hum. Mutat. 1 (2): 113–23. doi:10.1002/humu.1380010206. PMID 1301198. 
• Münke M, Kraus JP, Ohura T, Francke U (1988). "The gene for cystathionine beta-synthase (CBS) maps to the subtelomeric region on human chromosome 21q and to proximal mouse chromosome 17". Am. J. Hum. Genet. 42 (4): 550–9. PMC 1715237. PMID 2894761. 
• Hu FL, Gu Z, Kozich V, et al. (1994). "Molecular basis of cystathionine beta-synthase deficiency in pyridoxine responsive and nonresponsive homocystinuria". Hum. Mol. Genet. 2 (11): 1857–60. doi:10.1093/hmg/2.11.1857. PMID 7506602. 
• Sperandeo MP, Panico M, Pepe A, et al. (1995). "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". J. Inherit. Metab. Dis. 18 (2): 211–4. doi:10.1007/BF00711769. PMID 7564249. 
• Chassé JF, Paly E, Paris D, et al. (1995). "Genomic organization of the human cystathionine beta-synthase gene: evidence for various cDNAs". Biochem. Biophys. Res. Commun. 211 (3): 826–32. doi:10.1006/bbrc.1995.1886. PMID 7598711. 
• Shih VE, Fringer JM, Mandell R, et al. (1995). "A missense mutation (I278T) in the cystathionine beta-synthase gene prevalent in pyridoxine-responsive homocystinuria and associated with mild clinical phenotype". Am. J. Hum. Genet. 57 (1): 34–9. PMC 1801250. PMID 7611293. 
• Kluijtmans LA, Blom HJ, Boers GH, et al. (1995). "Two novel missense mutations in the cystathionine beta-synthase gene in homocystinuric patients". Hum. Genet. 96 (2): 249–50. doi:10.1007/BF00207394. PMID 7635485. 
• Sebastio G, Sperandeo MP, Panico M, et al. (1995). "The molecular basis of homocystinuria due to cystathionine beta-synthase deficiency in Italian families, and report of four novel mutations". Am. J. Hum. Genet. 56 (6): 1324–33. PMC 1801112. PMID 7762555. 
• Marble M, Geraghty MT, de Franchis R, et al. (1995). "Characterization of a cystathionine beta-synthase allele with three mutations in cis in a patient with B₆ nonresponsive homocystinuria". Hum. Mol. Genet. 3 (10): 1883–6. doi:10.1093/hmg/3.10.1883. PMID 7849717. 
• Kraus JP, Le K, Swaroop M, et al. (1994). "Human cystathionine beta-synthase cDNA: sequence, alternative splicing and expression in cultured cells". Hum. Mol. Genet. 2 (10): 1633–8. doi:10.1093/hmg/2.10.1633. PMID 7903580. 
• de Franchis R, Kozich V, McInnes RR, Kraus JP (1995). "Identical genotypes in siblings with different homocystinuric phenotypes: identification of three mutations in cystathionine beta-synthase using an improved bacterial expression system". Hum. Mol. Genet. 3 (7): 1103–8. doi:10.1093/hmg/3.7.1103. PMID 7981678. 
• Kruger WD, Cox DR (1994). "A yeast system for expression of human cystathionine beta-synthase: structural and functional conservation of the human and yeast genes". Proc. Natl. Acad. Sci. U.S.A. 91 (14): 6614–8. doi:10.1073/pnas.91.14.6614. PMC 44253. PMID 8022826. 
• Kozich V, de Franchis R, Kraus JP (1993). "Molecular defect in a patient with pyridoxine-responsive homocystinuria". Hum. Mol. Genet. 2 (6): 815–6. doi:10.1093/hmg/2.6.815. PMID 8353501. 

External links

• CBS Main Page at University of Colorado Health Sciences Center
• Cystathionine beta-synthase in BRENDA: The Comprehensive Enzyme Information System
• Cystathionine beta-Synthase: Protein Data Bank Entry

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

• 1. ホモシステインの概要 overview of homocysteine
• 2. 先天性代謝異常：疫学、病因、および臨床的特徴 inborn errors of metabolism epidemiology pathogenesis and clinical features
• 3. 水溶性ビタミンの概要 overview of water soluble vitamins
• 4. 小児および若年成人における虚血性脳卒中：病因と臨床的特徴 ischemic stroke in children and young adults etiology and clinical features
• 5. 切除不能悪性胸膜中皮腫に対する全身療法 systemic treatment for unresectable malignant pleural mesothelioma

English Journal

• The gasotransmitter hydrogen sulfide induces nrf2-target genes by inactivating the keap1 ubiquitin ligase substrate adaptor through formation of a disulfide bond between cys-226 and cys-613.

• Hourihan JM, Kenna JG, Hayes JD.Source1 Jacqui Wood Cancer Centre, Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee , Dundee, Scotland, United Kingdom .
• Antioxidants & redox signaling.Antioxid Redox Signal.2013 Aug 10;19(5):465-81. doi: 10.1089/ars.2012.4944. Epub 2013 Jan 16.
• Abstract Aims: The signaling molecule hydrogen sulfide (H2S) protects cells against oxidative stress and activates NF-E2 p45-related factor 2 (Nrf2), a transcription factor that regulates antioxidant genes. We sought to establish whether H2S requires Nrf2 to protect against oxidative stress, and whe
• PMID 23145493

• Hyperhomocysteinemia is detrimental to pregnancy in mice and is associated with preterm birth.

• Sonne SR, Bhalla VK, Barman SA, White RE, Zhu S, Newman TM, Prasad PD, Smith SB, Offermanns S, Ganapathy V.SourceDepartment of Biochemistry and Molecular Biology, Georgia Regents University, Augusta, GA 30912, USA. Electronic address: ssonne@gru.edu.
• Biochimica et biophysica acta.Biochim Biophys Acta.2013 Aug;1832(8):1149-58. doi: 10.1016/j.bbadis.2013.04.006. Epub 2013 Apr 8.
• Elevated levels of homocysteine produce detrimental effects in humans but its role in preterm birth is not known. Here we used a mouse model of hyperhomocysteinemia to examine the relevance of homocysteine to preterm birth. The mouse carries a heterozygous deletion of cystathionine β-synthase (Cbs(
• PMID 23579073

• Tumor-derived hydrogen sulfide, produced by cystathionine-β-synthase, stimulates bioenergetics, cell proliferation, and angiogenesis in colon cancer.

• Szabo C, Coletta C, Chao C, Módis K, Szczesny B, Papapetropoulos A, Hellmich MR.SourceDepartments of Anesthesiology, Surgery, and Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555.
• Proceedings of the National Academy of Sciences of the United States of America.Proc Natl Acad Sci U S A.2013 Jul 8. [Epub ahead of print]
• The physiological functions of hydrogen sulfide (H2S) include vasorelaxation, stimulation of cellular bioenergetics, and promotion of angiogenesis. Analysis of human colon cancer biopsies and patient-matched normal margin mucosa revealed the selective up-regulation of the H2S-producing enzyme cystat
• PMID 23836652

Japanese Journal

• A Cystathionine-β-Synthase Domain-Containing Protein, CBSX2, Regulates Endothecial Secondary Cell Wall Thickening in Anther Development

• Jung Kwang Wook,Kim Yun Young,Yoo Kyoung Shin [他]
• Plant and Cell Physiology 54(2), 195-208, 2013-02
• NAID 40019596714

• 十二指腸重炭酸イオン分泌における硫化水素の役割

• 林 周作,竹内 孝治
• 日本薬理學雜誌 = Folia pharmacologica Japonica 139(1), 9-12, 2012-01-01
• … 硫化水素（H2S）は哺乳動物の体内でL-システインからcystathionine <I>β</I>-synthaseやcystathionine <I>γ</I>-lyaseなどの産生酵素によって作られており，ガス状のシグナル分子として認識されている．近年，H2Sは神経調節物質や平滑筋弛緩因子として機能することが提案され，細胞保護，抗炎症作用や疼痛への関与など生体内において多様な役割を演じていることが明らか …
• NAID 10030455950

• 硫化水素 : 生合成, 放出, 生理機能

• 木村 英雄
• 日本薬理學雜誌 = Folia pharmacologica Japonica 139(1), 6-8, 2012-01-01
• … 卵の腐敗臭を放つ毒ガスとして知られている硫化水素（H2S）が，生体内で作られることが日本でもようやく知られるようになってきた．Cystathionine <I>β</I>-synthase（CBS），cystathionine <I>γ</I>-lyase（CSE），3-mercaptopyruvate surfurtransferase（3MST）の3つの酵素が脳，肝臓，腎臓，血管，膵島などでH2Sを生産する．そして，神経伝達調節，平滑筋弛緩，細胞保護作用，インスリ …
• NAID 10030455931

Related Links

• Homocystinuria Caused by Cystathionine Beta-Synthase ...

Homocystinuria caused by cystathionine β-synthase (CBS) deficiency is characterized by developmental delay/intellectual disability, ectopia lentis and/or severe myopia, skeletal abnormalities (excessive height and length of the ...

• CBS cystathionine-beta-synthase [ (human)]

The protein encoded by this gene acts as a homotetramer to catalyze the conversion of homocysteine to cystathionine, the first step in the transsulfuration pathway. The encoded protein is allosterically activated by ...

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★リンクテーブル★

リンク元	「シスタチオニンβ-シンターゼ」
拡張検索	「cystathionine synthase deficiency」
関連記事	「synthase」

「シスタチオニンβ-シンターゼ」

　　[★]

英

cystathionine beta-synthase

同

シスタチオニン合成酵素、cystathionine synthase、シスタチオニンβシンターゼ

関

PLP酵素

• ホモシステイン　－(cystathionine synthase)→ シスタチオニン
• 補酵素：PLP(ビタミンB6)

臨床関連

• ホモシスチン尿症 homocystinuria

「cystathionine synthase deficiency」

　　[★] シスタチオニン合成酵素欠損症

「synthase」

　　[★]

• n.

• (脱離酵素リアーゼの逆反応である合成方向の反応を指す) シンターゼ, 合成酵素, 付加酵素

関

lyase、synthetase、transferase