WordNet

to remain unmolested, undisturbed, or uninterrupted -- used only in infinitive form; "let her be"
work in a specific place, with a specific subject, or in a specific function; "He is a herpetologist"; "She is our resident philosopher" (同)follow
have life, be alive; "Our great leader is no more"; "My grandfather lived until the end of war" (同)live
be identical to; be someone or something; "The president of the company is John Smith"; "This is my house"
happen, occur, take place; "I lost my wallet; this was during the visit to my parents house"; "There were two hundred people at his funeral"; "There was a lot of noise in the kitchen"
have the quality of being; (copula, used with an adjective or a predicate noun); "John is rich"; "This is not a good answer"
occupy a certain position or area; be somewhere; "Where is my umbrella?" "The toolshed is in the back"; "What is behind this behavior?"
spend or use time; "I may be an hour"
stake on the outcome of an issue; "I bet $100 on that new horse"; "She played all her money on the dark horse" (同)wager, play
the act of gambling; "he did it on a bet" (同)wager
maintain with or as if with a bet; "I bet she will be there!" (同)wager
second in order of importance; "the candidate, considered a beta male, was perceived to be unable to lead his party to victory"
the 2nd letter of the Greek alphabet
preliminary or testing stage of a software or hardware product; "a beta version"; "beta software"
beets (同)genus Beta

PrepTutorEJDIC

《連結語として補語を伴なって…『である』,…だ,…です / 《位置・場所を表す語句を伴って》(…に)『ある』,いる(occupy a place or situation) / 〈物事が〉『存在する』,ある(exist);〈生物が〉生存する,生きている(live) / 行われる,起こる,発生する(take place, occur) / 存続する,そのままでいる(remain as before) / 《『be to』 do》 / …する予定である,…することになっている / …すべきだ / 《受動態の不定詞を伴って》…できる / 《命令》…するのだ / 《条件節に》…する意図がある / 《『if…were to』 do》…するとしたなら / 《『be』 do『ing』》《進行形》 / 《進行中の動作》…している,しつつある / 《近い未来》…しようとしている,するつもり / 《動作の反復》(いつも)…している / 《『be』+『他動詞の過去分詞』》《受動態》…される,されている / 《『be』+『自動詞の過去分詞』》《完了形》…した[状態にある]
『かけ』・(…との)かけ《+『with』+『名』》 / かけた物(金) / かけの対象 / 〈金・物〉'を'『かける』 / (かけ事・ゲームなどで)〈人〉‘と'『かけをする』《+『名』〈人〉+『on』+『名』》 / (…に)『かける』《+『on』(『against』)+『名』(one's do『ing』)》
ベータ(ギリシア語アルファベットの第2文字;B,β;英語のB,b に遭当)

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/11/30 16:06:19」(JST)

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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:^[2]

L-serine + L-homocysteine 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.^[3]

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. ^[4]

Structure

Sequence and secondary structure of the CBS enzyme.^[1]

The human enzyme cystathionine β-synthase is a tetramer and comprises 551 amino acids with a subunit molecular weight of 63 kDa. It displays a modular organization of three modules with the N-terminal heme domain followed by a core that contains the PLP cofactor.^[5] The cofactor is deep in the heme domain and is linked by a Schiff base.^[6] 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.^[5] 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.^[5] 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.^[5] Mutations in this domain are correlated with hereditary diseases.^[7]

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.^[6] 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.^[5] 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.^[5]

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

Enzymatic activity

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.^[8]

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.^[5]

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.^[5] The final product, L-cystathionine can also form an aminoacrylate intermediate, indicating that the entire reaction of CBS is reversible.^[9]

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.^[5]

One of the alternate reactions involving CBS is the condensation of cysteine with homocysteine to form cystathionine and hydrogen sulfide (H₂S).^[9] H₂S in the brain is produced from L-cysteine by CBS. This alternative metabolic pathway is also dependent on adoMet.^[10]

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.^[9]

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.^[3] 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.^[5] This protein may use the morpheein model of allosteric regulation. ^[11]

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.^[12]

In mammals, CBS is a highly regulated enzyme, which contains a heme cofactor that functions as a redox sensor,^[7] 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.^[5] 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.^[13]

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.^[5]

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.^[5]

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.^[12] 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.^[14]

References

^ ^a ^b PDB: 1JBQ; Meier M, Janosik M, Kery V, Kraus JP, Burkhard P (August 2001). "Structure of human cystathionine beta-synthase: a unique pyridoxal 5'-phosphate-dependent heme protein". The EMBO Journal 20 (15): 3910–6. doi:10.1093/emboj/20.15.3910. PMC 149156. PMID 11483494.
^ "Entrez Gene: CBS cystathionine-beta-synthase".
^ ^a ^b Janosík M, Kery V, Gaustadnes M, Maclean KN, Kraus JP (September 2001). "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". Biochemistry 40 (35): 10625–33. doi:10.1021/bi010711p. PMID 11524006.
^ EC 4.2.1.23
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m Banerjee R, Zou CG (January 2005). "Redox regulation and reaction mechanism of human cystathionine-beta-synthase: a PLP-dependent hemesensor protein". Archives of Biochemistry and Biophysics 433 (1): 144–56. doi:10.1016/j.abb.2004.08.037. PMID 15581573.
^ ^a ^b Yamanishi M, Kabil O, Sen S, Banerjee R (December 2006). "Structural insights into pathogenic mutations in heme-dependent cystathionine-beta-synthase". Journal of Inorganic Biochemistry 100 (12): 1988–95. doi:10.1016/j.jinorgbio.2006.08.020. PMID 17069888.
^ ^a ^b Kabil O, Zhou Y, Banerjee R (November 2006). "Human cystathionine beta-synthase is a target for sumoylation". Biochemistry 45 (45): 13528–36. doi:10.1021/bi0615644. PMID 17087506.
^ Nozaki T, Shigeta Y, Saito-Nakano Y, Imada M, Kruger WD (March 2001). "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". The Journal of Biological Chemistry 276 (9): 6516–23. doi:10.1074/jbc.M009774200. PMID 11106665.
^ ^a ^b ^c Jhee KH, Kruger WD (2005). "The role of cystathionine beta-synthase in homocysteine metabolism". Antioxidants & Redox Signaling 7 (5–6): 813–22. doi:10.1089/ars.2005.7.813. PMID 15890029.
^ Eto K, Kimura H (November 2002). "A novel enhancing mechanism for hydrogen sulfide-producing activity of cystathionine beta-synthase". The Journal of Biological Chemistry 277 (45): 42680–5. doi:10.1074/jbc.M205835200. PMID 12213817.
^ T. Selwood and E. K. Jaffe. (2011). "Dynamic dissociating homo-oligomers and the control of protein function". Arch. Biochem. Biophys. 519 (2): 131–43. doi:10.1016/j.abb.2011.11.020. PMC 3298769. PMID 22182754.
^ ^a ^b Ignoul S, Eggermont J (December 2005). "CBS domains: structure, function, and pathology in human proteins". American Journal of Physiology. Cell Physiology 289 (6): C1369–78. doi:10.1152/ajpcell.00282.2005. PMID 16275737.
^ Puranik M, Weeks CL, Lahaye D, Kabil O, Taoka S, Nielsen SB, Groves JT, Banerjee R, Spiro TG (May 2006). "Dynamics of carbon monoxide binding to cystathionine beta-synthase". The Journal of Biological Chemistry 281 (19): 13433–8. doi:10.1074/jbc.M600246200. PMC 2745537. PMID 16505479.
^ Liang R, Yu WD, Du JB, Yang LJ, Shang M, Guo JZ (November 2006). "Localization of cystathionine beta synthase in mice ovaries and its expression profile during follicular development". Chinese Medical Journal 119 (22): 1877–83. PMID 17134586.

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. 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
2. ホモシステインの概要 overview of homocysteine
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

BODIPY-based azamacrocyclic ensemble for selective fluorescence detection and quantification of homocysteine in biological applications.

Li Z1, Geng ZR2, Zhang C1, Wang XB1, Wang ZL3.
Biosensors & bioelectronics.Biosens Bioelectron.2015 Oct 15;72:1-9. doi: 10.1016/j.bios.2015.04.085. Epub 2015 Apr 28.
Considering the significant role of plasma homocysteine in physiological processes, two ensembles (F465-Cu(2+) and F508-Cu(2+)) were constructed based on a BODIPY (4,4-difluoro-1,3,5,7-tetramethyl-4-bora-3a,4a-diaza-s-indacene) scaffold conjugated with an azamacrocyclic (1,4,7-triazacyclononane and
PMID 25951084

Sodium thiosulfate protects brain in rat model of adenine induced vascular calcification.

Subhash N1, Sriram R2, Kurian GA3.
Neurochemistry international.Neurochem Int.2015 Sep 9. pii: S0197-0186(15)30046-2. doi: 10.1016/j.neuint.2015.09.004. [Epub ahead of print]
Vascular bed calcification is a common feature of ends stage renal disease that may lead to a complication in cardiovascular and cerebrovascular beds, which is a promoting cause of myocardial infarction, stroke, dementia and aneurysms. Sodium thiosulfate (STS) due to its multiple properties such as
PMID 26363090

Laminar shear flow increases hydrogen sulfide and activates a nitric oxide producing signaling cascade in endothelial cells.

Huang B1, Chen CT2, Chen CS3, Wang YM4, Hsieh HJ5, Wang DL6.
Biochemical and biophysical research communications.Biochem Biophys Res Commun.2015 Sep 4;464(4):1254-9. doi: 10.1016/j.bbrc.2015.07.115. Epub 2015 Jul 26.
Laminar shear flow triggers a signaling cascade that maintains the integrity of endothelial cells (ECs). Hydrogen sulfide (H2S), a new gasotransmitter is regarded as an upstream regulator of nitric oxide (NO). Whether the H2S-generating enzymes are correlated to the enzymes involved in NO production
PMID 26212441

Japanese Journal

L-serine attenuate steatosis by suppression of hyperhomocysteinemia

SIM Woo-Cheol,CHOI Ho-Sung,YIN Hu-Quan,KWAK Hui Chan,LEE Byung-Hoon,KIM Sang Kyum
日本毒性学会学術年会 39.2(0), AP-222, 2012
… Transfection of the cells with siRNA for betaine homocysteine S-methyltransferase (BHMT) or cystathionine beta-synthase (CBS) increased cellular homocysteine and triglyceride level possibly due to the increase in the activation of SREBP-1. … These results demonstrate that L-ser inhibits hyperhomocysteinemia by accelerating the conversion of homocysteine to cystathionine which results in the amelioration of SREBP-1 activation and fatty liver. …
NAID 130005009167

Carbon monoxide stimulates global protein methylation via its inhibitory action on cystathionine .BETA.-synthase

Yamamoto Takehiro,Takano Naoharu,Ishiwata Kyoko,Suematsu Makoto
Journal of Clinical Biochemistry and Nutrition 48(1), 96-100, 2010
… Based on our previous results in vivo suggesting carbon monoxide serves as an inhibitor of cystathionine β-synthase that rate-limits transsulfuration pathway for generation of hydrogen sulfide, we have herein hypothesized that the gas might serve as a regulator of protein methylation through accelerating turnover of remethylation cycle residing at the upstream of the enzyme. …
NAID 130004879240

Modulation of Cystathionine .BETA.-Synthase Activity by Altering Heme Environment

Ozaki Shin-ichi,Doi Masafumi,Migita Catharina T.
Chemistry Letters 37(2), 208-209, 2008
… Human cystathionine β-synthase (CBS) is unique in bearing not only a catalytically important pyridoxal-5′-phosphate (PLP) but also heme. …
NAID 130004425055

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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
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NCBI	proteins

Cystathionine-beta-synthase
	Structure of human cystathionine beta-synthase.
Available structures
PDB	Ortholog search: PDBe, RCSB
List of PDB id codes
	1JBQ, 1M54, 4COO, 4L0D, 4L27, 4L28, 4L3V, 4PCU, 4UUU
Identifiers
Symbols	CBS ; HIP4
External IDs	OMIM: 613381 MGI: 88285 HomoloGene: 37258 GeneCards: CBS Gene
EC number	4.2.1.22
Gene ontology
Molecular function	• cystathionine beta-synthase activity; • protein binding; • oxygen binding; • enzyme binding; • heme binding; • pyridoxal phosphate binding; • ubiquitin protein ligase binding; • identical protein binding; • protein homodimerization activity; • metal ion binding; • nitrite reductase (NO-forming) activity; • carbon monoxide binding; • nitric oxide binding; • modified amino acid binding; • S-adenosyl-L-methionine binding;
Cellular component	• nucleus; • nucleolus; • cytoplasm; • cytosol; • intracellular membrane-bounded organelle;
Biological process	• sulfur amino acid metabolic process; • cysteine biosynthetic process from serine; • L-serine metabolic process; • L-serine catabolic process; • cysteine biosynthetic process via cystathionine; • cysteine biosynthetic process; • transsulfuration; • L-cysteine catabolic process; • cellular nitrogen compound metabolic process; • DNA protection; • homocysteine catabolic process; • small molecule metabolic process; • homocysteine metabolic process; • oxidation-reduction process; • hydrogen sulfide biosynthetic process;
	Sources: Amigo / QuickGO
Orthologs
	v; t; e;