Cystathionine beta synthase

Source: Wikipedia, the free encyclopedia.
CBS
Gene ontology
Molecular function
Cellular component
Biological process
Sources:Amigo / QuickGO
Ensembl

ENSG00000160200

ENSMUSG00000024039

UniProt

P35520
P0DN79

Q91WT9

RefSeq (mRNA)

NM_000071
NM_001178008
NM_001178009
NM_001320298
NM_001321072

NM_001271353
NM_144855
NM_178224

RefSeq (protein)

NP_001258282
NP_659104
NP_835742

Location (UCSC)Chr 21: 43.05 – 43.08 MbChr 17: 31.83 – 31.86 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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:[5]

L-serine + L-homocysteine
H2O

CBS uses the

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.[6]

Nomenclature

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

  • β-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.[7]

Structure

Sequence and secondary structure of the CBS enzyme.[8]

The human enzyme cystathionine β-synthase is a

hereditary diseases.[11]

The heme domain contains an N-terminal loop that binds heme and provides the axial

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.[9]

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
ExPASy
NiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins
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.[12]

CBS occupies a pivotal position in mammalian sulfur metabolism at the

amino acids under conditions of excess.[9]

In analogy with other β-replacement enzymes, the reaction catalyzed by CBS is predicted to involve a series of

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.[9] The final product, L-cystathionine can also form an aminoacrylate intermediate, indicating that the entire reaction of CBS is reversible.[13]

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-substituent of serine is not released from the enzyme prior to binding of homocysteine.[9]

One of the alternate reactions involving CBS is the condensation of

adoMet.[14]

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.[13]

Regulation

AdoMet is an allosteric activator that increases the Vmax of the CBS reaction but does not affect the Km for the substrates. In other words, AdoMet stimulates CBS activity by increasing the turnover rate rather than the binding of substrates to the enzyme.[9] This protein may use the morpheein model of allosteric regulation.[15]

Human CBS performs a crucial step in the

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.[16]

In mammals, CBS is a highly regulated enzyme, which contains a heme cofactor that functions as a redox sensor,[11] 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.[9] 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.[17]

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.[9]

CBS is regulated at the transcriptional level by

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).

MTR, and 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.[9]

adoMet.[16] 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.[18]

Absence of Cystathionine beta synthase in mice provokes infertility due to the loss of uterine protein expression.[19]

Mutations

The genes that control CBS enzyme expression may not operate at 100% efficiency in individuals who have one of the SNPs (

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

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000160200 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000024039 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Entrez Gene: CBS cystathionine-beta-synthase".
  6. ^
    PMID 11524006
    .
  7. ^ EC 4.2.1.23
  8. PMID 11483494
    .
  9. ^
    PMID 15581573
    .
  10. ^
    PMID 17069888
    .
  11. ^
    PMID 17087506
    .
  12. PMID 11106665
    .
  13. ^
    PMID 15890029
    .
  14. PMID 12213817
    .
  15. PMID 22182754
    .
  16. ^
    PMID 16275737
    .
  17. PMID 16505479
    .
  18. S2CID 23891500
    .
  19. PMID 16984962
    .

Further reading

External links
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