Cystathionine β synthase

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Cystathionine ß synthase

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Background

• Cystathionine-ß-synthase, also known as CBS
  enzyme, is an enzyme (EC 4.2.1.22) that in humans
  is encoded by the CBS gene. 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.

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Structure

• CBS is localized to the cytoplasm and is a
  homotetramer composed by 63 kDa subunits. CBS is
  a haemoglobin protein belonging to the ß family
  of pyridoxal phosphate (PLP)-dependent enzymes.
  Each subunit binds to the two cofactors
  haemoglobin and PLP. Human CBS includes a
  haemoglobin-binding region, a highly conserved
  catalytic domain, and a regulatory domain.
  Haemoglobin binds to the first 70 amino acid
  residues at the N-terminus, where Cys52 and His65
  are heme iron-binding residues. The highly
  conserved catalytic domain is located at amino
  acid residues 40 to 413 and can form a 45 kDa
  active center. The Lys119 residue in this region
  is a PLP-binding residue, and PLP is a requisite
  for the CBS catalyzed reaction. 

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Catalytic Mechanism

• Hcy is a sulfur-containing amino acid, which is
  formed by the demethylation of methionine, and
  its metabolism has two pathways of
  transsulfuration and methylation. CBS is a key
  enzyme in the transsulfuration pathway. Under the
  participation of PLP as a coenzyme, CBS catalyzes
  the ß-substitution reaction, which mediates the
  condensation of Hcy and serine to generate
  cystathionine. Cystathionine is further converted
  to cysteine a-ketobutyric acid by the action of
  cystathionine-?-lyase (CSE). In the human body,
  about 53 of Hcy is irreversibly converted into
  cysteine by CBS and CSE. The methylation pathway
  is that Hcy re-synthesizes methionine with the
  aid of folic acid and VitB12. The above two
  pathways mainly rely on AdoMet concentration to
  coordinate roughly balance, and the decrease of
  CBS activity may lead to HHcy caused by the
  failure of the transsulfuration pathway.

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Influencing Factors

• First, allosteric activators. AdoMet is an
  allosteric activator of CBS that increases its
  activity by 2 to 5 fold. The activation mechanism
  may be related to the spatial conformational
  change of self-inhibitory regions in the
  C-terminal regulatory domain where AdoMet
  induces. Second, the cofactors. Haemoglobin is a
  redox sensor, and its redox state can result in
  changes of CBS activity. Therefore, cofactors
  that can cause changes in the redox state of
  hemoglobin can affect CBS activity. Third, gene
  mutations of CBS. Mutations in the CBS gene can
  cause changes in the stability of the enzyme, the
  binding of the enzyme to the cofactor and the
  substrate, and the disruption of the regulation
  of the allosteric agents, thereby affecting the
  enzyme activity. So far, 132 CBS gene mutations
  have been found, mostly in exon 3 and exon 8.
  Most of them are missense mutations, followed by
  deletion mutations, insertion mutations, and
  splicing mutations.

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Related Diseases

• Mutations in the CBS gene cause the decrease of
  CBS activity and the formation of HHcy, and HHcy
  participates in the formation of AS. At present,
  most clinical and epidemiological studies have
  shown that the level of tHcy is related to the
  extent of atherosclerosis in carotid artery,
  coronary artery, and peripheral artery. It can
  participate in the formation of AS from the
  following aspects.

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