Cystathionine beta synthase

1JBQ, 1M54, 4COO, 4L0D, 4L27, 4L28, 4L3V, 4PCU, 4UUU87512411ENSG00000160200ENSMUSG00000024039P35520P0DN79Q91WT9NM_000071NM_001178008NM_001178009NM_001320298NM_001321072NM_001271353NM_144855NM_178224NP_001308002NP_001340935NP_001340936NP_001340937NP_001340938NP_001340939NP_001340941NP_001340943NP_001340944NP_001258282NP_659104NP_835742Cystathionine-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:1jbq: STRUCTURE OF HUMAN CYSTATHIONINE BETA-SYNTHASE: A UNIQUE PYRIDOXAL 5'-PHOSPHATE DEPENDENT HEMEPROTEIN1m54: CYSTATHIONINE-BETA SYNTHASE: REDUCED VICINAL THIOLS(See Template:Leucine metabolism in humans – this diagram does not include the pathway for β-leucine synthesis via leucine 2,3-aminomutase) 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: 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. The systematic name of this enzyme class is L-serine hydro-lyase (adding homocysteine; L-cystathionine-forming). Other names in common use include: 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. 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. Transsulfuration, catalyzed by CBS, converts homocysteine to cystathionine, which cystathione gamma lyase converts to cysteine.