Cystathionine β-synthase (CBS; EC 4.2.1.22) is a unique pyridoxal 5’-phosphate (PLP) enzyme which plays a crucial role in the transsulfuration metabolic pathway of sulfur-containing amino acid, L-methionine.
PLP enzymes are divided into four families on the basis of similarities in three dimensional structure, sequence, secondary structure, and hydrophobicity profiles. CBS is a member of the β family or Fold type II, which also contains O-acetylserine sulfhydrylase (OASS) and O-acetyl-L-serine(thiol)lyase (OASTL)[1].
Structure of CBS
The human form of CBS is a homotetramer consisting of 63-kDa subunits each of 551 amino acids in length. Two cofactors, pyridoxal 5’-phosphate (PLP) and heme, and two substrates, L-homocysteine and L-serine, are bound to every monomer and the function is further allosterically regulated by S-adenosyl-L-methionine (AdoMet).
The monomer has a complex domain structure as it is composed of three functional domains, two of which are regulatory and one is catalytic. The middle domain contains the catalytic core responsible for the pyridoxal 5’-phosphate-catalyzed reaction and is flanked by an N-terminal heme-binding domain (70 amino acids), which probably regulates the enzyme in response to redox conditions, and a C-terminal Bateman module consisting of two CBS domains (CBS1, CBS2), protein folding motifs also found in inosine 5’-monophosphate dehydrogenase, chloride channels and several other proteins in various organisms.[2] The C-terminal domain also contains a negative regulatory region that is responsible for allosteric activation of the enzyme by AdoMet.
Truncation of N-terminal domain produces an enzyme that is still active albeit less so (19%) than the wild type. Truncation of C-terminal domain activates the enzyme by ~2-fold over full-length wild type. In addition, deletion of the Bateman module leads to a change in oligomerization from a tetrameric to a dimeric form of the enzyme (4,7).
The CBS tetramer of the full-length enzyme has a strong tendency to aggregate, which makes physical studies very difficult. Therefore recombinant human CBS comprising the amino acid residues 1±413 (C-terminal domain missing), which does not exhibit the aggregating properties, is described.
The monomer is composed of 11 α-helices, seven short 310 helices and two β-sheets consisting of four (in the N-terminal domain) and six strands (in the C-terminal domain), respectively. The additional β-strand 1 interacts with strand 2 of the C-terminal sheet of the other monomer in the dimer in a parallel manner. The heme binding motif lacks any secondary structure with the exception of a short 310 helix.
The dimer interface is mainly hydrophobic in character and is composed of the side chains of the residues Ile76, Leu77, Ile80, Thr87, Val90, Ile92, Ile152, Leu156, Val160, Val180, Ala183, Leu184, Ile339, Ala340, Leu344, Leu345, Val378, Met382 and Leu386.
The central part of the dimer interface is formed by the residues Phe111 and Phe112 close to the 2-fold dimer axis, thus Phe112 of monomer A interacts with Phe112 of monomer B and vice versa. Polar interactions also contribute to the dimer interactions. On the other hand, the guanidium group of Arg379 is completely buried within the core of the dimer interface and rather than involved in any polar interactions between monomers forms hydrogen bonds to Gly115 and Asn380 of the same monomer.[3]
Disease
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Structural highlights
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