Serine hydroxymethyltransferase

The structure of the SHMT monomer is similar across prokaryotes and eukaryotes, but whereas the active enzyme is a dimer in prokaryotes, the enzyme exists as a tetramer in eukaryotic cells, though the evolutionary basis for this difference in structure is unknown. The interaction between two monomers within a dimer subunit has been found to occur over a greater contact area and is thus much tighter than the interaction between the two dimers. has recently been shown to be involved in regulation of the BRISC deubiquitylase complex, linking metabolism to inflammation. The SHMT2 dimer, but not the PLP-bound tetramer, is a potent inhibitor of the multimeric BRISC complex, revealing a potential mechanism for SHMT2 regulation of inflammation. A single SHMT monomer can be subdivided into three domains: an N-terminus “arm,” a “large” domain, and a “small” domain. The active site structure is highly conserved across eukaryotic and prokaryotic forms. The PLP is anchored by means of a lysine, which forms an aldimine Schiff base linkage with the PLP aldehyde. It has been hypothesized that a nearby tyrosine functions as the proton donor and acceptor during the transadimination step as well as the formyl transfer step and that an arginine residue engages the tyrosine side chain in a cation–π interaction, which helps to lower the pK of the tyrosine, lowering the barrier for proton transfer. ==Mechanism==

The mechanism commonly ascribed to SHMT enzymatic activity is a transamidation followed by a cleavage of amino acid side chain from the backbone. It is believed that a nearby tyrosine is responsible for much of the proton transfers that occur during the transaldimination. for SHMT, meaning the cleavage of serine and other β-hydroxy amino acids (such as threonine) can occur without the presence of THF and, in this case, the mechanism is a retro-aldol cleavage. Also, it seems that the subsequent dehydration of the carbinolamine intermediate to form the methylene bridge and fully cyclize into 5,10-CH2-THF is not catalyzed by the enzyme and this reaction may occur spontaneously. In fact, this conversion could occur outside the enzyme, but a study shows that this reaction is faster and thermodynamically favourable when occurs inside the SHMT aided by the Glu57 residue. Moreover, the cyclisation of the carbinolamine intermediate to form 5,10-CH2-THF is essential to Glu57 restore its proton that is used to protonate the quinonoid intermediate and complete the catalytic cycle. ==Clinical significance==

Folate metabolism has already been the subject of chemotherapeutic strategies, but SHMT inhibition, while researched, had not really been taken advantage of in commercial anticancer drugs. However, because the folates used by folate metabolic and folate-dependent enzymes are all very similar in structure and folate mimics are already common in medical use, it has not been difficult to find potential molecular structures that may inhibit SHMT. SHMT has also undergone investigation as a potential target for antimalarial drugs. Research indicates that the active site environment of Plasmodium SHMTs (PSHMTs) differs from that of human cytosolic SHMT, allowing for the possibility of selective inhibition of PSHMT and, thus, the treatment of malaria infections. In particular, certain pyrazolopyran molecules have been shown to have a selective nanomolar efficacy against PSHMTs. Poor pharmacokinetics, however, have prevented these pyrazolopyrans from being effective in living models. == Isoforms ==

Bacteria such as Escherichia coli and Bacillus stearothermophilus have versions of this enzyme and there appear to be two isoforms of SHMT in mammals, one in the cytoplasm (cSHMT) and another in the mitochondria (mSHMT). In mammals, the enzyme is a tetramer of four identical subunits of approximately 50,000 daltons each. The intact holoenzyme has a molecular weight of approximately 200,000 daltons and incorporates four molecules of PLP as a coenzyme. == Other reactions ==

As well as its primary role in folate metabolism, SHMT also catalyzes other reactions that may be biologically significant, including the conversion of 5,10-Methenyltetrahydrofolate to 10-Formyltetrahydrofolate. When coupled with C1-tetrahydrofolate synthase and tetrahydropteroate, cSHMT also catalyzes the conversion of formate to serine. == Role in Smith–Magenis syndrome ==

Smith–Magenis syndrome (SMS) is a rare disorder that manifests as a complex set of traits including facial abnormalities, unusual behaviors, and developmental delay. It results from an interstitial deletion within chromosome 17p11.2, including the cSHMT gene and a small study showed SHMT activity in SMS patients was ~50% of normal. Reduced SHMT would result in a reduced glycine pool, which could affect the nervous system by reducing the functioning of NMDA receptors. This could be a potential mechanism for explaining SMS. == Figures ==