Serine hydroxymethyltransferase

Serine hydroxymethyltransferase (SHMT) is a pyridoxal phosphate (PLP) (Vitamin B6) dependent enzyme (EC 2.1.2.1) which plays an important role in cellular one-carbon pathways by catalyzing the reversible, simultaneous conversions of L-serine to glycine and tetrahydrofolate (THF) to 5,10-methylenetetrahydrofolate (5,10-CH2-THF).

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.

[7] The mechanism commonly ascribed to SHMT enzymatic activity is a transamidation followed by a cleavage of amino acid side chain from the backbone.

[14] 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.

[12] 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.

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.

[18] 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).

[2] Smith–Magenis syndrome (SMS) is a rare disorder that manifests as a complex set of traits including facial abnormalities, unusual behaviors, and developmental delay.

[21] 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.

PyMol rendered crystal structure of serine hydroxymethyltransferase
A glutamate in the SHMT active site deprotonates the serine hydroxyl from the external aldimine forming a formaldehyde intermediate. Tetrahydrofolate (THF) then attacks the formaldehyde forming a carbinolamine followed by several proton transfers and dehydration of the carbinolamine, all steps facilitated by the enzyme. The methylene-THF intermediate cyclizes to 5,10-CH 2 -THF. Lastly, the glycine external aldimine reforms before hydrolysis and release from the active site. [ 8 ] [ 11 ] [ 12 ]
Biological role of SHMT:
a ) Serine–glycine interconversion catalyzed by SHMT. THF = tetrahydrofolate, CH2-THF = N-5,N-10-methylenetetrahydrofolate. The red dot highlights the carbon that is transferred from Ser to THF.
b ) Schematic overview of human SHMT (hSHMT) function. MTHFD = methylenetetrahydrofolate dehydrogenase-cyclohydrolase, CH2-THF = N-5,N-10-methylenetetrahydrofolate, CH+-THF = 5,10-methenyltetrahydrofolate, CHO-THF = 10-formyltetrahydrofolate, NADP+ = Nicotinamide adenine dinucleotide phosphate, NADPH = NADP+ reduced form.
c ) SHMT, dihydrofolate reductase (DHFR), and thymidylate synthase (TS) in the folate cycle. THF = tetrahydrofolate, CH2-THF = 5,10-methylenetetrahydrofolate, DHF = dihydrofolate, FdUMP = fluorodeoxyuridine-5′-monophosphate, dUMP = deoxyuridine monophosphate, dTMP = deoxythymidine monophosphate.
From Nonaka et al., 2019. [ 22 ]