Serine hydroxymethyltransferase (SHMT) is an enzyme (EC 22.214.171.124) which plays an important role in cellular one-carbon pathways by catalyzing the reversible, simultaneous conversions of L-serine to glycine (retro-aldol cleavage) and tetrahydrofolate to 5,10-methylenetetrahydrofolate (hydrolysis). This reaction provides the largest part of the one-carbon units available to the cell.
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). Plants may have an additional SHMT isoform within chloroplasts.
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 pyridoxal phosphate (Vitamin B6) as a coenzyme.
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 interstital 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 less glycine which could affect the nervous system by acting as an agonist to the NMDA receptor and this could be a mechanism behind SMS.
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- ^ a b c Stover P, Schirch V (August 1990). "Serine hydroxymethyltransferase catalyzes the hydrolysis of 5,10-methenyltetrahydrofolate to 5-formyltetrahydrofolate". J. Biol. Chem. 265 (24): 14227–33. PMID 2201683.
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- PAMs: Alcohols (e.g., brometone, chlorobutanol (chloretone), ethanol, tert-butanol (2M2P), tribromoethanol, trichloroethanol, trifluoroethanol)
- Alkylbenzene sulfonate
- Barbiturates (e.g., pentobarbital, sodium thiopental)
- Dihydropyridines (e.g., nicardipine)
- Ginseng constituents (e.g., ginsenosides (e.g., ginsenoside-Rf))
- Glutamic acid (glutamate)
- Neuroactive steroids (e.g., alfaxolone, pregnenolone (eltanolone), pregnenolone acetate, minaxolone, Org 20599)
- Nitrous oxide
- Penicillin G
- Tropeines (e.g., atropine, bemesetron, cocaine, LY-278584, tropisetron, zatosetron)
- Volatiles/gases (e.g., chloral hydrate, chloroform, desflurane, diethyl ether (ether), enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, toluene, trichloroethane (methyl chloroform), trichloroethylene)
- Antagonists: 2-Aminostrychnine
- Endocannabinoids (e.g., 2-AG, anandamide (AEA))
- Gaboxadol (THIP)
- Isobutyric acid
- Isonipecotic acid
- Nipecotic acid
- Quinolines (e.g., 4-hydroxyquinoline, 4-hydroxyquinoline-3-carboxylic acid, 5,7-CIQA, 7-CIQ, 7-TFQ, 7-TFQA)
- NAMs: Amiloride
- Benzodiazepines (e.g., bromazepam, clonazepam, diazepam, flunitrazepam, flurazepam)
- Dihydropyridines (e.g., nicardipine, nifedipine, nitrendipine)
- Ginkgo constituents (e.g., bilobalide, ginkgolides (e.g., ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, ginkgolide M))
- Neuroactive steroids (e.g., 3α-androsterone sulfate, 3β-androsterone sulfate, deoxycorticosterone, DHEA sulfate, pregnenolone sulfate, progesterone)
- Opioids (e.g., codeine, dextromethorphan, dextrorphan, levomethadone, levorphanol, morphine, oripavine, pethidine, thebaine)
- Picrotoxin (i.e., picrotin and picrotoxinin)
- Tropeines (e.g., bemesetron, LY-278584, tropisetron, zatosetron)