Serine hydroxymethyltransferase, or SHMT, is an enzyme found within nearly all living cells, from bacteria to humans. SHMT plays a fundamental role in various cellular activities, underpinning overall health and proper bodily function.
Understanding SHMT
Its full name, Serine Hydroxymethyltransferase, describes its function: it transfers a hydroxymethyl group. There are two primary forms of SHMT in human cells: cytosolic SHMT1, found in the cell’s main fluid, and mitochondrial SHMT2, located within the mitochondria, the cell’s powerhouses.
Both forms of SHMT rely on pyridoxal phosphate (PLP), a form of vitamin B6, as a necessary helper molecule for their catalytic activity. It is classified as a transferase, facilitating the movement of specific chemical groups from one molecule to another.
SHMT’s Role in One-Carbon Metabolism
SHMT’s primary function centers on a reversible chemical reaction involving the amino acid L-serine and a form of folate called tetrahydrofolate (THF). SHMT converts L-serine and THF into glycine and 5,10-methylenetetrahydrofolate (5,10-CH2-THF). This reaction is a central part of “one-carbon metabolism,” a complex network of biochemical pathways that involve the transfer of single carbon units.
One-carbon units are like tiny building blocks that are moved around the cell for various synthetic processes. The 5,10-CH2-THF produced by SHMT is a key carrier of these one-carbon units, making it available for other reactions. This metabolic pathway is important for cell growth and function.
How SHMT Supports Essential Bodily Functions
The one-carbon units generated by SHMT are important for several biological processes. These units are directly used to synthesize new DNA, which is crucial for cell division, growth, and repair throughout the body. This makes SHMT a part of the de novo thymidylate pathway, a process where new DNA building blocks are created. The enzymes involved in this pathway, including SHMT, can associate with the nuclear lamina and DNA replication machinery, suggesting that DNA building occurs right where DNA synthesis takes place.
SHMT also contributes to amino acid production, particularly the interconversion of serine and glycine. While it can convert serine to glycine, the overall flux often results in net glycine consumption, which can then be converted back to serine by the liver. Beyond these, the one-carbon units from SHMT indirectly support methylation processes. Methylation is a biochemical process where a methyl group (one carbon and three hydrogen atoms) is added to a molecule, influencing gene expression, the creation of neurotransmitters, and detoxification pathways.
The Connection Between SHMT and Health Conditions
Given its fundamental role in metabolism, imbalances or dysfunctions in SHMT activity can have implications for human health. SHMT’s involvement in DNA synthesis makes it a target in cancer research. Cancer cells, which divide rapidly, have a high demand for new DNA, and targeting SHMT can disrupt this process, potentially inhibiting tumor growth and proliferation. For instance, SHMT inhibitors are being explored as potential anti-cancer drugs, and some studies suggest SHMT2 may be a promising therapeutic target for certain cancers like renal cell carcinoma and colorectal cancer.
SHMT also plays a role in neurological health due to its indirect involvement in neurotransmitter synthesis and brain function. Mutations in the SHMT2 gene have been linked to neurodevelopmental disorders characterized by intellectual disability, spasticity, and brain abnormalities. Reduced SHMT activity, for example, has been observed in patients with Smith-Magenis syndrome, a rare genetic disorder that affects development and behavior, potentially by reducing the available glycine pool, which impacts the nervous system.
Furthermore, SHMT is closely intertwined with folate metabolism. Folate (Vitamin B9) is a cofactor for SHMT, and a deficiency in folate can impair SHMT’s function, affecting the entire one-carbon metabolism pathway. Imbalances in folate metabolism, potentially influenced by SHMT gene variations, have been associated with conditions like neural tube defects during development.