Threonine

The Biological Roles of Threonine

Broadly, amino acids are molecules with the molecular formula of R-CH(NH2)-COOH-NH2, where -NH2 is the basic amino group, COOH is an acidic carboxyl group, and R represents a molecular unit called a side chain. That side chain is unique for each amino acid, and its chemical properties create different classes of amino acids: nonpolar and neutral, polar and neutral, polar and acidic, and polar and basic.

Although hundreds of amino acids exist, only 20 of them are used for what amino acids are arguably most known for: forming the building blocks of proteins. Proteins are not only an essential macronutrient in the human diet; they’re molecules that perform most of the various functions of life. In addition to being major structural components of cells and tissues, proteins have incredibly diverse roles that range from driving chemical reactions (e.g., enzymes) to signaling (e.g., some types of hormones) to transporting and storing nutrients. Proteins are synthesized within cells through a two-phase process of transcription and translation, during which amino acids get linked together to form long chains (spanning anywhere from 20 to over 2,000 amino acids in length!).

So, while all proteins are made of amino acids, not all amino acids are used for making proteins! We use the term proteinogenic amino acids to refer specifically to the amino acids that get encoded into our DNA and incorporated into proteins. Meanwhile, non-proteinogenic amino acids do neither of these things (although they still have some very important biological roles!).

Amino acids can be further classified based on whether we can create them in our bodies, or need them from our diet. Essential amino acids are amino acids that can only be obtained from foods; these include histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. Non-essential amino acids are amino acids our bodies can synthesize metabolically from other molecules; these include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, serine, and tyrosine. And, some amino acids are conditionally essential, meaning our bodies can normally make them, but some circumstances (like illness or stress) can limit their synthesis and create a dietary requirement. These include arginine, cysteine, glutamine, tyrosine, glycine, ornithine, proline, and serine.

As an essential and proteinogenic amino acid, threonine must be supplied from dietary sources, and is used to synthesize a number of important proteins!

In fact, many of threonine’s functions are due to its presence as a residue of specific proteins, including collagen, elastin, and enamel. This makes it a contributor to dental health, skeletal strength, and connective tissue. It also influences growth and protein synthesis in skeletal muscles—both by serving as a precursor for protein synthesis, and also by acting as a signaling molecule to regulate the protein synthesis pathway.

Threonine is also needed for the synthesis of mucins—large glycoproteins produced by epithelial cells and that help form mucus secretions throughout the body (including the respiratory tract and GI tract). There’s particularly high demand for threonine in the intestine, since threonine is needed for synthesizing the intestinal mucus layer. Threonine availability in the intestinal lumen significantly impacts the mucin production there. Animal studies suggest that the body prioritizes the use of threonine for mucin production so much that in times of nutritional inadequacy, muscle growth and other protein-related tissue functions will be compromised in order to keep threonine available for mucin synthesis!

Threonine plays an important role in the metabolism of fat and porphyrins (important molecules found in hemoglobins, peroxidases, cytochromes, catalases, myoglobins, and more). Threonine is particularly critical for fat metabolism in the liver. Insufficient threonine leads to an increased expression of genes involved in fatty acid and triglyceride synthesis, while downregulating the expression of genes associated with fatty acid and triglyceride transport. So, adequate levels are needed in order to ensure fat is appropriately burned or transported instead of accumulating.

Threonine also plays a role in the immune system—especially gut immune function. In vitro experiments show that lymphocytes use threonine to support their proliferation and antibody secretion, and threonine can influence the secretion of immunoglobin A (IgA) and modulate the expression of inflammatory cytokines in the gut. Animal experiments show that threonine supplementation up-regulates interleukin-6 gene expression and down-regulates the expression of several inflammatory mediators (interferon γ, interleukin-12, and tumor necrosis factor alpha). And in animal models of bacterial infection, threonine deficiency can worsen the intestinal inflammatory response by promoting the gene expression of pro-inflammatory cytokines and inhibiting the expression of anti-inflammatory cytokines.

Interestingly, threonine may have a synergistic effect with fiber and other carbohydrates when it comes to enhancing immune function. Some studies show that threonine and pectin, for example, work together to promote intestinal immune responses during infection!

Although many animals can convert threonine into glycine (another amino acid) via the enzyme L-threonine 3-dehydrogenase, this pathway isn’t very active in humans! Our version of the gene responsible for L-threonine 3-dehydrogenase expression is a pseudogene—that is, a nonfunctional segment of DNA that structurally resembles a gene, but isn’t actually capable of coding for a protein. While animal experiments tend to show substantial degradation of threonine into glycine, similar studies in humans show that only a small amount of threonine gets catabolized through this pathway (and even then, only in the context of a very high protein intake). Because so much of what we know about threonine comes from animal experiments, and because some of the health effects of threonine seen in those studies is due to its conversion to glycine, it’s important to be cautious in how we interpret these findings for humans!

Up to 4 g of threonine daily for a period of one year appears to be safe for most people. Sometimes, minor side effects can occur from from supplementation, including headache, nausea, skin rash, and upset stomach. And, people taking NMDA antagonists (which are often used to treat Alzheimer’s disease) are advised to avoid using threonine supplements.