Threonine

General Features:
Abbreviated: Thr or T
Chemical formula: C₄H₉NO₃

pKa: 2.63 (carboxyl), 10.43 (amino)

Physiological Roles:
Threonine is a polar amino acid and is one of the three proteinogenic ("protein-building") amino acids that contains an alcohol group. Its start codons are ACU and ACA. Due to its two chiral centers, it has four possible stereoisomers. L-threonine is the most common stereoisomer (the other L-isomer, L-allo-threonine, is relatively rare). It is the only common amino acid along with isoleucine that contains a chiral carbon in its side chain.

Because of its hydrophilic nature, threonine can be found in substantial concentrations at the outer regions of soluble proteins. Its easily removed hydrogen on the hydroxyl side chain makes it a common hydrogen donor in enzymes. The exact role of threonine's hydrogen donating in enzymes remains unclear, however.

Threonine is capable of posttranslational modification. In both eukaryotic and prokaryotic cells, threonine residues are able to undergo phosphorylation, which may have different effects depending on the particular protein. Threonine is the second most commonly phosphorylated amino acid residue, following serine. Interestingly, threonine-phosphorylated proteins are the easiest to purify using antibodies and are thus the most well characterized in terms of phosphorylation effects. Phosphorylated amino acids generally lose a hydroxyl group and gain a negatively charged phosphate. This negative charge may significantly alter the biochemical properties of the entire protein. The figure below gives a good visual as to how this negative charge might affect the amino acid (note that serine and tyrosine are shown as well):

Side chain modification (phosphorylation)

A specific example of the importance of threonine phosphorylation (carried out by enzymes called threonine kinases) is the autoregulatory effects of threonine kinases in the bacterial organism Bacilus anthracis (Bryant-Hudson et al., 2011). This study shows the first hints of inhibitory phosphorylation by a prokaryotic serine/threonine kinase (STK). Within the regulatory domain/activation loop of the STK, there are specific serine and threonine phosphorylation sites that may lead to either activation or inhibition. The enzyme itself may phosphorylate these sites; thus, the enzyme is autoregulatory.

Protons may be quickly abstracted from threonine using the basic nitrogen of histidine, making threonine nucleophilic. This may have implications in downstream pathways.

Synthesis and metabolism:
Threonine is an essential amino acid in humans, meaning we are unable to synthesize it naturally and must obtain it from food sources. Plants and microorganisms are able to synthesize threonine and utilize a pathway involving aspartic acid via alpha-aspartyl-semialdehyde and homoserine.

Synthesis of threonine

The enzymes featured in this pathway are:

1. aspartokinase (AK)

2. beta-aspartate semialdehyde dehydrogenase (B-ASD)

3. homoserine dehydrogenase (HSD)

4. homoserine kinase (HSK)

5. threonine synthase (TS)

With the coupling of ATP hydrolysis, aspartokinase (AK) catalyzes the phosphorylation of aspartate to form aspartyl-beta-phosphate. It has been shown that both plant and bacterial AK are bifunctional enzymes that may contain homoserine dehydrogenase activity (Weisemann and Matthews, 1993). B-ASD subsequently removes the phosphate group. These two reactions result in the removal of an oxygen and addition of a hydrogen through the usage of an activating phosphate. HSD catalyzes the first reaction which is specific to threonine, methionine, and isoleucine biosynthesis. 

HSK is an essential branch point between threonine and methionine biosynthesis; if homoserine acetyltransferase was present instead, methionine synthesis would follow. HSK catalyzes the formation of O-phosopho-L-homoserine via O-phosphorylation of homoserine. O-phosphorylation simply implies the addition of (ortho)phosphoric acid H₃PO_4.

TS catalyzes the final step of this biosynthetic pathway and involves a hydrolysis of the phosphate group added by HSK. TS shows functional domains that share similarities with SAM-dependent methyltransferases in plants (Thomazeau et al., 2001). Many of the enzymes in this pathway are great examples of how versatile enzymes can be. This makes the organism much more energy-efficient.

Below is a more broad picture to give you an idea how threonine biosynthesis is coupled to the TCA cycle. For the purpose of this section, feel free to only pay attention to the left portion of the diagram (keeping in mind the importance of the figure as a whole, of course).

Deng et al., 2011

Metabolism of threonine may occur by two pathways: conversion to pyruvate or conversion to alpha-ketobutyrate (which enters the pathway that leads to synthesis of succinyl-CoA). Threonine may also be converted to glycine via threonine aldolase:

Jander et al., 2009

Additional resources:

If you're really excited about threonine biosynthesis, you can visit The Enzyme Database for a very comprehensive look at each point of the pathway! Or if you're feeling particularly adventurous, take a look at this original publication by Kaplan and Flavin. Or if genetics is more your thing, check out this publication by Marchenko et al.

Although we mainly focus on amino acids as they pertain to prokaryotic organisms, this site may enlighten you to all the nutritional benefits of threonine in human diets.