Proline

General Features:

Abbreviated: Pro or P

Molecular formula: C₅H₉NO₂

pKa: 2.351

 

Zwitterionic structure of both proline enantiomers: 

(S)-proline and (R)-proline

Physiological Roles:

Due to the cyclic structure of proline’s side chains, the amino acid is exceptionally rigid in its conformation when compared to other amino acids. It loses less conformational entropy when exposed to higher temperatures and thus is more prevalent in thermophilic organisms. For example, the secondary alcohol dehydrogenase from Thermoanaerobium brockii contains eight more prolines than its mesophilic homologue from Clostridium beijerinckii (Li et al, 1999).

Further, due to its side chain constraints and steric hindrance, proline is a structural disrupter of alpha helices. Methylene replaces what would normally be a hydrogen-bonding amide, and so the helix is disrupted. Polyproline helices, however, may be formed when multiple prolines are bound in sequence. This is a major component of collagen.

Takagi illustrates the final important roles of proline in biological systems in the article Proline as a stress protectant in yeast. In bacterial as well as plant cells, proline accumulates as an osmoprotectant in response to osmotic stress. In vitro, proline may also be employed to stabilize proteins and membranes, lower the T(m) of DNA, and scavenge reactive oxygen species. Because proline is an osmoprotectant, it is often used in pharmaceutical and biotech applications. 

Biosynthesis and metabolism:

Proline is not considered an essential amino acid, because it can be synthesized by the human body.

The mechanism of proline biosynthesis is a universal pathway found in both prokaryotes and eukaryotes, although the mechanism of synthesis of its precursor (L-glutamate) may vary between organisms. Although the image shown below is for that of bacteria, it is essentially the same as in eukaryotes. The location of the pathway differs between bacterial and human cells, however.

Pathway of proline biosynthesis

Proline synthesis begins with the conversion of L-glutamate to an acyl phosphate through a reaction with ATP via a kinase. The acyl phosphate (L-glutamly-gamma-phosphate) is then reduced to glutamic-gamma-semialdehyde by an NADPH-dependent reaction. The semialdehyde may be subsequently converted to an ornithine, which is a precursor of either proline or arginine depending on the final reaction. If the ornithine cyclizes to form P5C, this can be reduced by NADPH to form proline.

The figure below illustrates proline catabolism and degredation to glutamate:

Singh et al., 2012

According to Singh et al., proline utilization proteins (PutAs) are bifunctional enzymes that catalyze the oxidation of proline to glutamate. PutAs contain secondary structural elements and domains not found in related monofunctional enzymes, thus confirming their bifunctionality. 

Additional resources:

Click here for a more in-depth look at proline biosynthesis. Or if you'd rather spend your time appreciating proline metabolism, visit KEGG. You can even appreciate arginine metabolism while you're at it!

An indirect role of proline in the microbial world is its involvement in thymus development. Proline-rich polypeptides (PRP) can induce TH2 to TH1 shift. If this doesn't get you pumped, I don't know what does. Visit this website for more information on PRPs in the immune system!