Leucine

General Features:
Abbreviated: Leu or L
Molecular formula: C₆H₁₃NO<sub>2
pKa: 2.36 (carboxyl), 9.6 (amino)


Physiological Roles:</sub>
Leucine, an isomer of isoleucine, is the most abundant of the amino acids in terms of primary protein structure. Its start codons are UUA, UUG, CUU, and CUC. It is considered an essential amino acid because humans cannot synthesize it. Due to its aliphatic isobutyl (hydrocarbon) side chain, leucine is considered a hydrophobic amino acid. Also notable is its branched chain structure.


Because of its hydrophobic character, leucine residues can be found in rings around the narrowest regions of pores (Martinac et al, 2008). This helps to modulate the passage of ions through bacterial membranes. Hydrophobic amino acids such as leucine and/or methionine are also used to push the C-terminus of the beta-3 strand of penicillin binding proteins (PBPs) to the forefront of the active site (Sauvage et al). It is this conformation that allows PBPs to properly bind substrate to their active site. PBPs are essential in peptidoglycan synthesis, a major component of bacterial cell walls. They are heavily involved with the formation of cross-linked peptidoglycan (PG) from lipid precursors, and also in the removal of D-alanine from PG precursors. PBPs get their name for their ability to bind penicillin, a beta-lactam drug that inhibits cell wall synthesis. For more information about PBP involvement in PG synthesis as well as penicillin resistance, visit this site.


Certain eukaryotic receptors (such as Fas) contain C-terminal leucine-rich repeats (LRRs) which possess binding affinity for bacterial lipopolysaccharides (Immune Mechanisms in Inflammatory Bowel Disease). Lipopolysaccharides (LPS) are large molecules consisting a lipid and a polysaccharide joined by a covalent bond. They are present on the outer membranes of Gram negative bacteria and act as endotoxins. LPS elicits strong immune responses in animals.


Furthermore, Borowitz et al. found that leucine and not other amino acids stimulates CO₂ fixation to fatty acids in the ciliated protozoan Tetrahymena pyriformis.


_{Biosynthesis and metabolism:}
Although it cannot be synthesized in humans, leucine may be synthesized in plants and microorganisms starting from pyruvic acid. Note that the the beginning of the pathway may also lead to valine synthesis. Almost all of the genes encoding for the enzymes involved in this pathway may be regulated by attenuation.

Leucine synthesis

Enzymes featured in this pathway:

1. acetolacetate synthase (AAS)

2. acetohydroxy acid isomeroreductase (AHAIR)

3. dihydroxyacid dehydratase (DHADH)

4. alpha-isopropylmalate synthase (A-IPMS)

5. alpha-isopropylmalate isomerase (A-IPMI)

6. leucine aminotransferase (LAT)

It is not shown in the above figure, but two molecules of pyruvate are required for the synthesis of this amino acid.

Leucine biosynthesis involves a five-step conversion process starting from the valine precursor 2-oxoisovalerate (2-OIV). Both the first and the last enzymes of this pathway can be inhibited by high concentrations of leucine (called feedback or allosteric inhibition). The intermediate α-ketovalerate is converted to α-isopropylmalate and then β-isopropylmalate, which is dehydrogenated to α-ketoisocaproate, which in the final step undergoes reductive amination.

The last reaction of this pathway is catalyzed by a aminotransferase (also called a transaminase) of broad specificity. In addition to leucine this enzyme is inhibited by 2-OIV and one of its off-pathway products tyrosine.

The figure below shows the pathways used to derive acetyl-CoA and other metabolites from leucine:

Baumgartner et al., 2001

Leucine metabolism is regulated at two steps: (reversible) transamination to the keto acid or subsequent decarboxylation. It was found the leucine transamination operated several times faster than keto acid decarboxylation. Thus, it is this decarboxylation step that is rate-limiting in human leucine catabolism (Matthews et al., 1981).

Additional resources:

For a more comprehensive look at leucine biosynthesis, check out this site or KEGG.

I know you're now excited about leucine, especially how it can impact your own health:  Food sources high in leucine, The role of leucine in protein metabolism during exercise and recovery (Layman, 2002), The role of leucine in weight loss diets and glucose homeostasis (Layman, 2003), and Leucine metabolism in regulation of insulin secretion from pancreatic beta cells (Yang et al., 2010).