Leucine

Leucine (abbreviated as Leu or L) is an essential amino acid and one of three branched-chain amino acids (BCAAs). It is the most potent amino acid for stimulating muscle protein synthesis and plays a central role in the mTOR signaling pathway. Leucine cannot be synthesized by the body and must be obtained through diet.

Structure

Leucine has an aliphatic, branched side chain consisting of an isobutyl group. This hydrophobic side chain makes leucine non-polar, and it is typically found in the interior of protein structures.

Isomers

• L-Leucine: The biologically active form used in protein synthesis
• D-Leucine: Not used in mammalian proteins
• Isoleucine: A structural isomer (same formula, different arrangement)

Biological Functions

mTOR Pathway Activation

Leucine is the primary activator of the mechanistic target of rapamycin (mTOR) pathway:

• Directly activates mTORC1 signaling complex
• Stimulates translation initiation (protein synthesis)
• Activates S6 kinase (S6K1)
• Inhibits 4E-BP1, allowing translation to proceed

Muscle Protein Synthesis

Leucine's effects on muscle include:

• Initiation of muscle protein synthesis (MPS)
• Anti-catabolic effects (reduces protein breakdown)
• Enhanced recovery after exercise
• Preservation of lean mass during caloric restriction

Metabolic Functions

• Gluconeogenesis: Can be converted to glucose (glucogenic)
• Ketogenesis: Can form ketone bodies (ketogenic)
• Energy production: Oxidized in muscle for ATP
• Insulin secretion: Stimulates insulin release

Metabolic Pathway

Leucine is metabolized primarily in muscle tissue through the following pathway:

1. Transamination to α-ketoisocaproate (KIC) by BCAT
2. Oxidative decarboxylation by BCKDH complex
3. Conversion to isovaleryl-CoA
4. Further metabolism to HMB or acetyl-CoA

HMB Production

Approximately 5% of leucine is converted to β-hydroxy β-methylbutyrate (HMB), a metabolite with its own biological effects on muscle preservation and synthesis.

Food Sources

Requirements

Daily leucine requirements:

• WHO recommendation: 39 mg/kg body weight/day (minimum)
• Athletes/active individuals: 2-3 g per meal, 8-10 g/day total
• Elderly (for muscle preservation): May benefit from higher intake

Supplementation

Supplement Forms

• Free-form L-leucine: Pure amino acid powder
• BCAA supplements: Combined with isoleucine and valine (typically 2:1:1 ratio)
• EAA supplements: As part of essential amino acid blends
• Protein supplements: Whey is particularly high in leucine

Timing Considerations

• Pre-workout: May reduce muscle breakdown
• Post-workout: Maximizes MPS response
• With meals: Enhances protein synthesis from dietary protein
• Between meals: May help maintain elevated MPS

Research Applications

• Sarcopenia: Preventing age-related muscle loss
• Cachexia: Muscle wasting in disease states
• Athletic performance: Recovery and adaptation
• Weight loss: Preserving lean mass during caloric deficit

Safety Considerations

Leucine is generally safe when consumed in normal dietary amounts. Potential considerations include:

• High doses may affect blood sugar levels
• Maple syrup urine disease patients must restrict BCAAs
• Very high supplemental doses may cause GI discomfort

Related Topics

• Isoleucine – Fellow BCAA
• Valine – Third BCAA
• BCAAs – Branched-chain amino acids overview
• Essential Amino Acids – Complete list
• mTOR Pathway – Signaling pathway

References

1. Norton LE, Layman DK. "Leucine regulates translation initiation of protein synthesis in skeletal muscle after exercise." J Nutr. 2006.
2. Kimball SR, Jefferson LS. "Signaling pathways and molecular mechanisms through which branched-chain amino acids mediate translational control of protein synthesis." J Nutr. 2006.
3. Devries MC, Phillips SM. "Supplemental protein in support of muscle mass and health." Am J Clin Nutr. 2015.