L-Leucine (BCAA) | Supplementopedia

Overview

L‑Leucine is an essential, branched‑chain amino acid (BCAA) that humans must obtain from the diet because the body cannot synthesize it. It is a key building block of protein and serves as a primary signal molecule that regulates muscle protein synthesis, particularly after exercise or periods of catabolic stress.

Benefits

Muscle protein synthesis: Leucine-rich supplementation activates the mTORC1 pathway, increasing muscle protein synthesis and supporting lean‑mass gains in both athletes and older adults.
Exercise performance & recovery: Acute leucine dosing (2–3 g) before or after resistance training reduces muscle soreness and accelerates recovery of strength.
Metabolic health: In insulin‑resistant individuals, leucine improves glucose uptake by enhancing GLUT4 translocation, modestly improving glycemic control when combined with exercise.
Weight management: Leucine stimulates appetite‑regulating hormones (e.g., GLP‑1) and may help preserve lean mass during calorie restriction.
Cognitive support: Emerging data suggest leucine can influence neurotransmitter synthesis (e.g., glutamate) and may modestly improve cognitive performance under metabolic stress, though evidence remains preliminary.

How It Works

mTORC1 Activation: Leucine is a potent activator of the mechanistic target of rapamycin complex 1 (mTORC1) pathway, a central regulator of cellular growth.
Cellular Uptake: Upon entering muscle cells via LAT1 transporters, leucine binds to the sestrin2–GATOR2 complex, relieving inhibition of mTORC1.
Protein Synthesis: Activated mTORC1 phosphorylates downstream effectors (e.g., S6K1, 4E‑BP1), driving translation initiation and protein synthesis.
Insulin Secretion: Leucine stimulates insulin secretion via the pancreatic β‑cell leucine‑sensing mechanism, enhancing glucose uptake.
Neurotransmitter Precursor: In the brain, leucine serves as a precursor for the excitatory neurotransmitter glutamate and may modulate the kynurenine pathway, influencing neuro‑inflammation.
Overall Effects: These actions translate into enhanced muscle anabolism, improved metabolic signaling, and potential neuro‑protective effects.

Dosage

Typical Dosage: Supplemental leucine typically ranges from 2 g to 5 g per day.
Dosing Schedule: Doses are split into 1–3 g doses before and/or after training.
Older Adults: For older adults aiming to preserve muscle mass, 3 g taken twice daily (morning and evening) is common.
Athletes: Athletes often consume 2 g 30 minutes pre‑exercise and another 2 g within 30 minutes post‑exercise, ensuring total daily intake does not exceed 10 g to avoid nitrogen overload.
BCAA Combination: When combined with other BCAAs, a 2:1:1 leucine‑isoleucine‑valine ratio is standard.
Weight Loss: In weight‑loss protocols, 5 g taken with a protein‑rich meal can enhance satiety.
Special Considerations: Individuals with renal impairment should limit total leucine intake to ≤2 g per dose and monitor serum creatinine.

Safety & Side Effects

General Tolerance: L‑Leucine is generally well‑tolerated.
Side Effects: Common mild side effects include gastrointestinal discomfort (bloating, diarrhea) at doses >10 g/day.
Contraindications: Contraindications include severe renal impairment (eGFR < 30 mL/min/1.73 m²) because excess amino acids increase nitrogen load.
Drug Interactions: High leucine may augment insulin secretion, potentiating hypoglycemia risk when combined with sulfonylureas or insulin.
Specific Conditions: Individuals with maple‑syndrome (defective branched‑chain α‑ketoacid dehydrogenase) must avoid supplementation.
Pregnancy/Lactation: Pregnant or lactating women should limit intake to the Recommended Dietary Allowance (≈2 g/day) unless supervised by a clinician.

Chemistry

IUPAC Name: L‑Leucine (IUPAC: (2S)-2-amino‑4‑methylpentanoic acid)
Molecular Formula: C₆H₁₃NO₂
Molecular Weight: 131.18 g/mol
Structure: It is a chiral, non‑polar, aliphatic amino acid with an isobutyl side chain (‑CH₂‑CH(CH₃)₂) attached to the α‑carbon. The L‑configuration corresponds to the S‑enantiomer.
Solubility: It is sparingly soluble in water (≈22 g/L at 25 °C) and soluble in organic solvents such as ethanol.
pKa Values: The pKa of the α‑carboxyl group is ≈2.4; the α‑amino group has a pKa of ≈9.6, giving it a zwitterionic form at physiological pH (~7.4).

Sources & Quality

Dietary Sources: Dietary sources include whey, casein, soy, beef, poultry, and fish.
Commercial Production: Commercially, L‑leucine is produced by microbial fermentation (e.g., Corynebacterium glutamicum) followed by purification, or via chemical synthesis from α‑ketoisocaproic acid.
Purity: High‑purity pharmaceutical‑grade leucine is typically obtained through fermentation, offering >98 % purity and low heavy‑metal content.
Quality Assessment: Quality assessment includes verification of BCAAs ratio, absence of contaminants (e.g., heavy metals, residual solvents), and compliance with GMP and USP monographs.
Labeling: Certified “food‑grade” and “pharmaceutical‑grade” labels provide assurance of consistent potency and safety for supplementation.