L-leucine (Leu)

L-leucine is an essential branched-chain amino acid (BCAA) that serves as both a structural building block for proteins and a potent signaling molecule within the mammalian nutrient-sensing architecture [1, 2]. It is recognized as the primary nutritional activator of the mechanistic target of rapamycin complex 1 (mTORC1) pathway, which is a master regulator of cell growth, proliferation, and metabolism [1, 5, 6]. Mechanistically, L-leucine binds to the intracellular sensor protein Sestrin2, disrupting the Sestrin2-GATOR2 inhibitory complex and triggering the Rag GTPase-dependent recruitment of mTORC1 to the lysosomal membrane for activation [9, 18]. Clinically, L-leucine is widely used as a nutritional supplement to address muscle wasting conditions like sarcopenia and cachexia, and it is a fundamental component of parenteral and enteral nutrition formulas [2, 14, 16]. However, its metabolic regulation is critical, as genetic defects in its breakdown lead to toxic accumulation in Maple Syrup Urine Disease (MSUD), and chronically elevated levels are associated with insulin resistance in metabolic syndromes [5, 17]. Pharmacologically, L-leucine exhibits complex interactions, potentially enhancing the effects of insulin and sildenafil while interfering with the gastrointestinal absorption of levodopa and the endogenous synthesis of certain B-vitamins [4, 7, 19].

Other names

(S)-Leucine(S)-2-Amino-4-methylpentanoic acid2-Amino-4-methylvaleric acidL-2-Amino-4-methylpentanoic acidalpha-Aminoisocaproic acid

L-leucine acts as a signaling ligand that binds to the sensor protein Sestrin2. This binding causes Sestrin2 to dissociate from the GATOR2 complex, which then relieves the inhibition of Rag GTPases. The active Rag GTPases recruit the mTORC1 complex to the lysosomal surface, where it is activated by Rheb in response to growth factors. Once activated, mTORC1 phosphorylates downstream effectors such as p70S6K and 4E-BP1, thereby initiating mRNA translation and muscle protein synthesis [9, 17, 18].