Citrulline

Citrulline is a non‑essential, water‑soluble amino acid that is not incorporated into proteins but serves as a key intermediate in the urea cycle and nitric‑oxide (NO) production pathway. In dietary‑supplement form it is primarily used to boost endogenous arginine levels, thereby enhancing NO‑mediated vasodilation, which can support cardiovascular, metabolic, and exercise‑related outcomes.

• Citrulline (L‑citrulline) is a non‑proteinogenic α‑amino acid with the molecular formula C₆H₁₃N₃O₃ and a molecular weight of 175.19 g mol⁻¹.
• IUPAC name: (2S)-2‑amino‑5‑ureido‑pentanoic acid.
• The structure features a central α‑carbon bearing an amino group, a carboxylate, and a side chain terminating in a urea (–NH‑C(=O)‑NH₂) moiety, conferring both basic and acidic properties (pKa ≈ 9.1 for the α‑amino and ≈2.5 for the carboxyl).
• It is a zwitterion at physiological pH, highly soluble in water (>1 g mL⁻¹) and stable at pH 5–9.
• The urea group enables the conversion to arginine via the urea cycle enzymes, while the free amino group participates in nitrogen transport.

• Naturally, citrulline is abundant in watermelon (Citrullus lanatus) rind and flesh, with concentrations up to 250 mg kg⁻¹ fresh weight.
• Commercial supplements are derived either:
  • (i) from extraction of watermelon juice/seed or
  • (ii) via microbial fermentation (e.g., Corynebacterium glutamicum engineered to overproduce L‑citrulline).
• The latter yields high purity (>98 %) L‑citrulline with minimal pesticide residues.
• Citrulline‑malate is produced by chemically reacting citrulline with malic acid under controlled pH, producing a 2:1 molar complex that improves solubility and bioavailability.
• Quality considerations include verification of L‑isomer purity, absence of heavy metals (≤10 ppb lead), and compliance with USP/EFSA standards.
• Third‑party testing (e.g., NSF, Informed‑Sport) ensures product integrity for athletes and clinical users.