Correct Answer: B. L-arginine
Nitric oxide (NO) is synthesized exclusively from L-arginine via the enzyme nitric oxide synthase (NOS). This is a critical regulatory molecule in vascular endothelium, immune function, and neuronal signaling. The reaction is: L-arginine + NADPH + O₂ → NO + L-citrulline + NADP⁺. The enzyme NOS catalyzes the oxidation of the guanidinium group of L-arginine, releasing NO and producing L-citrulline as a byproduct. This pathway is essential in Indian clinical practice for understanding endothelial dysfunction in hypertension, diabetes, and atherosclerosis—all prevalent in the Indian population. L-arginine is the sole natural substrate; no other amino acid can serve as the precursor. The cofactors required include NADPH, tetrahydrofolate (BH₄), and heme. This is a high-yield concept because NO deficiency underlies many cardiovascular complications seen in Indian patients with metabolic syndrome.
Why the other options are wrong
A. Glycine — Glycine is a simple amino acid involved in collagen synthesis, creatine metabolism, and glutathione formation, but it is NOT a substrate for NO synthesis. NBE may trap students who confuse amino acid metabolism pathways—glycine is important in many biosynthetic routes, but not in NO production. This is a common distractor for students who know glycine is metabolically active but haven't memorized the specific NOS substrate. C. Lysine — Lysine is a basic amino acid involved in protein synthesis and collagen cross-linking (via hydroxylysine), but it has no role in NO synthesis. NBE includes this to exploit students' knowledge that lysine is a positively charged amino acid (like arginine), leading them to assume both can serve similar metabolic roles. The structural similarity is a cognitive trap. D. L-citrulline — L-citrulline is actually the product of NO synthesis, not the substrate. This is a classic NBE trap—students who know the NOS reaction may confuse the direction of the pathway. Citrulline is also involved in the urea cycle, which may further confuse students. The trap exploits incomplete understanding of the reaction stoichiometry.
High-Yield Facts
- L-arginine is the sole natural substrate for nitric oxide synthase (NOS); the reaction produces NO and L-citrulline.
- Nitric oxide synthase requires cofactors: NADPH, tetrahydrofolate (BH₄), FAD, FMN, and heme for catalytic activity.
- Endothelial NO is critical for vasodilation and is deficient in Indian patients with hypertension, diabetes, and atherosclerosis.
- L-citrulline is the byproduct of NO synthesis and is recycled back to L-arginine via the citrulline-NO cycle in endothelium.
- Arginine supplementation is sometimes used clinically to improve endothelial function, though evidence is mixed in Indian populations.
Mnemonics
NO from ARG ARGinine → NO (remember: ARGinine is the source of NO, not citrulline). Use when recalling the substrate of NOS. NOS Reaction: ARG → NO + CIT Arginine → Nitric Oxide + CITrulline. The forward reaction is unidirectional; citrulline is recycled, not a substrate.
NBE Trap
NBE pairs L-citrulline (the product) with the question to trap students who know the NOS pathway but confuse substrate and product. Additionally, the inclusion of lysine exploits the assumption that all basic amino acids have similar metabolic roles.
Clinical Pearl
In Indian patients with metabolic syndrome and hypertension, endothelial NO deficiency is a key mechanism of vascular dysfunction. L-arginine supplementation is sometimes attempted to restore NO production, though dietary sources (nuts, seeds, legumes) are more practical. Understanding this pathway is essential for comprehending why statins and ACE inhibitors improve endothelial function beyond their primary mechanisms.
_Reference: Harper Biochemistry Ch. 28 (Amino Acid Metabolism); KD Tripathi Pharmacology Ch. 10 (Vasodilators and NO pathway)_