Does impaired folate-dependent one-carbon metabolism cause FIGLU accumulation?

Mechanistic pathway and folate trapping

• Enzymatic conversion: Under normal physiological conditions, formiminoglutamic acid (FIGLU)—an intermediate of histidine catabolism—is converted to glutamate by the enzyme glutamate formiminotransferase (part of the bifunctional FTCD complex). This biochemical step requires active tetrahydrofolate (THF) as a substrate to accept the transferred formimino group.
• Depletion of THF: Impairments in folate-dependent one-carbon metabolism directly reduce the active intracellular THF pool. This depletion occurs through direct dietary folate deficiency or via vitamin B12 deficiency, which induces "folate trapping" by locking folate in the unusable 5-methyl-THF form.
• Enzymatic deficiency: Congenital deficiency of the FTCD enzyme can also directly halt this metabolic step, causing pathway disruption independently of folate levels.

Clinical and diagnostic implications

• Systemic accumulation: When the conversion of FIGLU to glutamate is blocked due to a lack of THF or FTCD enzymatic defects, FIGLU biochemically accumulates in tissues and the bloodstream.
• Urinary excretion: Elevated systemic levels lead to the excess excretion of FIGLU in the urine. This biological mechanism underlies the historical and clinical use of the urinary FIGLU biomarker test (often evaluated after an oral histidine load) to detect functional folate and vitamin B12 deficiencies.

Bottom line

• Impaired folate-dependent one-carbon metabolism depletes active tetrahydrofolate, blocking the enzymatic conversion of histidine-derived FIGLU to glutamate and causing systemic accumulation and urinary excretion of FIGLU.