rs61735836 — FTCD

FTCD p.Val101Met — When Histidine Catabolism Starves the Folate Cycle

Every amino acid you eat is eventually broken down. When your body catabolizes histidine, the final two steps of the pathway are handled by a single bifunctional enzyme — formimidoyltransferase cyclodeaminase (FTCD)¹¹ formimidoyltransferase cyclodeaminase (FTCD)
encoded on chromosome 21q22.3; enzyme is most abundantly expressed in liver. What makes this enzyme unusual is where its product goes: rather than simply releasing a waste metabolite, FTCD feeds a one-carbon unit directly into the [folate pool | the reservoir of tetrahydrofolate (THF) derivatives that carry methyl groups for DNA synthesis, methylation reactions, and homocysteine remethylation]. The p.Val101Met missense variant reduces this enzyme's efficiency, quietly throttling the histidine-to-folate pipeline.

The Mechanism

Histidine catabolism produces an intermediate called [formiminoglutamate (FIGLU) | formiminoglutamate — elevated FIGLU in urine has long been used as a clinical marker of folate deficiency; the FIGLU loading test challenges subjects with excess histidine to stress the folate pool]. FTCD's formiminotransferase domain transfers the formimino group from FIGLU onto tetrahydrofolate (THF), generating 5-formimino-THF. The enzyme's cyclodeaminase domain then strips ammonia from this intermediate, yielding [5,10-methenyl-THF | a one-carbon carrier that can be reduced to 5,10-methylene-THF or converted to 5-formyl-THF; both feed directly into folate-dependent reactions including DNA synthesis and methionine regeneration]. This one-carbon unit joins the central folate pool and ultimately supports SAM synthesis via the methionine cycle. The p.Val101Met substitution sits [between β-sheet 4 and α-helix 4 of the formiminotransferase N-subdomain | structural domain required for substrate binding and octamer assembly], a region important for both substrate binding and the protein's characteristic octameric quaternary structure. Computational predictors (SIFT score 1.0, PolyPhen-2 score 0.029) classify the substitution as tolerated; however, the genetic association evidence is unusually strong given the modest prediction scores — suggesting the variant subtly impairs enzyme efficiency at physiological substrate concentrations rather than abolishing activity outright.

The Evidence

The association was established by Pierce et al. 2019²² Pierce et al. 2019
Exome-wide association study of arsenic metabolism phenotypes in 1,660 Bangladeshi adults from the HEALS cohort. The T allele of rs61735836 showed genome-wide significant associations with all three urinary arsenic metabolites: increased inorganic arsenic (iAs%; P = 8×10⁻¹³), increased monomethylarsenic (MMA%; P = 2×10⁻¹⁶), and decreased dimethylarsenic (DMA%; P = 6×10⁻²³). This pattern indicates impaired [sequential methylation of arsenic | inorganic arsenic is methylated by AS3MT using SAM as methyl donor; DMA is the fully methylated, excretable form; low DMA% signals reduced methylation capacity] — exactly what reduced SAM availability from impaired FTCD activity would predict. Carriers of the T allele also showed increased arsenic-induced skin lesion risk (OR = 1.35; P = 1×10⁻⁵), making this a clinically consequential variant in high-arsenic environments. The biological logic connecting FTCD to arsenic metabolism runs through the folate and methionine cycles. A review of nutrition and one-carbon metabolism³³ review of nutrition and one-carbon metabolism
Abuawad et al., 2021 describes how FTCD-derived one-carbon units feed into the folate cycle, which then transfers methyl groups to the methionine cycle to regenerate SAM — the universal methyl donor used by AS3MT (and over 200 other methyltransferases). Reduced FTCD efficiency means fewer one-carbon units entering the folate pool, less SAM synthesized, and therefore impaired methylation capacity across the board. Multiple randomized controlled trials have confirmed that the folate-arsenic methylation link is causally upstream. A double-blind RCT in Bangladesh⁴⁴ double-blind RCT in Bangladesh
Gamble et al. 2006, n=200, 12 weeks showed that folic acid supplementation in folate-deficient adults significantly increased arsenic methylation, with greater DMA% and lower blood arsenic in the supplemented group. A more recent RCT of folic acid plus creatine⁵⁵ RCT of folic acid plus creatine
Bozack et al. 2019 found a 14% increase in blood DMA and a 0.19-unit improvement in the secondary methylation index at 12 weeks. These trials show that boosting the folate pool — which is precisely what FTCD normally does via histidine catabolism — improves methylation capacity. Carriers of the T allele who have reduced FTCD efficiency stand to benefit most from strategies that replenish the folate pool through alternative routes.

Practical Actions

For T allele carriers, the priority is compensating for the reduced input of one-carbon units from histidine catabolism. Because FTCD channels units into THF (not directly into the methyl-THF branch), supplementing with methylfolate (5-MTHF) provides pre-formed methyl groups that bypass the need for the FTCD step. Ensuring adequate vitamin B12 maintains methionine synthase activity, which recycles homocysteine and regenerates THF. Choline and betaine provide an alternative (folate-independent) remethylation route for homocysteine via BHMT, reducing pressure on the folate-dependent pathway. The arsenic association is most directly relevant in populations with high inorganic arsenic exposure (well water in South Asia, parts of South America, or western United States). For people in low-arsenic environments, the functional consequence of the variant is subtler but still present: reduced one-carbon input into the folate pool means that dietary folate demands are slightly higher than for people with efficient FTCD.

Interactions

FTCD feeds one-carbon units into the THF pool that MTHFR (rs1801133, rs1801131) then converts to 5-methylTHF for homocysteine remethylation. A person carrying both FTCD T allele (reduced input into THF pool) and MTHFR 677T (reduced conversion to 5-methylTHF) faces impairment at consecutive steps in the one-carbon pathway — less substrate entering the folate pool, and less efficient conversion of what does enter. The combined effect on methylation capacity would be greater than either variant alone. SHMT1 C1420T (rs1979277) also operates in this pathway, interconverting serine and glycine while transferring one-carbon units to THF. Carriers of variants in FTCD, MTHFR, and SHMT1 collectively represent persons with reduced throughput at multiple nodes of one-carbon metabolism. SLC19A1 (RFC1, rs1051266) governs cellular folate transport. Poor folate uptake by SLC19A1 variants compounds FTCD-related inefficiency by limiting the THF available for FTCD's product to integrate with.