Homocysteine metabolism (remethylation and transsulfuration)

The two competing cytosolic fates of L-homocysteine, the branch-point metabolite of the methionine cycle. Homocysteine is generated from S-adenosylhomocysteine after SAM-dependent methylation reactions, and its two disposal routes determine methionine/one-carbon homeostasis and sulfur-amino-acid supply. (1) Remethylation regenerates L-methionine: methylenetetrahydrofolate reductase (MTHFR) reduces 5,10-methylenetetrahydrofolate to 5-methyl-THF, the methyl donor that cobalamin-dependent methionine synthase (MTR) uses to transfer a methyl group to homocysteine (via an enzyme-bound methylcobalamin cofactor), producing methionine and regenerating tetrahydrofolate. Because MTR's cobalamin is periodically oxidised to inactive cob(II)alamin, methionine synthase reductase (MTRR), an NADPH-dependent diflavin oxidoreductase, reductively reactivates it; and the upstream cobalamin-processing enzyme MMACHC (cblC) decyanates/dealkylates incoming cobalamin to the cob(II)alamin precursor that supplies both methylcobalamin (to MTR) and adenosylcobalamin (to methylmalonyl-CoA mutase). (2) Transsulfuration commits homocysteine's sulfur to cysteine: the PLP-dependent cystathionine beta-synthase (CBS) condenses homocysteine with L-serine to cystathionine, which cystathionine gamma-lyase (CTH/CSE) then cleaves to L-cysteine (plus 2-oxobutanoate and ammonia); CBS and CTH are also the principal enzymatic sources of the gasotransmitter hydrogen sulfide. Inherited defects all cause homocystinuria / hyperhomocysteinemia with distinct biochemistry: CBS → classic homocystinuria (with hypermethioninemia); MTHFR → homocystinuria with low methionine; MTR → cblG and MTRR → cblE homocystinuria; MMACHC → cblC (combined methylmalonic aciduria and homocystinuria); CTH → (largely benign) cystathioninuria.

MODULE:homocysteine_metabolismDRAFTMetabolic Pathwaymodules/homocysteine_metabolism.yaml
homocysteine metabolic processGO:0050667
GO:0050667
homocysteine metabolic process
The module is grounded in the GO homocysteine metabolic process (GO:0050667), covering both the remethylation and transsulfuration fates.
Reactome:R-HSA-1614635
Sulfur amino acid metabolism
Step order and reaction stoichiometries follow the human Reactome sulfur amino acid / methionine-cycle reactions: R-HSA-200676 (MTHFR), R-HSA-3149539 (MTR), R-HSA-1614524 (CBS) and R-HSA-1614583 (CTH).
file:human/MTHFR/MTHFR-ai-review.yaml
MTHFR gene review (human)
The MTHFR step grounding (UniProtKB:P42898, GO:0004489 methylenetetrahydrofolate reductase [NAD(P)H] activity) matches the completed human MTHFR review.
file:human/MTR/MTR-ai-review.yaml
MTR gene review (human)
The methionine synthase step (UniProtKB:Q99707, GO:0008705 methionine synthase activity, cobalamin binding) matches the completed human MTR review.
file:human/MTRR/MTRR-ai-review.yaml
MTRR gene review (human)
The methionine-synthase-reductase reactivation step (UniProtKB:Q9UBK8, GO:0030586) matches the completed human MTRR review.
file:human/MMACHC/MMACHC-ai-review.yaml
MMACHC gene review (human)
The upstream cobalamin-processing step (UniProtKB:Q9Y4U1, GO:0033787) matches the completed human MMACHC review (cblC; supplies both MeCbl and AdoCbl arms).
file:human/CBS/CBS-ai-review.yaml
CBS gene review (human)
The transsulfuration entry step (UniProtKB:P35520, GO:0004122 cystathionine beta-synthase activity) matches the completed human CBS review.
file:human/CTH/CTH-ai-review.yaml
CTH gene review (human)
The transsulfuration cysteine-forming step (UniProtKB:P32929, GO:0004123 cystathionine gamma-lyase activity) matches the completed human CTH review.
6Nodes
5Parts
0Variant Sets
0Variants
6Annotons
3Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:homocysteine_metabolism deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Gene-review completeness (6/6 grounded genes reviewed)

5 complete review(s) · 1 with deep research · 0 missing review · 5 reviewed but lacking deep research

Gene Review Complete Deep research
CBS P35520 ✓ 73/74 ✓
CTH P32929 ✓ ✓ ✗
MMACHC Q9Y4U1 ✓ ✓ ✗
MTHFR P42898 ✓ ✓ ✗
MTR Q99707 ✓ ✓ ✗
MTRR Q9UBK8 ✓ ✓ ✗

Details

Context
cytosolGO:0005829
Homocysteine metabolism (remethylation + transsulfuration)Metabolic Pathwayhomocysteine_metabolism
homocysteine metabolic processGO:0050667
Context
cytosolGO:0005829

The two fates of homocysteine grounded to the human enzymes MTHFR (UniProtKB:P42898, GO:0004489, EC 1.5.1.20), MTR (Q99707, GO:0008705, EC 2.1.1.13), MTRR (Q9UBK8, GO:0030586, EC 1.16.1.8), MMACHC (Q9Y4U1, GO:0033787, EC 1.16.1.6) on the remethylation side, and CBS (P35520, GO:0004122, EC 4.2.1.22) and CTH (P32929, GO:0004123, EC 4.4.1.1) on the transsulfuration side. GO molecular-function terms were taken from the human GOA records; Reactome reaction ids and titles were verified against the local reactome cache. Each step uses a PANTHER family selector (generic over paralogs and orthologs) plus a concrete human representative member. This concrete homocysteine-disposal module complements the more abstract methionine (S-adenosylmethionine) cycle module (MODULE:methionine_cycle); the MMACHC cobalamin-processing step also feeds the adenosylcobalamin arm used by methylmalonyl-CoA mutase (see the propionyl-CoA catabolism module).

Connections

mthfr_step -> mtr_step Provides Input For
5-methyltetrahydrofolate made by MTHFR is the methyl donor consumed by methionine synthase (MTR) in remethylation.
cobalamin_support -> mtr_step Positively Regulates
MTRR reactivates and MMACHC supplies MTR's methylcobalamin cofactor; without this support the remethylation step fails (cblE/cblC/cblG).
cbs_step -> cth_step Provides Input For
Cystathionine made by CBS is cleaved to cysteine by CTH, completing the transsulfuration branch.
Part 1: remethylation — supply of the folate methyl donor
5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolateReactionmthfr_step

Annotons

MTHFR: methylenetetrahydrofolate reductase
mthfr_activity
Participant: Family: Methylenetetrahydrofolate reductase family (MTHFR)
Family:
Methylenetetrahydrofolate reductase family (MTHFR)PANTHER:PTHR45754
Representative Members: MTHFR (human)UniProtKB:P42898

Function

methylenetetrahydrofolate reductase [NAD(P)H] activityGO:0004489
Substrates: 5,10-methylenetetrahydrofolate NAD(P)H
Products: 5-methyltetrahydrofolate

Locations

cytosolGO:0005829

FAD-dependent, SAM-inhibited committed step that commits folate one-carbon units to methionine remethylation by making 5-methyl-THF. Deficiency (incl. the common c.677C>T thermolabile variant) causes homocystinuria with low methionine.

Part 2: remethylation — cobalamin-dependent methyl transfer to homocysteine
L-homocysteine + 5-methyl-THF to L-methionine + THFReactionmtr_step

Annotons

MTR: methionine synthase (methylcobalamin-dependent)
mtr_activity
Participant: Family: Cobalamin-dependent methionine synthase family (MTR)
Family:
Cobalamin-dependent methionine synthase family (MTR)PANTHER:PTHR45833
Representative Members: MTR (human)UniProtKB:Q99707

Function

methionine synthase activityGO:0008705
Substrates: L-homocysteine 5-methyltetrahydrofolate methylcobalamin (enzyme cofactor)
Products: L-methionine tetrahydrofolate

Locations

cytosolGO:0005829

Methylcobalamin-dependent transfer of the 5-methyl-THF methyl group to homocysteine, regenerating methionine and THF and linking the folate and methionine cycles. Deficiency causes cblG homocystinuria.

Part 3: remethylation — cobalamin cofactor maintenance / supply (supports MTR)
reactivation (MTRR) and processing (MMACHC) of MTR's cobalamin cofactorRegulatory Stepcobalamin_support

Annotons

MTRR: methionine synthase reductase
mtrr_activity
Participant: Family: Diflavin oxidoreductase (NOS/CPR-related) family (MTRR)
Family:
Diflavin oxidoreductase (NOS/CPR-related) family (MTRR)PANTHER:PTHR19384
Representative Members: MTRR (human)UniProtKB:Q9UBK8

Function

[methionine synthase] reductase (NADPH) activityGO:0030586
Substrates: cob(II)alamin-methionine synthase (oxidised) NADPH
Products: methylcobalamin-methionine synthase (reactivated)

Locations

cytosolGO:0005829

NADPH-dependent diflavin (FAD+FMN) reductase that reductively reactivates the periodically-oxidised methylcobalamin of MTR. Deficiency causes cblE homocystinuria.

MMACHC/cblC: cobalamin-processing enzyme
mmachc_activity
Participant: Family: cblC cobalamin-processing family (MMACHC)
Family:
cblC cobalamin-processing family (MMACHC)PANTHER:PTHR31457
Representative Members: MMACHC (human)UniProtKB:Q9Y4U1

Function

cyanocobalamin reductase (cyanide-eliminating) (NADP+) activityGO:0033787
Substrates: cyanocobalamin / alkylcobalamins glutathione (for dealkylation)
Products: cob(II)alamin (common precursor)

Locations

cytosolGO:0005829

Upstream cobalamin-processing enzyme that decyanates/dealkylates incoming cobalamin to the cob(II)alamin precursor feeding BOTH the MeCbl (MTR) and AdoCbl (MMUT) arms. Deficiency causes cblC disease (combined methylmalonic aciduria and homocystinuria).

Part 4: transsulfuration — condensation with serine (branch to cysteine)
L-homocysteine + L-serine to L-cystathionineReactioncbs_step

Annotons

CBS: cystathionine beta-synthase
cbs_activity
Participant: Family: Cystathionine beta-synthase family (CBS)
Family:
Cystathionine beta-synthase family (CBS)PANTHER:PTHR10314
Representative Members: CBS (human)UniProtKB:P35520

Function

cystathionine beta-synthase activityGO:0004122
Substrates: L-homocysteine L-serine
Products: L-cystathionine water

Locations

cytosolGO:0005829

Committed, SAM-activated (allosterically) first step of transsulfuration; PLP- and heme-dependent. Deficiency causes classic homocystinuria (with hypermethioninemia). Also a source of H2S.

Part 5: transsulfuration — cleavage to cysteine
L-cystathionine to L-cysteine + 2-oxobutanoate + NH3Reactioncth_step

Annotons

CTH/CSE: cystathionine gamma-lyase
cth_activity
Participant: Family: Transsulfuration enzyme (cystathionine gamma-lyase) family (CTH)
Family:
Transsulfuration enzyme (cystathionine gamma-lyase) family (CTH)PANTHER:PTHR11808
Representative Members: CTH (human)UniProtKB:P32929

Function

cystathionine gamma-lyase activityGO:0004123
Substrates: L-cystathionine water
Products: L-cysteine 2-oxobutanoate ammonia

Locations

cytosolGO:0005829

PLP-dependent cleavage of cystathionine to cysteine, completing transsulfuration; also a major enzymatic source of the gasotransmitter hydrogen sulfide. Deficiency causes (largely benign) cystathioninuria.