Glutathione-dependent formaldehyde detoxification

A bacterial detoxification module in which formaldehyde is captured by glutathione as S-(hydroxymethyl)glutathione, the hemithioacetal is oxidized to S-formylglutathione, and the thioester is hydrolyzed to formate while regenerating glutathione. Chemical capture, oxidation, and hydrolysis are represented as separate steps.

MODULE:glutathione_dependent_formaldehyde_detoxificationDRAFTBiological Processmodules/glutathione_dependent_formaldehyde_detoxification.yaml
formaldehyde catabolic processGO:0046294
PMID:21261833
Physiological responses of Pseudomonas putida to formaldehyde during detoxification
KT2440 oxidizes formaldehyde rather than assimilating it. PP_1616 and PP_1617 are induced by 0.5 mM formaldehyde, and their disruption impairs growth at 1.5 mM formaldehyde; the paper does not assign either protein to this glutathione-dependent reaction sequence.
PMID:21261833
Physiological responses of Pseudomonas putida to formaldehyde during detoxification
This study calls PP_3970 fhdA and glutathione-dependent, but reports a formaldehyde-sensitivity phenotype rather than a biochemical substrate or glutathione-dependence assay.
the fhdA gene encoding a glutathione‐dependent formaldehyde dehydrogenase (PP3970)
PMID:19304846
Redundancy of enzymes for formaldehyde detoxification in Pseudomonas putida
KT2440 PP_3970 knockout data support a contribution to labeled-formaldehyde mineralization, but do not establish the enzyme's substrate chemistry or glutathione dependence.
The results showed that both enzymes contributed to formaldehyde catabolism.
PMCID:PMC2687156
Open-access full text of PMID:19304846
The open-access full text calls PP_3970 fdhB during a comparative sequence-annotation analysis; its glutathione-independent classification is not established by a direct biochemical assay.
The PP0328 gene was annotated as fdhA, whereas the PP3970 gene was called fdhB (Table 1).
UniProtKB:Q88FV8
PSEPK PP_3970 UniProt record
The current unreviewed record names PP_3970 ybdR and assigns only a generic zinc-dependent, NAD(P)-binding oxidoreductase function; it does not assign formaldehyde as substrate or state glutathione dependence.
file:PSEPK/frmA/frmA-uniprot.txt
PSEPK FrmA UniProt record
Q88MF5 is an S-(hydroxymethyl)glutathione dehydrogenase.
UniProtKB:P25437
Reviewed Escherichia coli FrmA UniProt record
The reviewed E. coli FrmA record reports glutathione-dependent formaldehyde dehydrogenase activity, assigns GO:0051903 from direct assay, and classifies the protein in PTHR43880:SF12.
file:PSEPK/frmC/frmC-uniprot.txt
PSEPK FrmC UniProt record
Q88MF4 is an S-formylglutathione hydrolase.
file:interpro/panther/PTHR10061/PTHR10061-metadata.yaml
PANTHER PTHR10061 family metadata
PTHR10061 is the S-formylglutathione hydrolase family used for the FrmC selector.
file:modules/glutathione_dependent_formaldehyde_detoxification-deep-research-openscientist.md
OpenScientist review of glutathione-dependent formaldehyde detoxification
Supports the reusable three-step boundary, spontaneous first step, NAD+-biased FrmA oxidation, FrmC-family hydrolysis, and separation from glutathione-independent formaldehyde oxidation routes.
file:projects/P_PUTIDA/deep-research/PSEPK__glutathione_dependent_formaldehyde_detoxification__ppu00680-deep-research-openscientist.md
OpenScientist PSEPK pathway satisfiability review
Finds the branch satisfiable through adjacent frmA and frmC candidates while emphasizing that their exact KT2440 chemistry lacks direct enzymology and that PP_3970 belongs outside this defined branch.
PANTHER:PTN000191653
PAINT FrmA-function ancestral node
Local PTHR43880 PAINT data place GO:0051903 by IBD at PTN000191653, seeded in part by reviewed Escherichia coli FrmA P25437.
PANTHER:PTN000006872
PAINT S-formylglutathione-hydrolase ancestral node
Local PTHR10061 PAINT data place GO:0018738 by IBD at PTN000006872, seeded in part by reviewed E. coli FrmB P51025 and YeiG P33018.

The boundary begins with glutathione capture of formaldehyde and ends at formate plus regenerated glutathione. Formate oxidation to carbon dioxide, formaldehyde efflux, DNA repair, protein-quality control, and nitrosothiol reduction are distinct downstream or parallel functions. Organisms can carry additional formaldehyde oxidation routes, so this module represents the glutathione-dependent branch rather than the entire cellular response. In KT2440, PP_3970 has genetic evidence for a contribution to formaldehyde mineralization, but that does not place it in the defined FrmA-FrmC reaction sequence. The literature uses conflicting names and glutathione-dependence assignments for PP_3970, while UniProtKB:Q88FV8 currently assigns only a generic zinc-dependent, NAD(P)-binding oxidoreductase function. Its precise chemistry therefore remains unresolved. The exact contribution of PP_1616/FrmA and PP_1617/FrmC to this branch remains based on homology and should be tested directly.

4Nodes
3Parts
0Variant Sets
0Variants
2Annotons
2Connections

Derived QC

Recommended-field compliance

55.6% recommended fields populated
  • module.knowledge_gaps[0] · status (0/1)
  • module.knowledge_gaps[0] · provenance (0/1)
  • module.knowledge_gaps[1] · status (0/1)
  • module.knowledge_gaps[1] · provenance (0/1)

Module deep research

✓ present

  • glutathione_dependent_formaldehyde_detoxification-deep-research-openscientist.md (openscientist)

Leaf nodes lacking representative members

1 leaf node(s) with no concrete protein grounding:

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Gene-review completeness (2/5 grounded genes reviewed)

2 complete review(s) · 2 with deep research · 3 missing review · 0 reviewed but lacking deep research

Gene Review Complete Deep research
frmA Q88MF5 ✓ ✓ ✓
frmC Q88MF4 ✓ ✓ ✓
experimentally characterized E. coli FrmA exemplar P25437 ✗ — —
experimentally characterized E. coli YeiG exemplar P33018 ✗ — —
experimentally characterized E. coli FrmB exemplar P51025 ✗ — —

Details

Context
bacteriaNCBITaxon:2
Glutathione-dependent formaldehyde detoxificationBiological Processglutathione_dependent_formaldehyde_detoxification
formaldehyde catabolic processGO:0046294
Context
bacteriaNCBITaxon:2

Connections

Part 1: Glutathione capture of formaldehyde
S-(hydroxymethyl)glutathione formationReactionformaldehyde_glutathione_capture

Formaldehyde reacts with glutathione to form the hemithioacetal S-(hydroxymethyl)glutathione, which feeds the subsequent dehydrogenase step. This capture is spontaneous and has no gene participant.

Part 2: Hemithioacetal oxidation
S-(hydroxymethyl)glutathione oxidationReactionfrma_hemithioacetal_oxidation

A class-3 alcohol dehydrogenase oxidizes S-(hydroxymethyl)glutathione to S-formylglutathione. The GO term permits NAD(P)+, whereas characterized family members are NAD+-biased.

Annotons

FrmA S-(hydroxymethyl)glutathione dehydrogenase
frma_formaldehyde_dehydrogenase
Participant: Family: zinc-containing alcohol dehydrogenase family, class-3 lineage
Family:
zinc-containing alcohol dehydrogenase family, class-3 lineagePANTHER:PTHR43880:SF12
Representative Members: PSEPK FrmA exemplarUniProtKB:Q88MF5 experimentally characterized E. coli FrmA exemplarUniProtKB:P25437
Required Function:
S-(hydroxymethyl)glutathione dehydrogenase [NAD(P)+] activityGO:0051903

Function

S-(hydroxymethyl)glutathione dehydrogenase [NAD(P)+] activityGO:0051903
Substrates: S-(hydroxymethyl)glutathione NAD+
Products: S-formylglutathione NADH
Cofactors: zinc ion

Processes

formaldehyde catabolic processGO:0046294

Oxidizes the glutathione-bound formaldehyde intermediate.

Part 3: S-formylglutathione hydrolysis and glutathione regeneration
S-formylglutathione hydrolysisReactionfrmc_formylglutathione_hydrolysis

A serine hydrolase converts S-formylglutathione to formate and glutathione, completing detoxification and regenerating the carrier.

Annotons

FrmC S-formylglutathione hydrolase
frmc_formylglutathione_hydrolase
Participant: Family: FrmC family
Family:
FrmC familyPANTHER:PTHR10061
Representative Members: PSEPK FrmC exemplarUniProtKB:Q88MF4 experimentally characterized E. coli FrmB exemplarUniProtKB:P51025 experimentally characterized E. coli YeiG exemplarUniProtKB:P33018
Required Function:
S-formylglutathione hydrolase activityGO:0018738

Function

S-formylglutathione hydrolase activityGO:0018738
Substrates: S-formylglutathione water
Products: formate glutathione

Processes

formaldehyde catabolic processGO:0046294

Releases formate and regenerates glutathione.