Pyrroloquinoline quinone biosynthesis

Pyrroloquinoline quinone (PQQ) is made from conserved glutamate and tyrosine residues in the short ribosomally synthesized precursor peptide PqqA. A PqqD-family peptide chaperone presents PqqA to the radical-SAM enzyme PqqE, which forms the defining carbon-carbon cross-link. Proteolytic processing and PqqB-dependent oxygenation both contribute to formation of a late small-molecule precursor, although their relative order is unresolved. PqqC completes oxidative ring closure to mature PQQ. PQQ export and use by quinoprotein dehydrogenases are downstream of this module.

MODULE:pqq_biosynthesisDRAFTMetabolic Pathwaymodules/pqq_biosynthesis.yaml
pyrroloquinoline quinone biosynthetic processGO:0018189
UniPathway:UPA00539
Pyrroloquinoline quinone biosynthesis
UniPathway UPA00539 identifies the PqqA, PqqD, PqqE, PqqB, and PqqC pathway roles, together with PqqF as one implementation of the required precursor-proteolysis operation.
GO:0018189
pyrroloquinoline quinone biosynthetic process
GO:0018189 provides the biological-process identity for conversion of a peptide precursor into the PQQ cofactor.
file:modules/pqq_biosynthesis-deep-research-openscientist.md
OpenScientist module research for PQQ biosynthesis
OpenScientist retrieved the peptide-derived pathway boundary, the PqqA/PqqD/PqqE, PqqB, and PqqC roles, and distinct single-chain M16A, two-component M16B, and substitute-protease implementations. Its review also identifies the order of proteolysis versus PqqB oxygenation as a central unresolved point.
file:projects/P_PUTIDA/deep-research/PSEPK__pqq_biosynthesis__upa00539-deep-research-openscientist.md
OpenScientist PSEPK UPA00539 PQQ-biosynthesis research
The species-aware retrieval supports satisfaction of the conserved KT2440 steps by PqqA, PqqD1/PqqE, PqqB, PqqC, and single-chain M16 PqqF. It also correctly distinguishes the S9-family PP_0375 candidate from the unrelated two-component M16B PqqG implementation.
PMID:27287323
Regulation of Pyrroloquinoline Quinone-Dependent Glucose Dehydrogenase Activity in the Model Rhizosphere-Dwelling Bacterium Pseudomonas putida KT2440.
The KT2440 operon study maps pqqFABCDEG, identifies PP_0375 as a putative pqqG by locus and sequence conservation, and places pqqG on the pqqCDEG transcript while leaving its biochemical role unresolved.
PMID:19902179
The PQQ biosynthetic operons and their transcriptional regulation in Pseudomonas aeruginosa.
Genetics in Pseudomonas aeruginosa separates the PA1990/PqqH phenotype, loss of extracellular PQQ, from the inability of a pqqF mutant to produce PQQ. This distinction leaves the direct biochemical role of S9-family PqqH/PqqG candidates unresolved.
PMID:31427437
A two-component protease in Methylorubrum extorquens with high activity toward the peptide precursor of the redox cofactor pyrroloquinoline quinone.
Biochemical characterization identifies a heterodimeric M16B PqqF/PqqG protease that cleaves PqqA, providing a distinct implementation from the S9-family Pseudomonas protein also named PqqG or PqqM. The full article places zinc binding on PqqF and catalytic R/Y residues on PqqG, so the molecular function is assigned to the heterodimer rather than to either subunit alone.
UniProtKB:A0ACD6BAY6
Serratia sp. FS14 coenzyme PQQ synthesis protein F
UniProtKB resolves A0ACD6BAY6 as the Serratia sp. FS14 PqqF, and RCSB SIFTS maps the PDB:5CIO polymer entity to this accession.
UniProtKB:C5AQL6
Methylorubrum extorquens AM1 PqqF
UniProtKB resolves C5AQL6 as the 460-residue pqqF product from strain AM1.
UniProtKB:C5AQL7
Methylorubrum extorquens AM1 PqqG
UniProtKB resolves C5AQL7 as the 427-residue pqqG product from strain AM1.
RHEA:56836
PqqE-dependent PqqA cross-linking
Rhea 56836 defines radical-SAM formation of the glutamate-tyrosine carbon-carbon cross-link in the PQQ precursor peptide.
RHEA:10692
pyrroloquinoline-quinone synthase reaction
Rhea 10692 defines the terminal PqqC oxidation of the late quinoline precursor to mature PQQ.
file:PSEPK/pqqD1/pqqD1-ai-review.yaml
PqqD1 gene review
The PqqD1 review supports a PqqA-binding peptide-chaperone role and does not treat generic quinone binding as its core molecular function.
file:PSEPK/pqqE/pqqE-ai-review.yaml
PqqE gene review
The PqqE review supports radical-SAM PqqA peptide cyclase activity in PQQ biosynthesis.
file:PSEPK/PP_0375/PP_0375-ai-review.yaml
PP_0375 PqqG-candidate gene review
The PP_0375 review assesses the S9 serine-peptidase annotation and the literature-supported association of this Pseudomonas pqqG candidate with the PQQ pathway without assigning an unproven pathway substrate or conflating precursor maturation with PQQ excretion.
file:PSEPK/pqqB/pqqB-ai-review.yaml
PqqB gene review
The PqqB review supports an inferred non-heme hydroxylase role while retaining uncertainty about the native substrate and exact product.
file:PSEPK/pqqC/pqqC-ai-review.yaml
PqqC gene review
The PqqC review supports the terminal pyrroloquinoline-quinone synthase reaction.
file:VARPS/pqqA/pqqA-ai-review.yaml
Variovorax paradoxus S110 pqqA gene review
C5CPT7 (Vapar_3057) encodes the 24-residue ribosomally synthesized PqqA precursor peptide supplying Glu16 and Tyr20 for PQQ biosynthesis.
Ribosomally synthesized 24-residue precursor peptide that supplies the conserved Glu16 and Tyr20 side chains for PqqD/PqqE-mediated carbon-carbon cross-linking and subsequent proteolytic and oxidative maturation into pyrroloquinoline quinone (PQQ); acts as a biosynthetic precursor scaffold rather than a catalytic enzyme.
file:VARPD/pqqB/pqqB-ai-review.yaml
Variovorax paradoxus pqqB gene review
A0A0H2M8Q2 (VPARA_00950) encodes the metallo-beta-lactamase-fold non-heme iron hydroxylase PqqB in the pqqBCDE operon.
Non-heme iron-dependent hydroxylase of the metallo-beta-lactamase fold that catalyzes O2-dependent aromatic ring oxygenation of a PqqA-derived Glu-Tyr cross-linked intermediate to form the hydroxyquinone precursor of AHQQ during pyrroloquinoline quinone biosynthesis.
file:VARPD/pqqC/pqqC-ai-review.yaml
Variovorax paradoxus pqqC gene review
A0A0H2MDI9 (VPARA_00940) encodes the cofactor-less pyrroloquinoline-quinone synthase PqqC in the pqqBCDE operon.
Catalyzes the terminal cofactor-independent ring cyclization and eight-electron oxidation of AHQQ using molecular oxygen to produce mature pyrroloquinoline quinone (PQQ), hydrogen peroxide, and water (EC 1.3.3.11, RHEA:10692).
file:VARPD/pqqD/pqqD-ai-review.yaml
Variovorax paradoxus pqqD gene review
A0A0H2M992 (VPARA_00930) encodes the cofactor-less RiPP recognition element (RRE) peptide chaperone PqqD in the pqqBCDE operon.
Cofactor-less RiPP recognition element (RRE) peptide chaperone that binds the unmodified PqqA precursor peptide and presents it in a ternary complex to the radical SAM cyclase PqqE to initiate pyrroloquinoline quinone biosynthesis.
file:VARPD/pqqE/pqqE-ai-review.yaml
Variovorax paradoxus pqqE gene review
A0A0H2MPV4 (VPARA_00920) encodes the radical SAM/SPASM-domain PqqA peptide cyclase PqqE in the pqqBCDE operon.
Radical SAM/SPASM-domain PqqA peptide cyclase (EC 1.21.98.4, RHEA:56836) that catalyzes the initiating committed step of pyrroloquinoline quinone biosynthesis by forming an intramolecular carbon-carbon cross-link between the conserved glutamate and tyrosine residues of PqqA in a PqqD-dependent ternary complex.

This is a reusable pathway module. Pseudomonas putida KT2440 proteins are representative members, not a taxonomic restriction or an exhaustive member list. Two PqqD paralogs from KT2440 illustrate that one family role may have multiple concrete implementations; the module does not require two PqqD proteins in every organism. Proteolytic processing and PqqB oxygenation are maturation operations, but their exact substrate handoff and order are left unresolved. PP_0375 is a strong Pseudomonas pqqG candidate, but its S9 peptidase family differs from the M16B PqqG partner characterized in some other bacteria; neither is forced into the conserved core without a defined reaction. PQQ-dependent dehydrogenases, transport, pathway regulation, and unrelated proteins adjacent to pqq loci are outside the boundary. The OpenScientist module report inconsistently states both that proteolysis must precede small-molecule steps and that proteolysis-versus-PqqB ordering is unresolved; the latter, evidence-limited interpretation is retained here. The species-aware report's proposed GO:0033735 identifier for PqqC and its use of biological-process GO:0018189 as though it captured PqqE molecular function were rejected. Its neighborhood-based PqqD2 specialization remains a hypothesis; PqqD1 and PqqD2 are exemplars of one nonduplicated family role.

9Nodes
5Parts
1Variant Sets
3Variants
8Annotons
5Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✓ present

  • pqq_biosynthesis-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.

Function consistency and core coverage

7 gene-function check(s) reflected in core functions · 0 conflict(s) · 5 evidence or coverage gap(s) (14 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
pqqe_peptide_cyclase PqqE (Pseudomonas putida KT2440)
UniProtKB:Q88QV8
Family Representative
cyclase activity
GO:0009975
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pqqe_peptide_cyclase PqqE (Variovorax paradoxus)
UniProtKB:A0A0H2MPV4
Family Representative
cyclase activity
GO:0009975
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
single_chain_pqqf_metalloendopeptidase Structurally characterized PqqF (Serratia sp. FS14)
UniProtKB:A0ACD6BAY6
Family Representative
metalloendopeptidase activity
GO:0004222
Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
single_chain_pqqf_metalloendopeptidase PqqF (Pseudomonas putida KT2440)
UniProtKB:Q88QV3
Family Representative
metalloendopeptidase activity
GO:0004222
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pqqfg_m16b_metalloendopeptidase PROTEIN_COMPLEX
Gene
metalloendopeptidase activity
GO:0004222
Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
alternative_pqqa_peptidase ANY_WITH_FUNCTION
Gene
peptidase activity
GO:0008233
Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
pqqb_hydroxylase PqqB (Pseudomonas putida KT2440)
UniProtKB:Q88QV5
Family Representative
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen
GO:0016705
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pqqb_hydroxylase PqqB (Variovorax paradoxus)
UniProtKB:A0A0H2M8Q2
Family Representative
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen
GO:0016705
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pqqc_pqq_synthase PqqC (Pseudomonas putida KT2440)
UniProtKB:Q88QV6
Family Representative
pyrroloquinoline-quinone synthase activity
GO:0033732
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pqqc_pqq_synthase PqqC (Variovorax paradoxus)
UniProtKB:A0A0H2MDI9
Family Representative
pyrroloquinoline-quinone synthase activity
GO:0033732
Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pqqe_peptide_cyclase PqqE radical-SAM peptide cyclase family
InterPro:IPR011843
Family
cyclase activity
GO:0009975
Family Review Missing
No supported structured family review is available for InterPro:IPR011843.
single_chain_pqqf_metalloendopeptidase single-chain PqqF M16 peptidase family
InterPro:IPR011844
Family
metalloendopeptidase activity
GO:0004222
Family Review Missing
No supported structured family review is available for InterPro:IPR011844.
pqqb_hydroxylase PqqB family
InterPro:IPR011842
Family
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen
GO:0016705
Family Review Missing
No supported structured family review is available for InterPro:IPR011842.
pqqc_pqq_synthase PqqC-like family
InterPro:IPR011845
Family
pyrroloquinoline-quinone synthase activity
GO:0033732
Family Review Missing
No supported structured family review is available for InterPro:IPR011845.

Gene-review completeness (12/15 grounded genes reviewed)

12 complete review(s) · 7 with deep research · 3 missing review · 5 reviewed but lacking deep research

Gene Review Complete Deep research
Structurally characterized PqqF (Serratia sp. FS14) A0ACD6BAY6 ✗ — —
Methylorubrum extorquens AM1 PqqF C5AQL6 ✗ — —
Methylorubrum extorquens AM1 PqqG C5AQL7 ✗ — —
pqqA C5CPT7 ✓ ✓ ✗
pqqA Q88QV4 ✓ ✓ ✓
pqqB A0A0H2M8Q2 ✓ ✓ ✗
pqqB Q88QV5 ✓ ✓ ✓
pqqC A0A0H2MDI9 ✓ ✓ ✗
pqqC Q88QV6 ✓ ✓ ✓
pqqD A0A0H2M992 ✓ ✓ ✗
pqqD1 Q88QV7 ✓ ✓ ✓
pqqD2 Q88JG8 ✓ ✓ ✓
pqqE A0A0H2MPV4 ✓ ✓ ✗
pqqE Q88QV8 ✓ ✓ ✓
pqqF Q88QV3 ✓ ✓ ✓

Details

Context
BacteriaNCBITaxon:2
Pyrroloquinoline quinone biosynthesisMetabolic Pathwaypqq_biosynthesis
pyrroloquinoline quinone biosynthetic processGO:0018189
Context
BacteriaNCBITaxon:2

Connections

PqqA supplies the precursor peptide bound by PqqD and modified by PqqE.
pqqde_crosslinking -> pqqa_proteolysis Provides Input For
A PqqA-derived precursor undergoes pathway-associated proteolytic processing.
pqqde_crosslinking -> pqqb_oxygenation Provides Input For
PqqB acts on an intermediate derived from cross-linked PqqA.
pqqa_proteolysis -> pqqc_ring_closure Provides Input For
Proteolysis is required to generate the small-molecule precursor used late in the pathway.
pqqb_oxygenation -> pqqc_ring_closure Provides Input For
PqqB-dependent oxygenation contributes to formation of the late PqqC substrate.
Part 1: PqqA precursor-peptide supply
PqqA precursor-peptide supplyBiological Processpqqa_precursor_supply

PqqA supplies the conserved glutamate and tyrosine residues from which the PQQ ring system is constructed.

Annotons

PqqA precursor-peptide role
pqqa_precursor_role
Participant: Family: PqqA precursor-peptide family
Family:
PqqA precursor-peptide familyInterPro:IPR011725 Short PQQ precursor peptides recognized by InterPro IPR011725 and Pfam PF08042.
Representative Members: PqqA (Pseudomonas putida KT2440)UniProtKB:Q88QV4 PqqA (Variovorax paradoxus S110)UniProtKB:C5CPT7

Processes

pyrroloquinoline quinone biosynthetic processGO:0018189

Provides the peptide-bound glutamate and tyrosine substrates for PqqE-dependent cross-link formation.

Part 2: PqqD-assisted radical-SAM cross-link formation
PqqD-assisted PqqE cross-linkingReactionpqqde_crosslinking

A PqqD-family peptide chaperone binds PqqA and presents it to PqqE. PqqE then forms the carbon-carbon bond between the precursor glutamate and tyrosine residues.

Annotons

PqqD peptide-chaperone role
pqqd_peptide_chaperone
Participant: Family: PqqD peptide-chaperone family
Family:
PqqD peptide-chaperone familyInterPro:IPR022479 PqqA-binding proteins recognized by InterPro IPR008792, IPR022479, and IPR041881.
Representative Members: PqqD1 (Pseudomonas putida KT2440)UniProtKB:Q88QV7 PqqD2 (Pseudomonas putida KT2440)UniProtKB:Q88JG8 PqqD (Variovorax paradoxus)UniProtKB:A0A0H2M992

Processes

pyrroloquinoline quinone biosynthetic processGO:0018189

Presents the PqqA precursor peptide to PqqE; no specific GO molecular-function term currently captures this chaperone role.

PqqE PqqA peptide cyclase activity
pqqe_peptide_cyclase
Participant: Family: PqqE radical-SAM peptide cyclase family
Family:
PqqE radical-SAM peptide cyclase familyInterPro:IPR011843
Representative Members: PqqE (Pseudomonas putida KT2440)UniProtKB:Q88QV8 PqqE (Variovorax paradoxus)UniProtKB:A0A0H2MPV4

Function

cyclase activityGO:0009975
Substrates: PQQ precursor protein S-adenosyl-L-methionine
Products: glutamate-tyrosine-cross-linked PQQ precursor protein 5'-deoxyadenosine L-methionine

Processes

pyrroloquinoline quinone biosynthetic processGO:0018189

Creates the first committed covalent modification of the PqqA precursor peptide.

Part: Proteolytic release of a PqqA-derived intermediate
PqqA-derived precursor proteolysisBiological Processpqqa_proteolysis

Proteolysis removes peptide context during maturation toward a small-molecule PQQ intermediate. The responsible protease repertoire varies among PQQ-producing organisms, and more than one protease may contribute in a given organism.

Variant set: PQQ precursor-proteolysis implementation by protease repertoire (One Or More)

Single-chain PqqF/M16A-like proteases and two-component M16B PqqF/PqqG complexes are distinct supported implementations. Some PQQ producers lack PqqF, implying replacement by other cellular proteases whose identities and division of labor may be unresolved.

Single-chain PqqF/M16A-like protease routeReactionsingle_chain_pqqf_m16a_route

A full-length PqqF-family M16 peptidase contains the catalytic and substrate-enclosing regions in one polypeptide. Its exact native PqqA-derived substrate state may remain unresolved.

Annotons

Single-chain PqqF metalloendopeptidase activity
single_chain_pqqf_metalloendopeptidase
Participant: Family: single-chain PqqF M16 peptidase family
Family:
single-chain PqqF M16 peptidase familyInterPro:IPR011844
Representative Members: Structurally characterized PqqF (Serratia sp. FS14)UniProtKB:A0ACD6BAY6 PqqF (Pseudomonas putida KT2440)UniProtKB:Q88QV3

Function

metalloendopeptidase activityGO:0004222
Substrates: PqqA-derived peptide precursor
Products: smaller PqqA-derived peptide intermediates

Processes

pyrroloquinoline quinone biosynthetic processGO:0018189

Provides the single-polypeptide PqqF implementation of pathway-associated precursor proteolysis.

Two-component PqqF/PqqG M16B protease routeReactiontwo_component_pqqfg_m16b_route

Separate M16B PqqF and PqqG subunits assemble into a heterodimeric protease that cleaves PqqA-derived peptide.

Annotons

PqqF/PqqG M16B metalloendopeptidase complex
pqqfg_m16b_metalloendopeptidase
Participant: Protein Complex: PqqF/PqqG M16B protease complex
Protein Complex:
PqqF/PqqG M16B protease complex
Active units:
PqqF zinc-binding subunit1
Participant: Ortholog Of: Methylorubrum extorquens AM1 PqqF
Ortholog Of:
Methylorubrum extorquens AM1 PqqFUniProtKB:C5AQL6
Role: zinc-binding M16B peptidase subunit
PqqG partner subunit1
Participant: Ortholog Of: Methylorubrum extorquens AM1 PqqG
Ortholog Of:
Methylorubrum extorquens AM1 PqqGUniProtKB:C5AQL7
Role: M16B partner supplying catalytic R/Y residues

Function

metalloendopeptidase activityGO:0004222
Substrates: PqqA-derived peptide precursor
Products: smaller PqqA-derived peptide intermediates

Processes

pyrroloquinoline quinone biosynthetic processGO:0018189

Provides the split-subunit M16B implementation of pathway-associated precursor proteolysis.

Alternative cellular-protease routeBiological Processalternative_cellular_protease_route

In PQQ producers without PqqF, other cellular proteases must provide the required precursor processing. This alternative is represented by the required peptidase activity without assigning an unsupported protein family.

Annotons

Alternative PqqA-pathway peptidase activity
alternative_pqqa_peptidase
Participant: Any With Function: peptidase activity
Required Function:
peptidase activityGO:0008233

Function

peptidase activityGO:0008233
Substrates: PqqA-derived peptide precursor
Products: smaller PqqA-derived peptide intermediates

Processes

pyrroloquinoline quinone biosynthetic processGO:0018189

Captures the required proteolysis atom when the responsible pathway-specific protease family is unknown.

Part: PqqB-dependent oxygenation
PqqB-dependent precursor oxygenationReactionpqqb_oxygenation

PqqB is a metal-dependent hydroxylase implicated in oxygenation of a PqqA-derived pathway intermediate. The native substrate and product remain incompletely defined.

Annotons

PqqB oxygen-incorporating oxidoreductase activity
pqqb_hydroxylase
Participant: Family: PqqB family
Family:
PqqB familyInterPro:IPR011842
Representative Members: PqqB (Pseudomonas putida KT2440)UniProtKB:Q88QV5 PqqB (Variovorax paradoxus)UniProtKB:A0A0H2M8Q2

Function

oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygenGO:0016705
Substrates: PqqA-derived PQQ-pathway intermediate molecular oxygen
Products: oxygenated PQQ-pathway intermediate

Processes

pyrroloquinoline quinone biosynthetic processGO:0018189

Introduces oxygen-dependent chemistry required before terminal PqqC ring closure.

Part 5: Terminal oxidative ring closure
PqqC terminal PQQ formationReactionpqqc_ring_closure

PqqC catalyzes oxidative ring closure and multi-electron oxidation of the late quinoline precursor to mature PQQ.

Annotons

Pyrroloquinoline-quinone synthase activity
pqqc_pqq_synthase
Participant: Family: PqqC-like family
Family:
PqqC-like familyInterPro:IPR011845
Representative Members: PqqC (Pseudomonas putida KT2440)UniProtKB:Q88QV6 PqqC (Variovorax paradoxus)UniProtKB:A0A0H2MDI9

Function

pyrroloquinoline-quinone synthase activityGO:0033732
Substrates: 6-(2-amino-2-carboxyethyl)-7,8-dioxo-1,2,3,4,7,8-hexahydroquinoline-2,4-dicarboxylate molecular oxygen
Products: pyrroloquinoline quinone hydrogen peroxide water

Processes

pyrroloquinoline quinone biosynthetic processGO:0018189

Produces mature PQQ from the late pathway intermediate.