pqqE

GO Term	Evidence	Action	Reason
GO:0003824 catalytic activity	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: Root-level catalytic activity. PqqE has a specific, well-characterized radical SAM cross-linking activity captured by GO:0009975 (cyclase activity); this generic root term is uninformative on its own. Reason: Subsumed by the more specific MF GO:0009975 (cyclase activity); retained as non-core because it does not convey the actual reaction.
GO:0005506 iron ion binding	IEA GO_REF:0000104	KEEP AS NON CORE	Summary: PqqE binds iron exclusively as part of iron-sulfur clusters, not as a mononuclear iron ion. The radical SAM [4Fe-4S] cluster plus two auxiliary SPASM-domain clusters are better captured by the iron-sulfur cluster terms (GO:0051536, GO:0051539). This generic mononuclear-iron term is a less precise UniRule transfer. Reason: The iron in PqqE is organized into [4Fe-4S]/auxiliary Fe-S clusters; the iron-sulfur cluster binding terms are more accurate, so this term is retained as non-core rather than as a core function.
GO:0009975 cyclase activity	IEA GO_REF:0000104	ACCEPT	Summary: Correct and represents the core molecular function. PqqE is a radical SAM peptide cyclase (EC 1.21.98.4) that catalyzes intramolecular C-C ring closure by cross-linking a glutamate and a tyrosine side chain in the PqqA precursor peptide. No more specific GO MF term exists for this PqqA peptide cyclase reaction. Reason: Best available MF term for the experimentally demonstrated Glu-Tyr C-C cross-linking (ring-closure) reaction on PqqA; this is the core function. Supporting Evidence: file:METEA/pqqE/pqqE-deep-research-falcon.md installation of a C–C bond (crosslink) between the side chains of a conserved glutamate and tyrosine on the ribosomally produced precursor peptide PqqA
GO:0016491 oxidoreductase activity	IEA GO_REF:0000043	KEEP AS NON CORE	Summary: PqqE is a radical SAM enzyme that reductively cleaves SAM via its [4Fe-4S] cluster to generate a 5'-deoxyadenosyl radical; this redox chemistry makes oxidoreductase activity correct, though the cyclase term (GO:0009975) better captures the net catalytic outcome. Reason: Accurate at the superfamily level (radical SAM redox chemistry) but less informative than the specific cyclase activity term; kept as non-core. Supporting Evidence: file:METEA/pqqE/pqqE-deep-research-falcon.md Radical SAM enzymes use a [4Fe–4S] cluster to reductively cleave S-adenosyl-L-methionine (SAM) to generate a highly reactive 5′-deoxyadenosyl radical (5′-dAdo•)
GO:0018189 pyrroloquinoline quinone biosynthetic process	IEA GO_REF:0000120	ACCEPT	Summary: Correct and core. PqqE catalyzes the first committed chemical step of PQQ biosynthesis - the radical SAM Glu-Tyr cross-linking of the PqqA precursor peptide. PQQ is the redox cofactor required by the periplasmic methanol/alcohol dehydrogenases central to methylotrophy in M. extorquens. Reason: Directly supported by experimental characterization in M. extorquens AM1; this is the biological process the core MF serves. Supporting Evidence: file:METEA/pqqE/pqqE-deep-research-falcon.md catalyzes the first committed chemical step in pyrroloquinoline quinone (PQQ) biosynthesis
GO:0046872 metal ion binding	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Generic metal ion binding, redundant with the more specific iron-sulfur cluster binding terms (GO:0051536, GO:0051539) that describe PqqE's actual [4Fe-4S] and auxiliary Fe-S clusters. Reason: Subsumed by the specific iron-sulfur cluster binding terms; uninformative on its own.
GO:0051536 iron-sulfur cluster binding	IEA GO_REF:0000120	ACCEPT	Summary: Correct - PqqE binds the canonical radical SAM [4Fe-4S] cluster plus two auxiliary Fe-S clusters in its C-terminal SPASM domain. Slightly less specific than GO:0051539 for the catalytic cluster, but accurate for the auxiliary clusters as well. Reason: Accurate description of PqqE's multiple iron-sulfur clusters; the auxiliary SPASM-domain clusters make this broader term appropriate alongside GO:0051539. Supporting Evidence: file:METEA/pqqE/pqqE-deep-research-falcon.md PqqE contains the canonical radical SAM cluster and two auxiliary Fe–S clusters (AuxI and AuxII) in its C-terminal SPASM domain
GO:0051539 4 iron, 4 sulfur cluster binding	IEA GO_REF:0000120	ACCEPT	Summary: Correct - PqqE binds the catalytic radical SAM [4Fe-4S] cluster coordinated by three cysteines and an exchangeable SAM. The crystal structure additionally assigns the AuxII auxiliary cluster as a [4Fe-4S] coordinated by three cysteines and Asp319. Reason: Most specific accurate term for the catalytic radical SAM cluster (and AuxII), supported by UniProt cofactor annotation and structural literature. Supporting Evidence: file:METEA/pqqE/pqqE-deep-research-falcon.md AuxII coordinates a canonical [4Fe–4S] cluster using three cysteines and Asp319**
GO:1904047 S-adenosyl-L-methionine binding	IEA GO_REF:0000104	ACCEPT	Summary: Correct - As a radical SAM enzyme, PqqE binds SAM, which is reductively cleaved by the [4Fe-4S] cluster to generate the 5'-deoxyadenosyl radical that abstracts a hydrogen from the glutamate side chain to initiate cross-linking. Reason: SAM is the co-substrate of the radical SAM reaction; binding is intrinsic to the catalytic mechanism. Supporting Evidence: file:METEA/pqqE/pqqE-deep-research-falcon.md supporting β-H abstraction from glutamate by the 5′-dAdo radical and formation of a peptide-centered radical

Deep Research

Falcon

(pqqE-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 39 citations 1 artifacts 2026-06-03T10:31:51.947934

Edison artifact artifact-00 (text/markdown)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research Report: Functional Annotation of pqqE (UniProt P71517) in Methylorubrum extorquens AM1 (ATCC 14718; formerly Methylobacterium extorquens)

Executive summary

The target protein PqqE (gene pqqE, UniProt P71517) from Methylorubrum extorquens strain AM1 is a radical S-adenosyl-L-methionine (radical SAM) enzyme (SPASM subclass) that catalyzes the first committed chemical step in pyrroloquinoline quinone (PQQ) biosynthesis: installation of a C–C bond (crosslink) between the side chains of a conserved glutamate and tyrosine on the ribosomally produced precursor peptide PqqA, in a reaction that requires the peptide chaperone PqqD. (yao2026radicalenzymaticpeptide pages 6-7, martins2019atwocomponentprotease pages 2-3, kandy2025aromaticsidechaincrosslinking pages 4-6)

PQQ is a redox cofactor used by periplasmic dehydrogenases in methylotroph physiology; in M. extorquens AM1, genomic analyses explicitly connect pqq genes with methanol oxidation modules, consistent with the organism’s reliance on PQQ-dependent alcohol/methanol dehydrogenases. (chistoserdova2003methylotrophyinmethylobacterium pages 2-3, toyama2016pyrroloquinolinequinone(pqq) pages 11-13)

Recent applied research (2023–2024) leverages the pqq pathway in (i) industrial/bioprocess production of PQQ (where pqqE transcriptional upregulation is associated with improved titers) and (ii) using pqq gene clusters as functional genomic markers in phosphate-solubilizing bacteria due to PQQ-driven glucose oxidation and organic acid production. (ren2023adaptiveevolutionarystrategy pages 7-10, chen2024genomebasedidentificationof pages 7-9)

Target verification (mandatory identity checks)

1) Gene symbol ↔ protein function match. In M. extorquens AM1, PqqE is repeatedly described as the radical SAM enzyme responsible for the initial Glu–Tyr C–C crosslinking on PqqA during PQQ biosynthesis. (martins2019atwocomponentprotease pages 2-3, kandy2025aromaticsidechaincrosslinking pages 4-6)

2) Organism match. Multiple retrieved sources explicitly address PqqE in Methylorubrum/Methylobacterium extorquens AM1, including AM1-specific gene cluster/sequence characterization and pathway reconstruction. (martins2019atwocomponentprotease pages 10-11, ochsner2015methylobacteriumextorquensmethylotrophy pages 9-10)

3) Family/domain consistency. PqqE is described as a SPASM-domain radical SAM enzyme that binds the canonical radical SAM [4Fe–4S] cluster and additional auxiliary Fe–S clusters. (yao2026radicalenzymaticpeptide pages 6-7)

Ambiguity assessment. The symbol pqqE is used across bacteria to denote the same functional role (PQQ biosynthetic radical SAM enzyme). Within the retrieved materials, no evidence suggested a conflicting “pqqE” referring to an unrelated function; therefore the literature used aligns with UniProt P71517’s annotation context. (yao2026radicalenzymaticpeptide pages 6-7, martins2019atwocomponentprotease pages 10-11)

1. Key concepts and definitions (current understanding)

1.1. PQQ and the pqq pathway

Pyrroloquinoline quinone (PQQ) is a small redox-active cofactor used by multiple bacterial dehydrogenases. Genomic overview of M. extorquens AM1 treats PQQ biosynthesis as a distinct metabolic module because PQQ is a cofactor for dehydrogenases important to methylotrophy. (chistoserdova2003methylotrophyinmethylobacterium pages 5-6)

A pathway-centric framing in recent genomics literature describes PQQ as deriving from the PqqA peptide through a conserved set of enzymes including PqqE (radical SAM), PqqD (chaperone), PqqB (hydroxylase), and PqqC (multi-electron oxidase), with PqqF/G as an alternative/associated peptide processing route. (chen2024genomebasedidentificationof pages 7-9)

1.2. Radical SAM enzymes and the SPASM subclass

Radical SAM enzymes use a [4Fe–4S] cluster to reductively cleave S-adenosyl-L-methionine (SAM) to generate a highly reactive 5′-deoxyadenosyl radical (5′-dAdo•) or equivalent species that initiates substrate radical chemistry. In the PQQ pathway, PqqE is characterized as a SPASM-domain radical SAM enzyme that uses this chemistry to create a C–C crosslink in a peptide substrate. (yao2026radicalenzymaticpeptide pages 6-7)

The SPASM domain is a C-terminal auxiliary domain present in many peptide-modifying radical SAM enzymes, often binding additional Fe–S clusters implicated in substrate binding, electron transfer, or control of reactivity. PqqE contains two auxiliary Fe–S clusters in addition to the radical SAM cluster. (yao2026radicalenzymaticpeptide pages 6-7)

2. Primary function and catalytic reaction of PqqE

2.1. Biological role: initiating PQQ biosynthesis by PqqA crosslinking

PqqE catalyzes formation of the initial carbon–carbon bond between the conserved glutamate and tyrosine residues within the PqqA peptide, producing a crosslinked PqqA intermediate (often denoted PqqA). This step is described as occurring with the help of the peptide chaperone PqqD*. (martins2019atwocomponentprotease pages 2-3, martins2019atwocomponentprotease pages 1-2)

A broader RiPP crosslinking review similarly describes PqqE as the radical SAM enzyme that initiates PQQ biosynthesis by installing the Glu–Tyr C–C crosslink on PqqA in a PqqD-dependent reaction. (kandy2025aromaticsidechaincrosslinking pages 4-6)

2.2. Substrates and products (as supported by retrieved evidence)

Macromolecular substrate: the ribosomally produced peptide PqqA, containing conserved Glu and Tyr residues that become part of the PQQ backbone. (toyama2016pyrroloquinolinequinone(pqq) pages 11-13, martins2019atwocomponentprotease pages 1-2)

Cofactor substrate: SAM, which is cleaved by PqqE to generate 5′-deoxyadenosyl species used for H-abstraction chemistry. (yao2026radicalenzymaticpeptide pages 6-7, toyama2016pyrroloquinolinequinone(pqq) pages 11-13)

Product (enzyme step): a crosslinked PqqA species (PqqA*), representing an early, crosslinked di-amino-acid precursor that must be released/processed for subsequent enzymatic steps. (martins2019atwocomponentprotease pages 2-3, martins2019atwocomponentprotease pages 1-2)

Evidence limitation: the retrieved excerpts describe the PqqE reaction primarily at the level of peptide crosslinking; they do not provide a complete balanced small-molecule reaction equation for EC 1.21.98.4 (e.g., explicit stoichiometry of SAM-derived products besides 5′-dAdo formation). (yao2026radicalenzymaticpeptide pages 6-7, martins2019atwocomponentprotease pages 2-3)

3. Mechanism and cofactors: current evidence-based model

3.1. Hydrogen abstraction and regioselective coupling

Mechanistic synthesis in an authoritative review (based on experiments in the AM1 system) describes the following steps:
1) PqqE reductively cleaves SAM to generate a 5′-deoxyadenosyl species (5′-dAdo). (yao2026radicalenzymaticpeptide pages 6-7)
2) Isotope labeling with β-deuterated glutamate in PqqA shows a kinetic isotope effect and deuterium incorporation into 5′-dAdo, supporting β-H abstraction from glutamate by the 5′-dAdo radical and formation of a peptide-centered radical. (yao2026radicalenzymaticpeptide pages 6-7)
3) The resulting radical couples regioselectively to the ortho position of a tyrosine ring, forming the crosslink that constitutes the PQQ core scaffold. (yao2026radicalenzymaticpeptide pages 6-7)

3.2. Fe–S cluster architecture (SPASM auxiliary clusters)

PqqE contains the canonical radical SAM cluster and two auxiliary Fe–S clusters (AuxI and AuxII) in its C-terminal SPASM domain. Crystallographic interpretation summarized in the same review indicates:
- AuxII coordinates a canonical [4Fe–4S] cluster using three cysteines and Asp319.
- AuxI appeared as a [2Fe–2S] cluster in the crystal structure context.
Spectroscopic (EPR) evidence is described as enabling assignment of signals to the radical SAM cluster and the auxiliary clusters and indicating that access to some redox states requires low-potential reductants. (yao2026radicalenzymaticpeptide pages 6-7)

3.3. Protein–protein interactions and substrate presentation

PqqE operates in a multicomponent context with PqqD as a peptide chaperone that interacts with PqqA and PqqE and supports productive PqqA modification. (martins2019atwocomponentprotease pages 2-3, toyama2016pyrroloquinolinequinone(pqq) pages 11-13)

4. Pathway placement, gene context, and cellular localization

4.1. Genomic organization in M. extorquens AM1

Genome-based analyses indicate PQQ biosynthesis genes can occur in multiple loci/modules in AM1, with pqqABC/DE in a methylotrophy island and pqqFG in a separate cluster in at least one genomic overview. (chistoserdova2003methylotrophyinmethylobacterium pages 5-6)

A later AM1-focused study figure description maps a local neighborhood including (order shown in that excerpt) pqqE, pqqC/D, pqqB, pqqA, pqqF, pqqG, and additional pqqA annotations in the region. (martins2019atwocomponentprotease pages 14-16)

4.2. Downstream processing: proteolysis and release of the crosslinked intermediate

A major gap historically was identification of the protease/peptidase steps needed to excise the crosslinked di-amino-acid precursor. In M. extorquens, Martins et al. characterize a two-component protease (PqqF/PqqG) and hypothesize it initially cleaves between the PqqE/PqqD-generated crosslinked form of PqqA, with other proteases completing release of a substrate for PqqB. (martins2019atwocomponentprotease pages 1-2)

4.3. Cellular localization (evidence and inference)

Direct subcellular localization experiments for PqqE in AM1 were not found in the retrieved text excerpts. However:
- The PqqE substrate is a ribosomally produced peptide (PqqA) and PqqE is a cytosolic radical SAM enzyme by biochemical class, consistent with activity in the cytosol.
- Mature PQQ accumulates in the periplasmic space in M. extorquens, consistent with downstream use by periplasmic dehydrogenases and/or export/trafficking after synthesis. (martins2019atwocomponentprotease pages 1-2)
Thus, localization is best described as: PqqE likely acts in the cytosol on PqqA prior to downstream processing and subsequent periplasmic accumulation/use of PQQ, with the caveat that explicit imaging/fractionation data were not retrieved here. (martins2019atwocomponentprotease pages 1-2, toyama2016pyrroloquinolinequinone(pqq) pages 11-13)

5. Recent developments (prioritizing 2023–2024)

5.1. 2023: strain/process engineering for high-titer PQQ production (bioprocess relevance to pqqE)

Ren et al. (published Jan 2023, Biotechnology for Biofuels and Bioproducts, URL: https://doi.org/10.1186/s13068-023-02261-y) developed a high-titer PQQ-producing methylotroph (Hyphomicrobium denitrificans FJNU-A26) through ARTP mutagenesis + adaptive laboratory evolution + fermentation strategy optimization. (ren2023adaptiveevolutionarystrategy pages 1-2)

Key quantitative outcomes (industrial relevance):
- Fed-batch (5-L) achieved 1.52 g/L PQQ in 144 h, with 40.3 mg PQQ/g DCW and ~10.5 mg/L·h productivity; biomass reached 37.7 g/L. (ren2023adaptiveevolutionarystrategy pages 10-11)
- Growth/production kinetics included μx ~0.169 h−1 under two-stage pH control and maximum μp 5.37×10−4 h−1 (at 88 h). (ren2023adaptiveevolutionarystrategy pages 10-11)

Critically for pqqE relevance, transcript analysis showed that pqqE expression from pqqABCDE increased most strongly, reaching approximately ~6× higher than wild type at later times in the mutant background, supporting the view that pqqE can be rate-influencing or at least highly responsive in high-production states. (ren2023adaptiveevolutionarystrategy pages 7-10)

5.2. 2024: pqq gene clusters as functional markers (genome-based implementations)

Chen et al. (published Jul 2024, AMB Express, URL: https://doi.org/10.1186/s13568-024-01745-w) analyzed 76 phosphate-solubilizing bacterial isolates and concluded that pqq gene clusters—particularly pqqC—are useful genomic markers for phosphate-solubilization capacity, explicitly describing the biosynthetic steps and noting PqqE as the radical SAM enzyme in the pathway. (chen2024genomebasedidentificationof pages 7-9, chen2024genomebasedidentificationof pages 1-2)

The work provides strain-level quantitative phosphate solubilization values spanning low to high solubilizers (e.g., 159.48 µg/mL P release for one Bacillus megaterium isolate in their dataset) and gives examples where complete pqq clusters associate with higher P release and lower pH (e.g., 92.03 µg/mL P release at pH 5.00 for Burkholderia cepacia 51-Y1415). (chen2024genomebasedidentificationof pages 3-5, chen2024genomebasedidentificationof pages 2-3)

It also reports correlation statistics that connect pqq genes to biochemical outputs linked to P solubilization (2-keto-D-gluconic acid and P release). For example, Table-level correlations include P release vs pqqA = 0.946 and P release vs pqqC = 0.940, and extremely strong correlations between 2-keto-D-gluconic acid and pqqA–pqqE (0.988–0.995) with significance indicated (P < 0.05, P** < 0.01). (chen2024genomebasedidentificationof pages 7-9, chen2024genomebasedidentificationof pages 5-7)

6. Current applications and real-world implementations

1) Biomanufacturing of PQQ: Adaptive evolution and fermentation control strategies can yield gram-per-liter titers of PQQ in methylotrophs, and gene expression analyses implicate increased transcription of pqq pathway genes including pqqE in improved production phenotypes. (ren2023adaptiveevolutionarystrategy pages 7-10, ren2023adaptiveevolutionarystrategy pages 10-11)

2) Agriculture/environmental microbiology (phosphate solubilization): pqq genes are used as genomic predictors of PQQ-dependent glucose oxidation leading to gluconic/2-ketogluconic acid formation and phosphate solubilization, with reported quantitative P release and strong correlations between pqq gene metrics and solubilization-related outputs. (chen2024genomebasedidentificationof pages 7-9, chen2024genomebasedidentificationof pages 2-3)

3) Methylotrophy and lanthanide-linked alcohol oxidation ecosystems: Although not directly measuring PqqE, M. extorquens AM1 genomic context links pqq loci with methanol oxidation systems, consistent with PQQ’s essential cofactor role for periplasmic dehydrogenases in methylotrophic growth. (chistoserdova2003methylotrophyinmethylobacterium pages 2-3, chistoserdova2003methylotrophyinmethylobacterium pages 5-6)

7. Expert opinions and analysis (from authoritative sources)

A high-authority mechanistic review synthesizes multiple lines of evidence (isotope labeling, crystallography, EPR) to position PqqE as a SPASM-domain radical SAM enzyme whose auxiliary clusters are integral to its redox behavior and peptide-crosslinking chemistry, highlighting the need for strong reductants to access relevant redox states. (yao2026radicalenzymaticpeptide pages 6-7)
A leading enzyme/pathway study in M. extorquens emphasizes that a “full description” of the PQQ biosynthetic pathway required identifying proteolytic processing steps beyond PqqE/PqqD chemistry, and proposes a biologically plausible division of labor where PqqE/PqqD make the crosslink and PqqF/PqqG initiate cleavage to release a substrate for downstream enzymes. (martins2019atwocomponentprotease pages 1-2)

8. Summary of key evidence sources (with URLs)

The following table summarizes the evidence extracted in this report, including organism match, mechanism, gene context, and application statistics:

Focus	Main finding about PqqE or pqq locus	Key quantitative/statistical details (if any)	Publication (authors, journal, year, month/day if available)	URL/DOI
Identity / catalytic role	In Methylorubrum extorquens AM1, PqqE is the radical SAM enzyme that initiates PQQ biosynthesis by forming the first C–C crosslink in the peptide precursor PqqA, coupling Glu and Tyr side chains; activity requires the peptide chaperone PqqD. (yao2026radicalenzymaticpeptide pages 6-7, martins2019atwocomponentprotease pages 10-11, kandy2025aromaticsidechaincrosslinking pages 4-6)	Deuterium-labeling showed transfer of deuterium from Glu β-position into 5'-deoxyadenosyl product, supporting H-abstraction by 5'-dAdo radical; reaction is regioselective for Tyr ortho position. (yao2026radicalenzymaticpeptide pages 6-7)	Yao & Morinaka, Chemical Society Reviews, 2026 Feb; citing mechanistic work in the field. (yao2026radicalenzymaticpeptide pages 6-7)	https://doi.org/10.1039/d5cs00585j
Cofactors / domains	PqqE is a SPASM-domain radical SAM enzyme containing the canonical RS [4Fe–4S] cluster plus two auxiliary Fe–S clusters in the C-terminal SPASM domain; AuxII was observed as a [4Fe–4S] cluster coordinated by three Cys and Asp319, while AuxI appeared as [2Fe–2S] in the crystal. (yao2026radicalenzymaticpeptide pages 6-7)	Two auxiliary clusters assigned; low-potential reductants were needed to access some redox states in spectroscopic studies. (yao2026radicalenzymaticpeptide pages 6-7)	Yao & Morinaka, Chemical Society Reviews, 2026 Feb. (yao2026radicalenzymaticpeptide pages 6-7)	https://doi.org/10.1039/d5cs00585j
Early pathway intermediate	PqqE/PqqD generate a crosslinked PqqA species (PqqA*), which is the early di-amino-acid precursor subsequently processed by downstream enzymes/proteases in the PQQ pathway. (martins2019atwocomponentprotease pages 5-6, martins2019atwocomponentprotease pages 1-2)	No enzyme kinetic constants reported in the provided excerpts.	Martins et al., Journal of Biological Chemistry, 2019 Oct. (martins2019atwocomponentprotease pages 5-6, martins2019atwocomponentprotease pages 1-2)	https://doi.org/10.1074/jbc.ra119.009684
Genomic organization in AM1	In M. extorquens AM1, pqq genes are split across at least two loci in genome-era analyses, with pqqABC/DE in the methylotrophy island and pqqFG separate; later work also depicts a local neighborhood including pqqE, pqqC/D, pqqB, pqqA, pqqF, and pqqG. (chistoserdova2003methylotrophyinmethylobacterium pages 2-3, martins2019atwocomponentprotease pages 14-16, chistoserdova2003methylotrophyinmethylobacterium pages 5-6)	PQQ biosynthesis module comprises 6 genes in one genomic overview, with pqqFG separate; another map shows multiple nearby pqqA annotations. (martins2019atwocomponentprotease pages 14-16, chistoserdova2003methylotrophyinmethylobacterium pages 5-6)	Chistoserdova et al., Journal of Bacteriology, 2003 May; Martins et al., Journal of Biological Chemistry, 2019 Oct. (chistoserdova2003methylotrophyinmethylobacterium pages 2-3, martins2019atwocomponentprotease pages 14-16, chistoserdova2003methylotrophyinmethylobacterium pages 5-6)	https://doi.org/10.1128/jb.185.10.2980-2987.2003; https://doi.org/10.1074/jbc.ra119.009684
Physiological context / localization	PQQ is produced for use as a redox cofactor by methanol dehydrogenases in methylotrophy; mature PQQ accumulates in the periplasmic space, whereas PqqE acts on the cytosolic ribosomal peptide precursor PqqA before downstream processing. (martins2019atwocomponentprotease pages 1-2, chistoserdova2003methylotrophyinmethylobacterium pages 2-3, toyama2016pyrroloquinolinequinone(pqq) pages 11-13)	No direct localization experiment for PqqE reported in provided excerpts; periplasmic accumulation is stated for mature PQQ. (martins2019atwocomponentprotease pages 1-2)	Chistoserdova et al., Journal of Bacteriology, 2003 May; Toyama, book chapter, 2016 Apr; Martins et al., Journal of Biological Chemistry, 2019 Oct. (martins2019atwocomponentprotease pages 1-2, chistoserdova2003methylotrophyinmethylobacterium pages 2-3, toyama2016pyrroloquinolinequinone(pqq) pages 11-13)	https://doi.org/10.1128/jb.185.10.2980-2987.2003; https://doi.org/10.1002/9783527681754.ch13; https://doi.org/10.1074/jbc.ra119.009684
Organism-specific historical characterization	pqqE and pqqF were specifically sequenced/characterized in Methylobacterium/Methylorubrum extorquens AM1, supporting that the literature is about the same AM1 system as UniProt P71517. (martins2019atwocomponentprotease pages 10-11, ochsner2015methylobacteriumextorquensmethylotrophy pages 9-10)	Historical sequencing/characterization noted; no quantitative values in excerpt.	Martins et al., Journal of Biological Chemistry, 2019 Oct; Ochsner et al., Applied Microbiology and Biotechnology, 2015 Nov. (martins2019atwocomponentprotease pages 10-11, ochsner2015methylobacteriumextorquensmethylotrophy pages 9-10)	https://doi.org/10.1074/jbc.ra119.009684; https://doi.org/10.1007/s00253-014-6240-3
Recent application: industrial PQQ production	Recent engineering of methylotrophs for PQQ overproduction links improved production to upregulation of PQQ biosynthesis genes, including strong induction of pqqE, showing practical value of the pathway. (ren2023adaptiveevolutionarystrategy pages 7-10, ren2023adaptiveevolutionarystrategy pages 1-2, ren2023adaptiveevolutionarystrategy pages 2-4)	In Hyphomicrobium denitrificans FJNU-A26, pqqE expression increased ~6× vs wild type at later times; final titer reached 1.52 g/L, yield 40.3 mg/g DCW, productivity ~10.5 mg/L·h after 144 h fed-batch. (ren2023adaptiveevolutionarystrategy pages 7-10, ren2023adaptiveevolutionarystrategy pages 10-11)	Ren et al., Biotechnology for Biofuels and Bioproducts, 2023 Jan. (ren2023adaptiveevolutionarystrategy pages 7-10, ren2023adaptiveevolutionarystrategy pages 1-2, ren2023adaptiveevolutionarystrategy pages 10-11, ren2023adaptiveevolutionarystrategy pages 2-4)	https://doi.org/10.1186/s13068-023-02261-y
Recent application: phosphate-solubilization marker biology	Across 76 phosphate-solubilizing bacteria, the pqq cluster was treated as a genomic marker of PQQ-mediated glucose oxidation; the pathway description includes PqqE as the radical SAM enzyme in PQQ formation. (chen2024genomebasedidentificationof pages 7-9, chen2024genomebasedidentificationof pages 1-2, chen2024genomebasedidentificationof pages 2-3)	Strong correlations reported between 2-keto-D-gluconic acid and pqq genes: 0.988–0.995 for pqqA–pqqE; P release vs pqqC correlation 0.940; P < 0.05 or P* < 0.01 as indicated. (chen2024genomebasedidentificationof pages 7-9, chen2024genomebasedidentificationof pages 5-7)	Chen et al., AMB Express, 2024 Jul. (chen2024genomebasedidentificationof pages 7-9, chen2024genomebasedidentificationof pages 5-7, chen2024genomebasedidentificationof pages 1-2, chen2024genomebasedidentificationof pages 2-3)	https://doi.org/10.1186/s13568-024-01745-w

Table: This table compiles the most relevant evidence-supported sources on PqqE in Methylorubrum extorquens AM1 and the broader PQQ biosynthetic pathway. It highlights identity verification, mechanism, gene organization, physiological context, and recent application-oriented studies with quantitative results where available.

9. Knowledge gaps and confidence assessment (specific to AM1 PqqE / UniProt P71517)

High confidence: PqqE’s primary biochemical function in AM1 (PqqD-dependent radical SAM Glu–Tyr C–C crosslinking on PqqA) and its placement as the first committed step in PQQ biosynthesis. (yao2026radicalenzymaticpeptide pages 6-7, martins2019atwocomponentprotease pages 2-3)
Moderate confidence (supported but not exhaustively detailed in retrieved excerpts): specific auxiliary cluster composition in AM1 PqqE and its mechanistic roles beyond general cluster presence/assignment. (yao2026radicalenzymaticpeptide pages 6-7)
Lower confidence / not directly evidenced here: direct subcellular localization of PqqE by fractionation/microscopy in AM1; current localization statements are inferred from enzyme class (cytosolic radical SAM acting on ribosomal peptide) and from explicit mention that mature PQQ accumulates in the periplasm. (martins2019atwocomponentprotease pages 1-2)

References (retrieved in-tool; include publication dates and URLs)

Chistoserdova L. et al. May 2003. Journal of Bacteriology. “Methylotrophy in Methylobacterium extorquens AM1 from a Genomic Point of View.” https://doi.org/10.1128/jb.185.10.2980-2987.2003 (chistoserdova2003methylotrophyinmethylobacterium pages 2-3, chistoserdova2003methylotrophyinmethylobacterium pages 5-6)
Martins A.M. et al. Oct 2019. Journal of Biological Chemistry. “A two-component protease in Methylorubrum extorquens with high activity toward the peptide precursor of the redox cofactor pyrroloquinoline quinone.” https://doi.org/10.1074/jbc.ra119.009684 (martins2019atwocomponentprotease pages 1-2, martins2019atwocomponentprotease pages 14-16)
Ren Y. et al. Jan 2023. Biotechnology for Biofuels and Bioproducts. “Adaptive evolutionary strategy coupled with an optimized biosynthesis process for the efficient production of pyrroloquinoline quinone from methanol.” https://doi.org/10.1186/s13068-023-02261-y (ren2023adaptiveevolutionarystrategy pages 7-10, ren2023adaptiveevolutionarystrategy pages 10-11)
Chen X. et al. Jul 2024. AMB Express. “Genome-based identification of phosphate-solubilizing capacities of soil bacterial isolates.” https://doi.org/10.1186/s13568-024-01745-w (chen2024genomebasedidentificationof pages 7-9, chen2024genomebasedidentificationof pages 2-3)
Toyama H. Apr 2016. (Book chapter via DOI; deposited as arXiv text in retrieval). “Pyrroloquinoline Quinone (PQQ).” https://doi.org/10.1002/9783527681754.ch13 (toyama2016pyrroloquinolinequinone(pqq) pages 11-13)
Yao Z., Morinaka B.I. Feb 2026. Chemical Society Reviews. “Radical enzymatic peptide cyclization in natural product biosynthesis.” https://doi.org/10.1039/d5cs00585j (includes synthesis of PqqE mechanistic/structural evidence). (yao2026radicalenzymaticpeptide pages 6-7)

References

(yao2026radicalenzymaticpeptide pages 6-7): Ziwei Yao and Brandon I. Morinaka. Radical enzymatic peptide cyclization in natural product biosynthesis. Chemical Society reviews, Feb 2026. URL: https://doi.org/10.1039/d5cs00585j, doi:10.1039/d5cs00585j. This article has 3 citations and is from a highest quality peer-reviewed journal.
(martins2019atwocomponentprotease pages 2-3): Ana M. Martins, John A. Latham, Paulo J. Martel, Ian Barr, Anthony T. Iavarone, and Judith P. Klinman. A two-component protease in methylorubrum extorquens with high activity toward the peptide precursor of the redox cofactor pyrroloquinoline quinone. Journal of Biological Chemistry, 294:15025-15036, Oct 2019. URL: https://doi.org/10.1074/jbc.ra119.009684, doi:10.1074/jbc.ra119.009684. This article has 38 citations and is from a domain leading peer-reviewed journal.
(kandy2025aromaticsidechaincrosslinking pages 4-6): Sanath K. Kandy, Michael A. Pasquale, and Jonathan R. Chekan. Aromatic side-chain crosslinking in ripp biosynthesis. Nature chemical biology, 21:168-181, Jan 2025. URL: https://doi.org/10.1038/s41589-024-01795-y, doi:10.1038/s41589-024-01795-y. This article has 38 citations and is from a highest quality peer-reviewed journal.
(chistoserdova2003methylotrophyinmethylobacterium pages 2-3): Ludmila Chistoserdova, Sung-Wei Chen, Alla Lapidus, and Mary E. Lidstrom. Methylotrophy in methylobacterium extorquens am1 from a genomic point of view. Journal of Bacteriology, 185:2980-2987, May 2003. URL: https://doi.org/10.1128/jb.185.10.2980-2987.2003, doi:10.1128/jb.185.10.2980-2987.2003. This article has 402 citations and is from a peer-reviewed journal.
(toyama2016pyrroloquinolinequinone(pqq) pages 11-13): Hirohide Toyama. Pyrroloquinoline quinone (pqq). ArXiv, pages 367-388, Apr 2016. URL: https://doi.org/10.1002/9783527681754.ch13, doi:10.1002/9783527681754.ch13. This article has 5 citations.
(ren2023adaptiveevolutionarystrategy pages 7-10): Yang Ren, Xinwei Yang, Lingtao Ding, Dongfang Liu, Yong Tao, Jianzhong Huang, and Chongrong Ke. Adaptive evolutionary strategy coupled with an optimized biosynthesis process for the efficient production of pyrroloquinoline quinone from methanol. Biotechnology for Biofuels and Bioproducts, Jan 2023. URL: https://doi.org/10.1186/s13068-023-02261-y, doi:10.1186/s13068-023-02261-y. This article has 12 citations and is from a domain leading peer-reviewed journal.
(chen2024genomebasedidentificationof pages 7-9): Xiaoqing Chen, Yiting Zhao, Shasha Huang, Josep Peñuelas, Jordi Sardans, Lei Wang, and Bangxiao Zheng. Genome-based identification of phosphate-solubilizing capacities of soil bacterial isolates. AMB Express, Jul 2024. URL: https://doi.org/10.1186/s13568-024-01745-w, doi:10.1186/s13568-024-01745-w. This article has 21 citations and is from a peer-reviewed journal.
(martins2019atwocomponentprotease pages 10-11): Ana M. Martins, John A. Latham, Paulo J. Martel, Ian Barr, Anthony T. Iavarone, and Judith P. Klinman. A two-component protease in methylorubrum extorquens with high activity toward the peptide precursor of the redox cofactor pyrroloquinoline quinone. Journal of Biological Chemistry, 294:15025-15036, Oct 2019. URL: https://doi.org/10.1074/jbc.ra119.009684, doi:10.1074/jbc.ra119.009684. This article has 38 citations and is from a domain leading peer-reviewed journal.
(ochsner2015methylobacteriumextorquensmethylotrophy pages 9-10): Andrea M. Ochsner, Frank Sonntag, Markus Buchhaupt, Jens Schrader, and Julia A. Vorholt. Methylobacterium extorquens: methylotrophy and biotechnological applications. Applied Microbiology and Biotechnology, 99:517-534, Nov 2015. URL: https://doi.org/10.1007/s00253-014-6240-3, doi:10.1007/s00253-014-6240-3. This article has 229 citations and is from a domain leading peer-reviewed journal.
(chistoserdova2003methylotrophyinmethylobacterium pages 5-6): Ludmila Chistoserdova, Sung-Wei Chen, Alla Lapidus, and Mary E. Lidstrom. Methylotrophy in methylobacterium extorquens am1 from a genomic point of view. Journal of Bacteriology, 185:2980-2987, May 2003. URL: https://doi.org/10.1128/jb.185.10.2980-2987.2003, doi:10.1128/jb.185.10.2980-2987.2003. This article has 402 citations and is from a peer-reviewed journal.
(martins2019atwocomponentprotease pages 1-2): Ana M. Martins, John A. Latham, Paulo J. Martel, Ian Barr, Anthony T. Iavarone, and Judith P. Klinman. A two-component protease in methylorubrum extorquens with high activity toward the peptide precursor of the redox cofactor pyrroloquinoline quinone. Journal of Biological Chemistry, 294:15025-15036, Oct 2019. URL: https://doi.org/10.1074/jbc.ra119.009684, doi:10.1074/jbc.ra119.009684. This article has 38 citations and is from a domain leading peer-reviewed journal.
(martins2019atwocomponentprotease pages 14-16): Ana M. Martins, John A. Latham, Paulo J. Martel, Ian Barr, Anthony T. Iavarone, and Judith P. Klinman. A two-component protease in methylorubrum extorquens with high activity toward the peptide precursor of the redox cofactor pyrroloquinoline quinone. Journal of Biological Chemistry, 294:15025-15036, Oct 2019. URL: https://doi.org/10.1074/jbc.ra119.009684, doi:10.1074/jbc.ra119.009684. This article has 38 citations and is from a domain leading peer-reviewed journal.
(ren2023adaptiveevolutionarystrategy pages 1-2): Yang Ren, Xinwei Yang, Lingtao Ding, Dongfang Liu, Yong Tao, Jianzhong Huang, and Chongrong Ke. Adaptive evolutionary strategy coupled with an optimized biosynthesis process for the efficient production of pyrroloquinoline quinone from methanol. Biotechnology for Biofuels and Bioproducts, Jan 2023. URL: https://doi.org/10.1186/s13068-023-02261-y, doi:10.1186/s13068-023-02261-y. This article has 12 citations and is from a domain leading peer-reviewed journal.
(ren2023adaptiveevolutionarystrategy pages 10-11): Yang Ren, Xinwei Yang, Lingtao Ding, Dongfang Liu, Yong Tao, Jianzhong Huang, and Chongrong Ke. Adaptive evolutionary strategy coupled with an optimized biosynthesis process for the efficient production of pyrroloquinoline quinone from methanol. Biotechnology for Biofuels and Bioproducts, Jan 2023. URL: https://doi.org/10.1186/s13068-023-02261-y, doi:10.1186/s13068-023-02261-y. This article has 12 citations and is from a domain leading peer-reviewed journal.
(chen2024genomebasedidentificationof pages 1-2): Xiaoqing Chen, Yiting Zhao, Shasha Huang, Josep Peñuelas, Jordi Sardans, Lei Wang, and Bangxiao Zheng. Genome-based identification of phosphate-solubilizing capacities of soil bacterial isolates. AMB Express, Jul 2024. URL: https://doi.org/10.1186/s13568-024-01745-w, doi:10.1186/s13568-024-01745-w. This article has 21 citations and is from a peer-reviewed journal.
(chen2024genomebasedidentificationof pages 3-5): Xiaoqing Chen, Yiting Zhao, Shasha Huang, Josep Peñuelas, Jordi Sardans, Lei Wang, and Bangxiao Zheng. Genome-based identification of phosphate-solubilizing capacities of soil bacterial isolates. AMB Express, Jul 2024. URL: https://doi.org/10.1186/s13568-024-01745-w, doi:10.1186/s13568-024-01745-w. This article has 21 citations and is from a peer-reviewed journal.
(chen2024genomebasedidentificationof pages 2-3): Xiaoqing Chen, Yiting Zhao, Shasha Huang, Josep Peñuelas, Jordi Sardans, Lei Wang, and Bangxiao Zheng. Genome-based identification of phosphate-solubilizing capacities of soil bacterial isolates. AMB Express, Jul 2024. URL: https://doi.org/10.1186/s13568-024-01745-w, doi:10.1186/s13568-024-01745-w. This article has 21 citations and is from a peer-reviewed journal.
(chen2024genomebasedidentificationof pages 5-7): Xiaoqing Chen, Yiting Zhao, Shasha Huang, Josep Peñuelas, Jordi Sardans, Lei Wang, and Bangxiao Zheng. Genome-based identification of phosphate-solubilizing capacities of soil bacterial isolates. AMB Express, Jul 2024. URL: https://doi.org/10.1186/s13568-024-01745-w, doi:10.1186/s13568-024-01745-w. This article has 21 citations and is from a peer-reviewed journal.
(martins2019atwocomponentprotease pages 5-6): Ana M. Martins, John A. Latham, Paulo J. Martel, Ian Barr, Anthony T. Iavarone, and Judith P. Klinman. A two-component protease in methylorubrum extorquens with high activity toward the peptide precursor of the redox cofactor pyrroloquinoline quinone. Journal of Biological Chemistry, 294:15025-15036, Oct 2019. URL: https://doi.org/10.1074/jbc.ra119.009684, doi:10.1074/jbc.ra119.009684. This article has 38 citations and is from a domain leading peer-reviewed journal.
(ren2023adaptiveevolutionarystrategy pages 2-4): Yang Ren, Xinwei Yang, Lingtao Ding, Dongfang Liu, Yong Tao, Jianzhong Huang, and Chongrong Ke. Adaptive evolutionary strategy coupled with an optimized biosynthesis process for the efficient production of pyrroloquinoline quinone from methanol. Biotechnology for Biofuels and Bioproducts, Jan 2023. URL: https://doi.org/10.1186/s13068-023-02261-y, doi:10.1186/s13068-023-02261-y. This article has 12 citations and is from a domain leading peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Citations

yao2026radicalenzymaticpeptide pages 6-7
chistoserdova2003methylotrophyinmethylobacterium pages 5-6
chen2024genomebasedidentificationof pages 7-9
kandy2025aromaticsidechaincrosslinking pages 4-6
martins2019atwocomponentprotease pages 14-16
martins2019atwocomponentprotease pages 1-2
ren2023adaptiveevolutionarystrategy pages 1-2
ren2023adaptiveevolutionarystrategy pages 10-11
ren2023adaptiveevolutionarystrategy pages 7-10
martins2019atwocomponentprotease pages 2-3
chistoserdova2003methylotrophyinmethylobacterium pages 2-3
martins2019atwocomponentprotease pages 10-11
ochsner2015methylobacteriumextorquensmethylotrophy pages 9-10
chen2024genomebasedidentificationof pages 1-2
chen2024genomebasedidentificationof pages 3-5
chen2024genomebasedidentificationof pages 2-3
chen2024genomebasedidentificationof pages 5-7
martins2019atwocomponentprotease pages 5-6
ren2023adaptiveevolutionarystrategy pages 2-4
4Fe–4S
2Fe–2S
https://doi.org/10.1186/s13068-023-02261-y
https://doi.org/10.1186/s13568-024-01745-w
https://doi.org/10.1039/d5cs00585j
https://doi.org/10.1074/jbc.ra119.009684
https://doi.org/10.1128/jb.185.10.2980-2987.2003;
https://doi.org/10.1002/9783527681754.ch13;
https://doi.org/10.1074/jbc.ra119.009684;
https://doi.org/10.1007/s00253-014-6240-3
https://doi.org/10.1128/jb.185.10.2980-2987.2003
https://doi.org/10.1002/9783527681754.ch13
https://doi.org/10.1039/d5cs00585j,
https://doi.org/10.1074/jbc.ra119.009684,
https://doi.org/10.1038/s41589-024-01795-y,
https://doi.org/10.1128/jb.185.10.2980-2987.2003,
https://doi.org/10.1002/9783527681754.ch13,
https://doi.org/10.1186/s13068-023-02261-y,
https://doi.org/10.1186/s13568-024-01745-w,
https://doi.org/10.1007/s00253-014-6240-3,

📄 View Raw YAML

id: P71517
gene_symbol: pqqE
product_type: PROTEIN
taxon:
  id: NCBITaxon:272630
  label: Methylorubrum extorquens AM1
description: 'pqqE encodes PqqA peptide cyclase (EC 1.21.98.4), a radical S-adenosylmethionine
  (SAM) enzyme that catalyzes the critical cross-linking of glutamate and tyrosine
  residues in the PqqA precursor protein during pyrroloquinoline quinone (PQQ) biosynthesis.
  PQQ is the essential cofactor for both calcium-dependent (MxaFI) and lanthanide-dependent
  (XoxF) methanol dehydrogenases, making PqqE absolutely required for methylotrophic
  growth. The enzyme contains a [4Fe-4S] cluster coordinated by three cysteines and
  an exchangeable S-adenosyl-L-methionine, characteristic of the radical SAM superfamily.
  PqqE forms a ternary complex with the peptide chaperone PqqD and the substrate PqqA;
  this interaction with PqqD is necessary for PqqE activity. Crystal structure has
  been solved at 3.20 Å resolution (PDB: 6C8V). The enzyme catalyzes de novo carbon-carbon
  cross-linking within the PqqA peptide substrate, forming the E-Y cross-linked intermediate
  that is further processed to PQQ.'
existing_annotations:
- term:
    id: GO:0003824
    label: catalytic activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: Root-level catalytic activity. PqqE has a specific, well-characterized
      radical SAM cross-linking activity captured by GO:0009975 (cyclase activity);
      this generic root term is uninformative on its own.
    action: KEEP_AS_NON_CORE
    reason: Subsumed by the more specific MF GO:0009975 (cyclase activity); retained
      as non-core because it does not convey the actual reaction.
- term:
    id: GO:0005506
    label: iron ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000104
  review:
    summary: PqqE binds iron exclusively as part of iron-sulfur clusters, not as a
      mononuclear iron ion. The radical SAM [4Fe-4S] cluster plus two auxiliary
      SPASM-domain clusters are better captured by the iron-sulfur cluster terms
      (GO:0051536, GO:0051539). This generic mononuclear-iron term is a less precise
      UniRule transfer.
    action: KEEP_AS_NON_CORE
    reason: The iron in PqqE is organized into [4Fe-4S]/auxiliary Fe-S clusters; the
      iron-sulfur cluster binding terms are more accurate, so this term is retained
      as non-core rather than as a core function.
- term:
    id: GO:0009975
    label: cyclase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000104
  review:
    summary: Correct and represents the core molecular function. PqqE is a radical
      SAM peptide cyclase (EC 1.21.98.4) that catalyzes intramolecular C-C ring
      closure by cross-linking a glutamate and a tyrosine side chain in the PqqA
      precursor peptide. No more specific GO MF term exists for this PqqA peptide
      cyclase reaction.
    action: ACCEPT
    reason: Best available MF term for the experimentally demonstrated Glu-Tyr C-C
      cross-linking (ring-closure) reaction on PqqA; this is the core function.
    supported_by:
    - reference_id: file:METEA/pqqE/pqqE-deep-research-falcon.md
      supporting_text: installation of a C–C bond (crosslink) between the side chains
        of a conserved glutamate and tyrosine on the ribosomally produced precursor
        peptide PqqA
- term:
    id: GO:0016491
    label: oxidoreductase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: PqqE is a radical SAM enzyme that reductively cleaves SAM via its
      [4Fe-4S] cluster to generate a 5'-deoxyadenosyl radical; this redox chemistry
      makes oxidoreductase activity correct, though the cyclase term (GO:0009975)
      better captures the net catalytic outcome.
    action: KEEP_AS_NON_CORE
    reason: Accurate at the superfamily level (radical SAM redox chemistry) but less
      informative than the specific cyclase activity term; kept as non-core.
    supported_by:
    - reference_id: file:METEA/pqqE/pqqE-deep-research-falcon.md
      supporting_text: Radical SAM enzymes use a **[4Fe–4S] cluster** to reductively
        cleave **S-adenosyl-L-methionine (SAM)** to generate a highly reactive **5′-deoxyadenosyl
        radical (5′-dAdo•)**
- term:
    id: GO:0018189
    label: pyrroloquinoline quinone biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Correct and core. PqqE catalyzes the first committed chemical step of
      PQQ biosynthesis - the radical SAM Glu-Tyr cross-linking of the PqqA precursor
      peptide. PQQ is the redox cofactor required by the periplasmic methanol/alcohol
      dehydrogenases central to methylotrophy in M. extorquens.
    action: ACCEPT
    reason: Directly supported by experimental characterization in M. extorquens AM1;
      this is the biological process the core MF serves.
    supported_by:
    - reference_id: file:METEA/pqqE/pqqE-deep-research-falcon.md
      supporting_text: catalyzes the **first committed chemical step** in pyrroloquinoline
        quinone (**PQQ**) biosynthesis
- term:
    id: GO:0046872
    label: metal ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Generic metal ion binding, redundant with the more specific iron-sulfur
      cluster binding terms (GO:0051536, GO:0051539) that describe PqqE's actual
      [4Fe-4S] and auxiliary Fe-S clusters.
    action: KEEP_AS_NON_CORE
    reason: Subsumed by the specific iron-sulfur cluster binding terms; uninformative
      on its own.
- term:
    id: GO:0051536
    label: iron-sulfur cluster binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Correct - PqqE binds the canonical radical SAM [4Fe-4S] cluster plus
      two auxiliary Fe-S clusters in its C-terminal SPASM domain. Slightly less
      specific than GO:0051539 for the catalytic cluster, but accurate for the
      auxiliary clusters as well.
    action: ACCEPT
    reason: Accurate description of PqqE's multiple iron-sulfur clusters; the
      auxiliary SPASM-domain clusters make this broader term appropriate alongside
      GO:0051539.
    supported_by:
    - reference_id: file:METEA/pqqE/pqqE-deep-research-falcon.md
      supporting_text: PqqE contains the canonical radical SAM cluster and **two auxiliary
        Fe–S clusters (AuxI and AuxII)** in its C-terminal SPASM domain
- term:
    id: GO:0051539
    label: 4 iron, 4 sulfur cluster binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: Correct - PqqE binds the catalytic radical SAM [4Fe-4S] cluster
      coordinated by three cysteines and an exchangeable SAM. The crystal structure
      additionally assigns the AuxII auxiliary cluster as a [4Fe-4S] coordinated by
      three cysteines and Asp319.
    action: ACCEPT
    reason: Most specific accurate term for the catalytic radical SAM cluster (and
      AuxII), supported by UniProt cofactor annotation and structural literature.
    supported_by:
    - reference_id: file:METEA/pqqE/pqqE-deep-research-falcon.md
      supporting_text: AuxII** coordinates a canonical **[4Fe–4S] cluster** using three
        cysteines and **Asp319**
- term:
    id: GO:1904047
    label: S-adenosyl-L-methionine binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000104
  review:
    summary: Correct - As a radical SAM enzyme, PqqE binds SAM, which is reductively
      cleaved by the [4Fe-4S] cluster to generate the 5'-deoxyadenosyl radical that
      abstracts a hydrogen from the glutamate side chain to initiate cross-linking.
    action: ACCEPT
    reason: SAM is the co-substrate of the radical SAM reaction; binding is intrinsic
      to the catalytic mechanism.
    supported_by:
    - reference_id: file:METEA/pqqE/pqqE-deep-research-falcon.md
      supporting_text: supporting **β-H abstraction from glutamate** by the 5′-dAdo
        radical and formation of a peptide-centered radical
core_functions:
- description: 'PqqE is a radical S-adenosylmethionine (SAM) enzyme that catalyzes
    the critical carbon-carbon cross-linking of glutamate and tyrosine residues in
    the PqqA precursor peptide during PQQ biosynthesis. The enzyme contains a [4Fe-4S]
    cluster coordinated by three cysteines and an exchangeable SAM molecule, which
    generates a 5''-deoxyadenosyl radical to initiate the cross-linking reaction.
    PqqE functions in complex with the peptide chaperone PqqD, which is necessary
    for activity. PQQ is the essential prosthetic group for both Ca-dependent (MxaFI)
    and Ln-dependent (XoxF) methanol dehydrogenases, making PqqE absolutely required
    for methylotrophic growth on methanol. Crystal structure solved at 3.20 Å (PDB:
    6C8V).'
  molecular_function:
    id: GO:0009975
    label: cyclase activity
  directly_involved_in:
  - id: GO:0018189
    label: pyrroloquinoline quinone biosynthetic process
  supported_by:
  - reference_id: file:METEA/pqqE/pqqE-uniprot.txt
    supporting_text: Catalyzes the cross-linking of a glutamate residue and a
      tyrosine residue in the PqqA protein as part of the biosynthesis of
      pyrroloquinoline quinone (PQQ)...Binds 1 [4Fe-4S] cluster...Interacts with
      PqqD. The interaction is necessary for activity
  - reference_id: PMID:25817994
    supporting_text: PqqD is a novel peptide chaperone that forms a ternary complex
      with the radical S-adenosylmethionine protein PqqE in the pyrroloquinoline quinone
      biosynthetic pathway
  - reference_id: file:METEA/pqqE/pqqE-deep-research-falcon.md
    supporting_text: >-
      a **radical S-adenosyl-L-methionine (radical SAM)** enzyme (SPASM subclass)
      that catalyzes the **first committed chemical step** in pyrroloquinoline
      quinone (**PQQ**) biosynthesis: **installation of a C–C bond (crosslink)
      between the side chains of a conserved glutamate and tyrosine on the
      ribosomally produced precursor peptide PqqA**, in a reaction that requires
      the peptide chaperone **PqqD**
references:
- id: file:METEA/pqqE/pqqE-uniprot.txt
  title: UniProt entry for pqqE PqqA peptide cyclase
  findings: []
- id: PMID:25817994
  title: PqqD is a novel peptide chaperone that forms a ternary complex with the radical
    S-adenosylmethionine protein PqqE in the pyrroloquinoline quinone biosynthetic
    pathway.
  findings: []
- id: file:METEA/pqqE/pqqE-deep-research-falcon.md
  title: Falcon deep research on pqqE (Edison Scientific Literature, P71517, M. extorquens
    AM1)
  findings:
  - statement: PqqE is a SPASM-subclass radical SAM enzyme that catalyzes the first
      committed step of PQQ biosynthesis - installing a C-C cross-link between a
      conserved glutamate and tyrosine on the ribosomal precursor peptide PqqA, in
      a PqqD-dependent reaction.
    supporting_text: >-
      a **radical S-adenosyl-L-methionine (radical SAM)** enzyme (SPASM subclass)
      that catalyzes the **first committed chemical step** in pyrroloquinoline
      quinone (**PQQ**) biosynthesis: **installation of a C–C bond (crosslink)
      between the side chains of a conserved glutamate and tyrosine on the
      ribosomally produced precursor peptide PqqA**, in a reaction that requires
      the peptide chaperone **PqqD**
    reference_section_type: OTHER
  - statement: The cross-linking proceeds by 5'-deoxyadenosyl-radical abstraction of
      a beta-hydrogen from the PqqA glutamate, generating a peptide radical that
      couples regioselectively to the ortho position of the tyrosine ring to form
      the PQQ core scaffold (supported by deuterium-labeling kinetic isotope
      effects).
    supporting_text: >-
      The resulting radical **couples regioselectively to the ortho position of a
      tyrosine ring**, forming the crosslink that constitutes the PQQ core scaffold.
    reference_section_type: OTHER
  - statement: PqqE binds the canonical radical SAM [4Fe-4S] cluster plus two
      auxiliary Fe-S clusters (AuxI, AuxII) in its C-terminal SPASM domain; the
      crystal structure assigns AuxII as a [4Fe-4S] coordinated by three cysteines
      and Asp319, with AuxI appearing as a [2Fe-2S].
    supporting_text: >-
      PqqE contains the canonical radical SAM cluster and **two auxiliary Fe–S
      clusters (AuxI and AuxII)** in its C-terminal SPASM domain.
    reference_section_type: OTHER
  - statement: PqqE/PqqD generate a cross-linked PqqA intermediate (PqqA*), an early
      di-amino-acid precursor that is subsequently excised by the two-component
      PqqF/PqqG protease and processed by downstream enzymes toward mature PQQ.
    supporting_text: >-
      PqqE/PqqD make the crosslink and PqqF/PqqG initiate cleavage
    reference_section_type: OTHER
  - statement: PqqE acts in the cytosol on the ribosomal PqqA peptide; the mature
      PQQ cofactor accumulates in the periplasm where it serves periplasmic
      methanol/alcohol dehydrogenases central to methylotrophy in M. extorquens AM1.
    supporting_text: >-
      PqqE likely acts in the cytosol on PqqA prior to downstream processing and
      subsequent periplasmic accumulation/use of PQQ
    reference_section_type: OTHER
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms.
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000104
  title: Electronic Gene Ontology annotations created by transferring manual GO annotations
    between related proteins based on shared sequence features.
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods.
  findings: []
status: COMPLETE

Gene Description

Existing Annotations Review

Core Functions