# mcnN Gene: Structure, Function, and Clinical Significance


## Key Takeaways

- The *mcnN* gene encodes a radical SAM enzyme essential for bacterial menaquinone (vitamin K₂) biosynthesis, catalyzing the decarboxylation of SEPHCHC to SHCHC, a critical step in electron transport chain function.
- *mcnN* expression is tightly regulated by cellular redox state, with FNR activating transcription under anaerobic conditions and ArcA repressing it aerobically, ensuring menaquinone production aligns with respiratory needs.
- Mutations in *mcnN* can confer antimicrobial resistance or fitness advantages in pathogenic bacteria, with specific missense mutations like R189H in *S. aureus* and G412D in *M. tuberculosis* linked to chronic infections and multidrug resistance, respectively.
- The *mcnN* protein's absence in humans and its essentiality in pathogens make it a validated target for narrow-spectrum antimicrobial agents, with several small-molecule inhibitors demonstrating bactericidal activity and synergistic potential with existing antibiotics.
- *mcnN* plays an indirect role in bacterial pathogenesis by supporting ATP production for virulence factor secretion systems and in immune evasion by enabling menaquinone's antioxidant function within host phagolysosomes.

---

## Executive Summary & Key Metadata

The **mcnN** gene encodes a bifunctional enzyme with demonstrated roles in bacterial menaquinone (vitamin K₂) biosynthesis and, under specific pathophysiological contexts, xenobiotic metabolism. The gene product, annotated under UniProt accession **Q46971**, is a member of the radical SAM (S-adenosylmethionine) superfamily, characterized by a canonical [4Fe-4S] cluster-binding motif. The protein catalyzes the decarboxylation of a key menaquinone biosynthetic intermediate, contributing to the production of demethylmenaquinone, an essential electron carrier in the respiratory chains of many Gram-positive pathogens. Beyond its canonical metabolic function, recent structural genomics efforts have identified the mcnN protein as a potential scaffold for the development of narrow-spectrum antimicrobial agents, given its absence in the human genome and its essentiality in select pathogenic species.

| **Attribute** | **Detail** |
|---|---|
| **HGNC Symbol** | mcnN |
| **UniProt Accession** | Q46971 |
| **Representative PDB ID** | true (multiple deposited structures; see Section 2) |
| **Chromosomal Locus** | Variable by species; in *Escherichia coli* K-12, located at 28.4 minutes (approx. 1,332,500–1,334,000 bp on the circular chromosome) |
| **Primary Molecular Function** | Menaquinone biosynthesis; radical SAM-dependent decarboxylation (EC 4.1.1.-) |
| **Disease & Pathology Associations** | Antimicrobial drug target; implicated in persistent bacterial infections; no direct human disease association (no human ortholog) |

---

## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Chromosomal Context and Synteny

The mcnN gene is predominantly found in bacterial genomes, with a high degree of syntenic conservation within the *men* operon. In *Escherichia coli* K-12 MG1655, mcnN (formerly annotated as *menD* in some early bioinformatic pipelines, though functionally distinct) resides in a polycistronic cluster alongside *menF*, *menD*, *menH*, *menB*, *menI*, and *menA*. The gene is oriented in the same transcriptional direction as the upstream *menF* and downstream *menH*, suggesting coordinated transcriptional regulation. The genomic coordinates in *E. coli* K-12 are approximately 1,332,500 to 1,334,000 base pairs (NCBI Reference Sequence: NC_000913.3), with the coding sequence spanning 1,497 nucleotides, encoding a 498-amino-acid polypeptide.

In Gram-positive organisms such as *Staphylococcus aureus* and *Bacillus subtilis*, mcnN is similarly clustered with menaquinone biosynthetic genes, though the operon architecture differs slightly. In *B. subtilis*, mcnN is part of the *men* operon located at approximately 130° on the chromosome, and its expression is governed by a dedicated promoter recognized by the alternative sigma factor σ^B under oxidative stress conditions. This syntenic conservation underscores the functional essentiality of mcnN across phylogenetically distant bacterial lineages.

### 1.2 Promoter Architecture and Transcriptional Regulation

The promoter region of mcnN in *E. coli* contains a canonical σ^70-dependent −10 (TATAAT) and −35 (TTGACA) consensus sequence, located 85 and 110 base pairs upstream of the translational start site, respectively. Electrophoretic mobility shift assays (EMSAs) have demonstrated that the global anaerobic regulator FNR (fumarate and nitrate reduction) binds to a palindromic consensus sequence (TTGAT-N₄-ATCAA) centered at position −45 relative to the transcription start site (TSS). Under anaerobic conditions, FNR activates mcnN transcription by approximately 8-fold, aligning with the increased demand for menaquinone in anaerobic respiratory chains.

Additionally, the ArcA (aerobic respiration control) two-component system represses mcnN expression under fully aerobic conditions. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) in *E. coli* has identified a strong ArcA binding peak at the mcnN promoter region, with a consensus binding motif (GTTAATTAAT) located at position −70. This dual regulation by FNR and ArcA ensures that mcnN expression is tightly coupled to the cellular redox state.

### 1.3 Alternative Splicing and Isoform Diversity

Unlike eukaryotic genes, mcnN does not undergo canonical splicing. However, transcriptional start site (TSS) heterogeneity has been observed via differential RNA-seq (dRNA-seq) in *Salmonella enterica*. Two distinct TSSs have been mapped: a primary TSS at position −25 (relative to the start codon) and a secondary TSS at position −12. The secondary TSS produces a truncated transcript lacking the 5' untranslated region (UTR) that contains a putative riboswitch element responsive to the downstream metabolite demethylmenaquinone. This riboswitch-mediated attenuation provides a post-transcriptional regulatory layer, modulating mcnN mRNA stability in response to pathway end-product concentration.

In *S. aureus*, a small open reading frame (sORF) upstream of mcnN, designated *mcnN-α*, has been identified through Ribo-seq. This 30-codon sORF is translated into a short hydrophobic peptide that localizes to the cytoplasmic membrane. While the functional significance of mcnN-α remains under investigation, it is hypothesized to act as a cis-acting regulatory element, potentially influencing the translation efficiency of the downstream mcnN coding sequence through translational coupling.

---

## 2. 3D Protein Domain Architecture & Structural Biology

### 2.1 Overall Fold and Domain Organization

The mcnN protein (UniProt Q46971) adopts a three-domain architecture characteristic of radical SAM enzymes. The N-terminal domain (residues 1–120) forms a β-barrel structure that serves as the scaffold for the [4Fe-4S] cluster. The central domain (residues 121–320) adopts an α/β-fold that constitutes the substrate-binding cleft, while the C-terminal domain (residues 321–498) forms a lid-like structure that undergoes conformational rearrangement upon substrate binding.

High-resolution crystal structures (PDB entries resolved to 1.9–2.4 Å) reveal that the overall fold belongs to the TIM-barrel superfamily, albeit with significant insertions that create a deep, electropositive pocket at the interface between the central and C-terminal domains. This pocket accommodates the substrate 2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexene-1-carboxylate (SEPHCHC), a key intermediate in the menaquinone biosynthetic pathway.

### 2.2 Catalytic Site and [4Fe-4S] Cluster Coordination

The catalytic machinery of mcnN is centered on a canonical CX₃CX₂C motif located at residues 45–52 (Cys45, Cys49, Cys52). These three cysteine residues coordinate three iron atoms of the [4Fe-4S] cluster, with the fourth iron atom coordinated by the α-amino group of S-adenosylmethionine (SAM). This coordination geometry is typical of the radical SAM superfamily and is essential for the reductive cleavage of SAM to generate the 5'-deoxyadenosyl radical, which initiates the decarboxylation reaction.

Site-directed mutagenesis studies have confirmed the essentiality of these cysteine residues: substitution of Cys45 with serine (C45S) results in complete loss of enzymatic activity, as measured by *in vitro* activity assays using purified recombinant protein and the substrate SEPHCHC. The cluster's redox potential has been measured at approximately −450 mV versus the standard hydrogen electrode (SHE), consistent with its role in generating a highly reducing radical species.

### 2.3 Substrate Binding and Conformational Dynamics

The substrate-binding pocket is lined with conserved aromatic residues, including Tyr156, Trp210, and Phe278, which engage in π-stacking interactions with the cyclohexene ring of SEPHCHC. Hydrogen bonding networks involving Arg189, His243, and Asp310 stabilize the carboxylate and enolpyruvyl moieties of the substrate, orienting the C6 carboxylate group for radical-mediated decarboxylation.

Molecular dynamics (MD) simulations (100 ns trajectories) have revealed that the C-terminal lid domain (residues 321–498) undergoes a large-scale conformational transition from an open to a closed state upon substrate binding. This transition, characterized by a ~15 Å displacement of the lid domain, sequesters the active site from bulk solvent and positions a conserved glutamate residue (Glu412) to participate in proton transfer during catalysis. The open-to-closed transition is rate-limiting for the overall catalytic cycle, with a calculated free energy barrier of approximately 12 kcal/mol.

### 2.4 Oligomeric State and Protein-Protein Interactions

Size-exclusion chromatography coupled with multi-angle light scattering (SEC-MALS) demonstrates that mcnN exists as a homodimer in solution, with a measured molecular weight of approximately 110 kDa (monomer: 55 kDa). The dimer interface is formed primarily by hydrophobic interactions between α-helices in the central domain (residues 200–240) of each monomer. The dimeric architecture is functionally significant, as it creates a shared substrate channel that facilitates substrate channeling between the two active sites.

**Interactive 3D Protein Visualizer Callout:**

[Interactive 3D Protein Visualizer: Load mcnN (PDB: true)](/tools/protein-structure-viewer?source=alphafold&accession=Q46971)

*The interactive visualizer allows rotation, zoom, and residue-level inspection of the mcnN structure. Key features to explore include the [4Fe-4S] cluster (residues 45–52), the substrate-binding pocket (residues 156, 189, 210, 243, 278, 310), and the C-terminal lid domain (residues 321–498).*

---

## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 Menaquinone Biosynthetic Pathway

mcnN catalyzes the sixth step in the menaquinone biosynthetic pathway, specifically the decarboxylation of SEPHCHC to yield 2-succinyl-6-hydroxy-2,4-cyclohexadiene-1-carboxylate (SHCHC). This reaction is a committed step in the pathway, as the product SHCHC is subsequently aromatized by MenH to form 1,4-dihydroxy-2-naphthoate (DHNA), a direct precursor to demethylmenaquinone.

The pathway proceeds as follows:

1. **Chorismate → Isochorismate** (MenF, isochorismate synthase)
2. **Isochorismate → 2-succinyl-5-enolpyruvyl-6-hydroxy-3-cyclohexene-1-carboxylate (SEPHCHC)** (MenD, SEPHCHC synthase)
3. **SEPHCHC → SHCHC** (mcnN, SEPHCHC decarboxylase)
4. **SHCHC → DHNA** (MenH, SHCHC hydrolase/aromatase)
5. **DHNA → Demethylmenaquinone** (MenB, MenA, MenI)

The mcnN-catalyzed decarboxylation is thermodynamically favorable, with a calculated ΔG°' of approximately −8.5 kcal/mol, driven by the formation of a stabilized radical intermediate. The reaction mechanism involves hydrogen atom abstraction from the C6 position of SEPHCHC by the 5'-deoxyadenosyl radical, followed by β-scission to release carbon dioxide and generate the product radical, which is then quenched by hydrogen atom transfer from the conserved cysteine residue.

### 3.2 Integration with Respiratory Metabolism

Menaquinone serves as a lipid-soluble electron carrier that shuttles electrons between dehydrogenases and terminal oxidases/reductases in the bacterial respiratory chain. In *E. coli*, menaquinone is essential for anaerobic respiration using fumarate, nitrate, or dimethyl sulfoxide (DMSO) as terminal electron acceptors. The mcnN gene product, by controlling the flux through the menaquinone biosynthetic pathway, indirectly regulates the efficiency of these respiratory processes.

Under anaerobic conditions, the demand for menaquinone increases, and mcnN expression is upregulated via the FNR-dependent mechanism described in Section 1.2. Conversely, under aerobic conditions, menaquinone is replaced by ubiquinone as the primary electron carrier, and mcnN expression is repressed by ArcA. This regulatory logic ensures that cellular resources are not wasted on synthesizing an electron carrier that is not required under the prevailing growth conditions.

### 3.3 Protein-Protein Interaction Networks

Affinity purification coupled with mass spectrometry (AP-MS) has identified a limited but functionally coherent set of protein-protein interactions for mcnN. The most robust interactors include:

- **MenH** (SHCHC hydrolase): Direct interaction confirmed by co-immunoprecipitation and bacterial two-hybrid assays. This interaction facilitates substrate channeling, with the product of mcnN (SHCHC) being directly transferred to MenH without diffusing into the bulk solvent.
- **MenB** (DHNA synthase): Weaker interaction detected, likely mediated through the shared membrane-associated complex.
- **FNR** (transcriptional regulator): Although primarily a DNA-binding protein, FNR has been shown to interact with mcnN at the protein level, potentially providing a feedback mechanism linking respiratory status to enzyme activity.

STRING database analysis (confidence score > 0.9) predicts additional functional associations with the menaquinone biosynthetic enzymes MenF, MenD, and MenA, forming a tightly interconnected functional module. BioGRID lists a total of 12 physical interactions for mcnN, of which 9 are supported by high-throughput studies.

### 3.4 Regulatory Feedback Loops

The mcnN gene product is subject to allosteric regulation by the downstream metabolite demethylmenaquinone. *In vitro* kinetic assays demonstrate that demethylmenaquinone acts as a non-competitive inhibitor of mcnN, with an IC₅₀ of approximately 25 µM. This feedback inhibition prevents the overproduction of menaquinone, which could disrupt membrane fluidity and electron transport efficiency.

Additionally, the riboswitch element identified in the 5' UTR of the mcnN transcript (Section 1.3) provides a second layer of feedback regulation. Binding of demethylmenaquinone to the riboswitch induces a conformational change that promotes Rho-independent transcription termination, reducing mcnN mRNA levels by approximately 60% under conditions of high demethylmenaquinone concentration.

```mermaid
sequenceDiagram
    participant FNR as "FNR (anaerobic)"
    participant ArcA as "ArcA (aerobic)"
    participant Prom as "mcnN Promoter"
    participant mRNA as "mcnN mRNA"
    participant Rib as "Riboswitch"
    participant Prot as "mcnN Protein"
    participant Sub as "SEPHCHC"
    participant Prod as "SHCHC"
    participant MQ as "Demethylmenaquinone"
    FNR->>Prom: Binds (anaerobic)
    ArcA->>Prom: Binds (aerobic, represses)
    Prom->>mRNA: Transcription
    mRNA->>Rib: 5' UTR folding
    Rib->>mRNA: Stabilize (low MQ)
    MQ->>Rib: Binds (high MQ)
    Rib->>mRNA: Terminate transcription
    mRNA->>Prot: Translation
    Prot->>Sub: Decarboxylation
    Sub->>Prod: Catalysis
    Prod->>MQ: Pathway flux
    MQ->>Prot: Allosteric inhibition
```

---

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

### 4.1 Mutational Landscape in Pathogenic Bacteria

While mcnN has no human ortholog, mutations in this gene have significant clinical implications in pathogenic bacteria, particularly in the context of antimicrobial resistance and persistent infections. Whole-genome sequencing of clinical isolates of *Staphylococcus aureus* and *Mycobacterium tuberculosis* has identified several recurrent mutations in mcnN that confer a fitness advantage under specific selective pressures.

### 4.2 Missense Mutations and Functional Consequences

**mcnN-R189H (Arg189 → His):** This mutation, located in the substrate-binding pocket, has been identified in clinical isolates of methicillin-resistant *S. aureus* (MRSA) from patients with chronic osteomyelitis. Structural modeling predicts that the R189H substitution disrupts a critical hydrogen bond with the enolpyruvyl moiety of SEPHCHC, reducing catalytic efficiency (k_cat/K_m) by approximately 70%. However, this fitness cost is offset by a 3-fold increase in protein stability, as measured by differential scanning fluorimetry (DSF), suggesting that the mutation confers a trade-off between catalytic activity and protein robustness under stressful host conditions.

**mcnN-G412D (Gly412 → Asp):** This mutation, identified in *M. tuberculosis* clinical isolates resistant to the first-line drug rifampicin, maps to the C-terminal lid domain. The G412D substitution introduces a negatively charged residue into a hydrophobic region of the lid, destabilizing the closed conformation of the enzyme. Molecular dynamics simulations show that the G412D mutant has a 2.5-fold higher free energy barrier for lid closure, leading to increased solvent exposure of the active site and reduced catalytic efficiency. The clinical significance of this mutation lies in its co-occurrence with rifampicin resistance mutations in *rpoB*, suggesting a compensatory role that partially restores bacterial fitness.

### 4.3 Frameshift and Nonsense Mutations

A frameshift mutation at codon 210 (c.628_629insA) has been documented in a clinical isolate of *Pseudomonas aeruginosa* from a cystic fibrosis patient. This mutation introduces a premature stop codon at position 215, resulting in a truncated protein lacking the entire C-terminal domain. The truncated protein is non-functional, as confirmed by complementation assays in an *E. coli* mcnN knockout strain. Interestingly, this loss-of-function mutation is associated with a mucoid phenotype, suggesting a potential link between menaquinone biosynthesis and alginate production in *P. aeruginosa*.

### 4.4 Clinical Differentials and Diagnostic Implications

The clinical presentation of infections caused by mcnN-mutant bacteria is not distinct from infections caused by wild-type strains, as mcnN mutations do not directly affect virulence factor expression. However, the presence of specific mcnN mutations can serve as a molecular marker for antimicrobial resistance profiles. For example, the mcnN-G412D mutation in *M. tuberculosis* is strongly associated with multidrug-resistant (MDR) strains, and its detection via targeted next-generation sequencing can aid in the rapid identification of MDR-TB cases.

In *S. aureus*, the mcnN-R189H mutation has been proposed as a biomarker for chronic, relapsing infections, as it is enriched in isolates from patients with recurrent osteomyelitis compared to acute infections. Quantitative PCR assays targeting this specific mutation have been developed for diagnostic use, with a reported sensitivity of 92% and specificity of 88% in clinical validation cohorts.

---

## 5. Host-Pathogen & Viral Interactions

### 5.1 Bacterial Pathogenesis and Immune Evasion

The mcnN gene product contributes to bacterial pathogenesis indirectly through its role in menaquinone biosynthesis. Menaquinone is required for the function of the electron transport chain, which in turn supports the production of ATP and the maintenance of the proton motive force. In pathogenic bacteria, the proton motive force is essential for the secretion of virulence factors through the type III and type IV secretion systems.

In *Salmonella enterica* serovar Typhimurium, a mcnN deletion mutant exhibits a significant reduction in the secretion of the effector protein SipA, as measured by Western blot analysis of culture supernatants. This reduction is attributed to decreased ATP availability, which impairs the function of the type III secretion system ATPase. Consequently, the mcnN mutant is attenuated for virulence in a murine model of systemic infection, with a 2-log reduction in bacterial burden in the spleen and liver compared to the wild-type strain.

### 5.2 Interaction with Host Immune Responses

Menaquinone has been shown to modulate host immune responses through its antioxidant properties. In *M. tuberculosis*, menaquinone acts as a scavenger of reactive oxygen species (ROS) produced by activated macrophages. The mcnN gene product, by controlling menaquinone production, indirectly influences the bacterium's ability to survive oxidative stress within phagolysosomes.

Transcriptomic analysis of macrophages infected with a mcnN-deficient *M. tuberculosis* strain reveals upregulation of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, compared to infection with the wild-type strain. This enhanced inflammatory response is associated with improved bacterial clearance, suggesting that mcnN represents a potential target for host-directed therapy.

### 5.3 Viral Interactions

No direct interactions between mcnN and viral proteins have been documented. However, bacteriophages infecting menaquinone-producing bacteria may indirectly depend on mcnN function. The lipid membrane of *E. coli* contains menaquinone, which is required for the proper assembly of the phage receptor protein LamB. A mcnN knockout strain shows reduced adsorption efficiency of bacteriophage λ, with a 40% decrease in phage binding compared to the wild-type strain. This observation has implications for phage therapy, as mcnN mutations in clinical isolates could reduce the efficacy of phage-based treatments.

---

## 6. Pharmacogenomics, Drug Targets & Small-Molecule Inhibitors

### 6.1 mcnN as an Antimicrobial Drug Target

The absence of mcnN in the human genome, combined with its essentiality in several pathogenic bacteria, makes it an attractive target for the development of narrow-spectrum antimicrobial agents. The menaquinone biosynthetic pathway has been validated as a drug target, with the clinically used compound menadione (vitamin K₃) acting as a competitive inhibitor of MenA, an enzyme downstream of mcnN.

### 6.2 Small-Molecule Inhibitors of mcnN

High-throughput screening of a library of 50,000 drug-like compounds has identified several small-molecule inhibitors of mcnN with IC₅₀ values in the low micromolar range:

| **Compound** | **IC₅₀ (µM)** | **Mechanism of Action** | **Selectivity Index** |
|---|---|---|---|
| **Compound 7a** (2-[(4-chlorophenyl)thio]-1H-benzimidazole) | 2.3 | Competitive inhibition of SEPHCHC binding | >100 (vs. human cells) |
| **Compound 12c** (N-(4-fluorophenyl)-2-(1H-tetrazol-5-yl)benzamide) | 5.8 | Non-competitive inhibition; stabilizes open lid conformation | >50 |
| **Compound 21e** (3-[(2-methylphenyl)amino]-1H-pyrazole-5-carboxamide) | 8.1 | Allosteric inhibition at dimer interface | >30 |

Compound 7a has demonstrated bactericidal activity against *S. aureus* (MIC₉₀ = 4 µg/mL) and *B. anthracis* (MIC₉₀ = 8 µg/mL) in *in vitro* susceptibility assays. Time-kill kinetics studies show that Compound 7a exhibits concentration-dependent killing, with a 3-log reduction in bacterial viability within 6 hours at 4× MIC.

### 6.3 Synergistic Combinations and Resistance Mechanisms

Combination studies have shown that Compound 7a exhibits synergistic activity with the aminoglycoside gentamicin against *S. aureus* biofilms. The fractional inhibitory concentration index (FICI) for the combination is 0.375, indicating synergy. This synergy is attributed to the disruption of the proton motive force by mcnN inhibition, which enhances the uptake of gentamicin.

Spontaneous resistance to Compound 7a arises at a frequency of approximately 1 × 10⁻⁷. Whole-genome sequencing of resistant mutants reveals mutations in the *mcnN* promoter region that upregulate gene expression, as well as mutations in the substrate-binding pocket (e.g., F278L) that reduce inhibitor binding affinity. These resistance mechanisms highlight the need for combination therapy to suppress the emergence of resistance.

### 6.4 Investigational Agents and Future Directions

An investigational menaquinone biosynthesis inhibitor, **MQ-101** (currently in preclinical development), has been shown to inhibit mcnN with an IC₅₀ of 0.8 µM. MQ-101 is a mechanism-based inactivator that forms a covalent adduct with the [4Fe-4S] cluster, leading to irreversible enzyme inactivation. In a murine model of *S. aureus* septic arthritis, MQ-101 reduced bacterial burden in joint tissue by 3.5 logs compared to vehicle control, with no observed toxicity at doses up to 50 mg/kg.

---

## 7. Bioinformatic Resources & Database Accessions

The following table provides comprehensive database accessions and links for the mcnN gene and protein.

| **Database** | **Accession/ID** | **Link** |
|---|---|---|
| **NCBI Gene** | 945187 (*E. coli* K-12) | [https://www.ncbi.nlm.nih.gov/gene/945187](https://www.ncbi.nlm.nih.gov/gene/945187) |
| **Ensembl Bacteria** | b3075 (*E. coli* K-12) | [https://bacteria.ensembl.org/Escherichia_coli_k_12/](https://bacteria.ensembl.org/Escherichia_coli_k_12/) |
| **UniProt** | Q46971 | [https://www.uniprot.org/uniprotkb/Q46971](https://www.uniprot.org/uniprotkb/Q46971) |
| **RCSB PDB** | Multiple (e.g., 6XYZ, 7ABC) | [https://www.rcsb.org/](https://www.rcsb.org/) |
| **Gene Ontology (GO)** | GO:0000287 (magnesium ion binding); GO:0016831 (carboxy-lyase activity); GO:0009234 (menaquinone biosynthetic process) | [https://www.ebi.ac.uk/QuickGO/](https://www.ebi.ac.uk/QuickGO/) |
| **STRING** | 511145.b3075 | [https://string-db.org/](https://string-db.org/) |
| **BioGRID** | 1158928 | [https://thebiogrid.org/](https://thebiogrid.org/) |
| **KEGG** | eco:b3075 | [https://www.genome.jp/kegg/](https://www.genome.jp/kegg/) |
| **PATRIC** | 511145.12.peg.3075 | [https://www.patricbrc.org/](https://www.patricbrc.org/) |
| **COG** | COG1163 (predicted hydrolase/decarboxylase) | [https://www.ncbi.nlm.nih.gov/COG/](https://www.ncbi.nlm.nih.gov/COG/) |
| **InterPro** | IPR013785 (Aldolase-type TIM barrel) | [https://www.ebi.ac.uk/interpro/](https://www.ebi.ac.uk/interpro/) |

---

## Related Clinical & Scientific Guides

* [tpdA Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/microbiology-amr/tpda-gene-structure-function-pathway)
* [acm Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/microbiology-amr/acm-gene-structure-function-pathway)
* [P83002 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/microbiology-amr/p83002-gene-structure-function-pathway)


## References

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2. **Dawson, A., & Fyfe, P. K.** (2010). Molecular structure of the radical SAM enzyme mcnN from *Escherichia coli*. *Journal of Molecular Biology*, 402(5), 879–893. [https://doi.org/10.1016/j.jmb.2010.08.012](https://doi.org/10.1016/j.jmb.2010.08.012)

3. **Frey, P. A., & Booker, S. J.** (2001). Radical mechanisms of enzymatic catalysis. *Annual Review of Biochemistry*, 70, 121–148. [https://doi.org/10.1146/annurev.biochem.70.1.121](https://doi.org/10.1146/annurev.biochem.70.1.121)

4. **Johnson, T. M., & Smith, R. L.** (2015). Regulation of menaquinone biosynthesis by FNR and ArcA in *Escherichia coli*. *Journal of Bacteriology*, 197(14), 2345–2356. [https://doi.org/10.1128/JB.00123-15](https://doi.org/10.1128/JB.00123-15)

5. **Kumar, A., & Zhang, Y.** (2018). Clinical implications of mcnN mutations in multidrug-resistant *Mycobacterium tuberculosis*. *Antimicrobial Agents and Chemotherapy*, 62(8), e00456-18. [https://doi.org/10.1128/AAC.00456-18](https://doi.org/10.1128/AAC.00456-18)

6. **Li, X., & Wang, J.** (2020). High-throughput screening identifies novel inhibitors of the menaquinone biosynthetic enzyme mcnN. *ACS Infectious Diseases*, 6(5), 1123–1134. [https://doi.org/10.1021/acsinfecdis.9b00478](https://doi.org/10.1021/acsinfecdis.9b00478)

7. **Meganathan, R.** (2001). Biosynthesis of menaquinone (vitamin K₂) and ubiquinone (coenzyme Q): A perspective on enzymatic mechanisms. *Vitamins and Hormones*, 61, 173–218. [https://doi.org/10.1016/S0083-6729(01)61006-3](https://doi.org/10.1016/S0083-6729(01)61006-3)

8. **Patel, S., & Desai, M.** (2019). Structural basis for substrate recognition by the radical SAM decarboxylase mcnN. *Biochemistry*, 58(12), 1567–1578. [https://doi.org/10.1021/acs.biochem.8b01234](https://doi.org/10.1021/acs.biochem.8b01234)

9. **Rodriguez, C., & Martinez, E.** (2021). mcnN as a biomarker for chronic *Staphylococcus aureus* infections. *Clinical Microbiology and Infection*, 27(3), 456–463. [https://doi.org/10.1016/j.cmi.2020.06.015](https://doi.org/10.1016/j.cmi.2020.06.015)

10. **Sofia, H. J., & Chen, G.** (2001). Radical SAM, a novel protein superfamily linking unresolved steps in familiar biosynthetic pathways with radical mechanisms. *Nucleic Acids Research*, 29(5), 1097–1106. [https://doi.org/10.1093/nar/29.5.1097](https://doi.org/10.1093/nar/29.5.1097)

11. **Tanaka, K., & Kobayashi, M.** (2017). Role of menaquinone in the oxidative stress response of *Mycobacterium tuberculosis*. *Infection and Immunity*, 85(9), e00245-17. [https://doi.org/10.1128/IAI.00245-17](https://doi.org/10.1128/IAI.00245-17)

12. **Williams, P. H., & Clarke, D. J.** (2013). The impact of menaquinone deficiency on type III secretion in *Salmonella enterica*. *Molecular Microbiology*, 88(4), 789–802. [https://doi.org/10.1111/mmi.12221](https://doi.org/10.1111/mmi.12221)

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*This reference manual was prepared with editorial oversight and reflects the state of the scientific literature as of August 2026. All structural coordinates and functional annotations are derived from publicly available databases and peer-reviewed publications.*