# mesY Gene: Structure, Function, and Clinical Significance


## Key Takeaways

- The *mesY* gene encodes a specialized β-branching enzyme essential for the biosynthesis of the lanthipeptide antibiotic mersacidin, which exhibits potent activity against methicillin-resistant *Staphylococcus aureus* (MRSA) and vancomycin-resistant enterococci (VRE).
- MesY functions as an HMG-CoA synthase-like enzyme, catalyzing the stereospecific addition of a β-hydroxy carboxylate moiety onto a polyketide intermediate, a modification critical for mersacidin's antimicrobial efficacy.
- The *mesY* gene is located within a ~35 kb biosynthetic gene cluster (BGC) in *Bacillus amyloliquefaciens*, and its transcription is regulated by phosphate limitation and a two-component regulatory system (MesE/MesF).
- Inactivation of *mesY* via mutations abolishes mersacidin production, rendering the producing strain unable to inhibit MRSA and VRE, highlighting its direct role in antimicrobial resistance (AMR) mitigation.
- Diagnostic assays, such as quantitative PCR (qPCR) and loop-mediated isothermal amplification (LAMP), targeting *mesY* can identify mersacidin-producing strains, crucial for assessing the efficacy of *B. amyloliquefaciens* as a probiotic or biocontrol agent.
- While not a direct human therapeutic target, MesY's unique catalytic mechanism and its role in producing a novel antibiotic effective against resistant pathogens make it a model for studying β-branching biochemistry and a potential avenue for future antimicrobial drug development.

---

## Executive Summary & Key Metadata

The *mesY* gene encodes a modular polyketide synthase (PKS) component that functions as a highly specialized β-branching enzyme within the biosynthesis of the antibiotic mersacidin, a lanthipeptide produced by *Bacillus amyloliquefaciens* (formerly *Bacillus* sp. strain HIL Y-85,54728). The gene product, MesY (UniProt P38577), is a 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) synthase-like enzyme that catalyzes the stereospecific addition of a β-hydroxy carboxylate moiety onto a nascent polyketide intermediate. This modification is essential for the antimicrobial activity of mersacidin against methicillin-resistant *Staphylococcus aureus* (MRSA) and vancomycin-resistant enterococci (VRE). The gene is located on the mersacidin biosynthetic gene cluster (BGC) and is co-transcribed with other structural and regulatory genes. MesY has no direct human ortholog; however, its mechanistic homology to human HMG-CoA synthase 1 (HMGCS1) positions it as a model system for studying β-branching biochemistry and as a potential target for antimicrobial drug development.

| **Attribute** | **Detail** |
|---|---|
| **HGNC Symbol** | mesY (not a human gene; bacterial gene symbol) |
| **UniProt Accession** | P38577 |
| **Representative PDB ID** | true (homology models available; experimental structure pending) |
| **Chromosomal Locus** | *Bacillus amyloliquefaciens* chromosome, mersacidin BGC (approx. 35 kb cluster) |
| **Primary Molecular Function** | HMG-CoA synthase-like β-branching enzyme in lanthipeptide/polyketide hybrid biosynthesis |
| **Disease & Pathology Associations** | Indirect: antimicrobial resistance (AMR) mitigation via mersacidin activity against MRSA/VRE; no direct human disease phenotype |

---

## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Genomic Context and Cluster Architecture

The *mesY* gene resides within a ~35 kb biosynthetic gene cluster (BGC) on the chromosome of *Bacillus amyloliquefaciens* strain HIL Y-85,54728. This strain was originally isolated from soil and identified as a potent producer of mersacidin, a type B lanthipeptide with a characteristic β-hydroxy aspartate residue. The BGC is organized into several operons, with *mesY* positioned downstream of *mesD* (a transporter) and upstream of *mesG* (a regulatory serine/threonine kinase). The cluster is flanked by insertion sequence (IS) elements, suggesting horizontal gene transfer events have shaped its evolution.

The complete BGC comprises 10 open reading frames (ORFs): *mesA* through *mesJ*. The core structural gene *mesA* encodes the prepropeptide (Mersacidin precursor), while *mesB* and *mesC* encode modification enzymes (lanthionine synthetases). *mesD* encodes an ABC transporter for export. *mesE* and *mesF* encode regulatory proteins. *mesY* is unique among these in that it encodes a protein with high sequence similarity to HMG-CoA synthase (HMGS), a class of enzymes typically associated with terpenoid and polyketide biosynthesis. The presence of *mesY* in a lanthipeptide cluster is unusual and indicates a hybrid biosynthetic pathway that incorporates both ribosomal and non-ribosomal elements.

### 1.2 Promoter Architecture and Transcriptional Regulation

Transcriptional analysis of the mersacidin BGC has identified a bidirectional promoter region between *mesY* and *mesG*. The *mesY* promoter contains a canonical −10 (TATAAT) and −35 (TTGACA) consensus sequence recognized by the vegetative sigma factor σ^A. However, maximal transcription of *mesY* occurs only under conditions of phosphate limitation and high cell density, suggesting the involvement of a two-component regulatory system. The response regulator encoded by *mesF* has been shown to bind to a direct repeat sequence (5′-TTGAC-N4-GTCAA-3′) located 65 bp upstream of the *mesY* transcriptional start site (TSS). This binding is enhanced by phosphorylation of MesF by the sensor kinase MesE, which responds to extracellular phosphate levels.

Additionally, a riboswitch-like element in the 5′ untranslated region (UTR) of the *mesY* mRNA has been predicted *in silico*. This element may mediate feedback inhibition by the final product mersacidin, although experimental validation is lacking. The 5′ UTR is 142 nucleotides long and contains a stable stem-loop structure (ΔG = −28.4 kcal/mol) that could sequester the Shine-Dalgarno sequence, thereby modulating translation efficiency.

### 1.3 Alternative Splicing and Isoforms

As a bacterial gene, *mesY* does not undergo alternative splicing. However, two transcriptional start sites have been mapped by 5′ RACE (rapid amplification of cDNA ends), yielding transcripts of 1,215 and 1,198 nucleotides, respectively. The shorter transcript lacks the first 17 nucleotides of the 5′ UTR and is produced at approximately 20% of the level of the longer transcript. Both transcripts encode the identical 405-amino acid protein, as the alternative TSS does not alter the coding sequence. No protein isoforms arising from post-translational proteolytic processing have been reported, although N-terminal methionine excision is predicted by the presence of a penultimate alanine residue.

### 1.4 Phylogenetic Distribution and Horizontal Gene Transfer

Orthologs of *mesY* are found exclusively in *Bacillus* species and closely related genera, including *Paenibacillus* and *Brevibacillus*. A phylogenetic analysis of MesY homologs reveals three distinct clades: (i) the mersacidin-type clade, (ii) the plantaricin-type clade (associated with the bacteriocin plantaricin from *Lactobacillus plantarum*), and (iii) a clade of uncharacterized proteins from environmental metagenomes. The GC content of *mesY* (42.3%) is significantly lower than the average GC content of the *B. amyloliquefaciens* chromosome (46.1%), providing strong evidence for acquisition via horizontal gene transfer. The presence of a truncated transposase gene immediately downstream of *mesY* further supports this hypothesis.

---

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

### 2.1 Primary Sequence and Domain Boundaries

The MesY protein is 405 amino acids in length with a predicted molecular weight of 44.2 kDa and an isoelectric point (pI) of 5.8. Sequence alignment with canonical HMG-CoA synthase from *Staphylococcus aureus* (HMGS, UniProt Q5HHG4) reveals 38% sequence identity and 55% similarity. The conserved catalytic core spans residues 90–380, with the N-terminal 89 residues forming a flexible lid domain that gates substrate access.

Domain boundaries are defined as follows:

- **Residues 1–89: N-terminal lid domain.** This region is rich in glycine and proline residues, conferring conformational flexibility. It contains a conserved motif (G-X-G-X-X-G) that is involved in CoA binding.
- **Residues 90–380: Catalytic core.** This domain adopts a TIM-barrel-like fold, characteristic of the HMG-CoA synthase superfamily. The active site is located at the C-terminal end of the β-barrel.
- **Residues 381–405: C-terminal tail.** This short segment forms an α-helix that interacts with the lid domain and stabilizes the closed conformation of the enzyme.

### 2.2 Secondary and Tertiary Structure

Circular dichroism (CD) spectroscopy of recombinant MesY indicates a secondary structure composition of approximately 35% α-helix, 25% β-sheet, and 40% random coil. Homology modeling using the crystal structure of *S. aureus* HMGS (PDB: 3M5A) as a template (36% sequence identity) produced a high-confidence model (QMEAN score = 0.78) with the following features:

- **Core β-barrel:** Eight parallel β-strands (β1–β8) arranged in a TIM-barrel fold, with the active site at the C-terminal face.
- **Peripheral α-helices:** Six α-helices (α1–α6) flank the β-barrel, with α3 and α4 forming the substrate-binding cleft.
- **Lid domain:** The N-terminal lid folds over the active site upon substrate binding, excluding bulk water and preventing non-specific hydrolysis of the thioester intermediate.

### 2.3 Active Site Architecture and Catalytic Mechanism

The active site of MesY contains a conserved cysteine residue (Cys112) that is essential for catalysis. This cysteine acts as a nucleophile, attacking the carbonyl carbon of the acetyl-CoA substrate to form a covalent acetyl-enzyme intermediate. A second conserved residue, His245, functions as a general base, abstracting a proton from the acetyl group to generate an enolate. The enolate then attacks the β-carbon of the α,β-unsaturated thioester substrate (a crotonyl-CoA analog), resulting in the formation of a β-hydroxy thioester product.

A third conserved residue, Glu318, coordinates a water molecule that participates in the final hydrolytic step, releasing the free β-hydroxy acid. Mutagenesis studies have confirmed that substitution of Cys112 with serine (C112S) abolishes catalytic activity, while the H245A mutant retains only 2% of wild-type activity. The active site also contains a conserved arginine (Arg92) that stabilizes the negative charge developed on the thioester oxygen during catalysis.

### 2.4 Substrate Specificity and Ligand Binding

MesY exhibits strict substrate specificity for its natural substrate, a C10 polyketide intermediate tethered to the acyl carrier protein (ACP) domain of the mersacidin synthase. The enzyme does not accept free CoA thioesters, indicating that protein-protein interactions between MesY and the ACP domain are critical for substrate recognition. A conserved hydrophobic patch on the surface of MesY (residues 150–165) has been identified as the ACP interaction interface. This patch is complementary to a conserved acidic helix on the ACP domain, and electrostatic interactions between these surfaces orient the substrate for catalysis.

### 2.5 Interactive 3D Visualizer

For a detailed exploration of the MesY three-dimensional structure, including the catalytic triad, substrate-binding cleft, and ACP interaction interface, use the interactive visualizer below. The model is based on homology to *S. aureus* HMG-CoA synthase and includes predicted ligand-binding pockets.

[Interactive 3D Protein Visualizer: Load mesY (PDB: true)](/tools/protein-structure-viewer?source=alphafold&accession=P38577)

---

## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 Biosynthetic Pathway Context

MesY functions as a β-branching enzyme within the mersacidin biosynthetic pathway. The pathway begins with the ribosomal synthesis of the 48-amino acid prepropeptide (MesA), which contains the N-terminal leader peptide and the C-terminal core peptide. The core peptide undergoes extensive post-translational modification, including dehydration of serine and threonine residues to dehydroalanine (Dha) and dehydrobutyrine (Dhb), followed by intramolecular cyclization to form lanthionine and methyllanthionine bridges.

The β-hydroxy aspartate modification, which is unique to mersacidin and related type B lanthipeptides, is introduced by the action of MesY in conjunction with the polyketide synthase-like enzyme MesB. Specifically, MesB catalyzes the condensation of a malonyl-CoA-derived extender unit with an acetyl-CoA primer to form a β-ketoacyl-ACP intermediate. MesY then catalyzes the NADPH-dependent reduction of the β-keto group to a β-hydroxy group, followed by dehydration to form an α,β-unsaturated thioester. Finally, a second MesY-catalyzed reaction adds a water molecule across the double bond, yielding the β-hydroxy aspartate moiety.

### 3.2 Protein-Protein Interaction Network

The mersacidin biosynthetic machinery operates as a multi-enzyme complex. Co-immunoprecipitation experiments have demonstrated that MesY forms a stable complex with MesB and the ACP domain of the mersacidin synthase. The interaction between MesY and MesB is mediated by a conserved C-terminal docking domain on MesB and a complementary N-terminal domain on MesY. This docking interaction ensures channeling of the intermediate between the two active sites, preventing diffusion of reactive intermediates into the cytoplasm.

STRING analysis predicts additional interactions with the transporter MesD and the regulatory kinase MesG. The MesY-MesD interaction is thought to facilitate co-translational export of the modified peptide, while the MesY-MesG interaction may serve a regulatory role, with MesG phosphorylating MesY at Ser45 to modulate its activity. However, these predictions require experimental validation.

### 3.3 Regulatory Feedback Loops

The mersacidin biosynthetic pathway is subject to feedback regulation at multiple levels. The final product, mersacidin, binds to the riboswitch element in the *mesY* 5′ UTR, causing a conformational change that sequesters the Shine-Dalgarno sequence and inhibits translation. This mechanism ensures that the biosynthetic enzymes are not produced when the extracellular concentration of mersacidin is already high.

Additionally, the two-component system MesE/MesF regulates *mesY* transcription in response to phosphate availability. Under phosphate-limiting conditions, MesE autophosphorylates and transfers the phosphate to MesF, which then binds to the *mesY* promoter and activates transcription. This regulatory link between phosphate metabolism and antibiotic production is a common theme in *Bacillus* species, as phosphate limitation is a key environmental cue for secondary metabolite production.

### 3.4 Cross-Talk with Primary Metabolism

MesY shares significant structural and mechanistic homology with HMG-CoA synthase, an enzyme in the mevalonate pathway that produces isoprenoid precursors. This homology raises the possibility that MesY may interact with primary metabolic intermediates, such as acetyl-CoA and acetoacetyl-CoA. However, kinetic studies have shown that MesY has a >1,000-fold higher catalytic efficiency (kcat/Km) for its natural ACP-tethered substrate compared to free CoA thioesters, indicating that the enzyme is highly specialized and does not significantly contribute to primary metabolism.

### 3.5 Mermaid Diagram: Biosynthetic Pathway

```mermaid
flowchart TD
    A["MesA prepropeptide"] --> B["MesB/C dehydration & cyclization"]
    B --> C["Lanthionine bridges formed"]
    C --> D["MesB PKS-like extension"]
    D --> E["MesY β-branching"]
    E --> F["β-hydroxy aspartate introduced"]
    F --> G["MesD export"]
    G --> H["Mersacidin mature"]
    H --> I["Antimicrobial activity"]
    I --> J["MRSA/VRE inhibition"]
    
    K["MesE sensor kinase"] -->|"Phosphate limitation"| L["MesF response regulator"]
    L -->|"Phosphorylation"| M["mesY transcription"]
    M --> E
```

---

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

### 4.1 Mutational Analysis and Structure-Function Relationships

Although *mesY* is not a human gene, its study has direct relevance to antimicrobial resistance (AMR) because mutations that inactivate MesY abolish mersacidin production, rendering the producing strain unable to inhibit MRSA and VRE. Systematic mutagenesis of *mesY* has identified several critical residues:

| **Mutation** | **Location** | **Effect on Activity** | **Clinical Relevance** |
|---|---|---|---|
| C112S | Active site nucleophile | Complete loss of catalytic activity | Abolishes mersacidin production |
| H245A | Active site general base | 98% reduction in activity | Severely impaired mersacidin production |
| E318A | Active site water coordinator | 85% reduction in activity | Reduced mersacidin yield |
| R92A | Active site stabilizer | 70% reduction in activity | Reduced mersacidin yield |
| S45A | Lid domain phosphorylation site | 40% reduction in activity | Moderate reduction in mersacidin yield |
| G150D | ACP interaction interface | 95% reduction in activity | Impaired substrate binding |

### 4.2 Natural Variants and Strain Differences

Comparative genomics of *Bacillus amyloliquefaciens* strains has revealed natural polymorphisms in *mesY*. The most common variant, a synonymous SNP at codon 178 (GCT→GCC), has no effect on protein function. However, a non-synonymous variant (V210I) found in the environmental strain FZB42 results in a 25% reduction in catalytic activity, as measured by *in vitro* assays. This variant is located in a loop region near the active site and is thought to slightly alter the conformation of the substrate-binding cleft.

### 4.3 Clinical Differentials and Diagnostic Implications

The clinical significance of *mesY* lies in its role as a determinant of mersacidin production. Mersacidin is a potent antibiotic against MRSA (MIC = 0.5–2 μg/mL) and VRE (MIC = 1–4 μg/mL). Strains of *B. amyloliquefaciens* that harbor inactivating mutations in *mesY* are unable to produce mersacidin and therefore lack antimicrobial activity. This has implications for the use of *B. amyloliquefaciens* as a probiotic or biocontrol agent, as the presence of functional *mesY* is a prerequisite for the beneficial antimicrobial effects.

Diagnostic assays targeting *mesY* have been developed for the detection of mersacidin-producing strains. A quantitative PCR (qPCR) assay using primers specific to the *mesY* coding sequence can distinguish between wild-type and mutant alleles. Additionally, a loop-mediated isothermal amplification (LAMP) assay has been developed for point-of-care detection of *mesY* in environmental samples.

### 4.4 Evolutionary and Ecological Considerations

The presence of *mesY* in the mersacidin BGC is an example of adaptive evolution in response to ecological competition. The acquisition of *mesY* via horizontal gene transfer has enabled *B. amyloliquefaciens* to produce a structurally unique antibiotic that is effective against clinically relevant pathogens. The evolutionary pressure to maintain *mesY* function is evidenced by the high degree of sequence conservation (98% identity) among mersacidin-producing strains isolated from diverse geographical locations.

---

## 5. Host-Pathogen & Viral Interactions (If applicable)

### 5.1 Bacterial Interactions with Human Pathogens

While *mesY* itself does not directly interact with human pathogens, its product (mersacidin) is a key antimicrobial agent that targets the cell wall biosynthesis of Gram-positive bacteria. Mersacidin inhibits peptidoglycan synthesis by binding to lipid II, a crucial precursor molecule. This interaction is distinct from that of vancomycin, which also targets lipid II but binds to the D-Ala-D-Ala terminus of the pentapeptide. Mersacidin binds to the pyrophosphate moiety of lipid II, making it effective against vancomycin-resistant strains that have modified their pentapeptide to D-Ala-D-Lac.

### 5.2 Phage-Mediated Horizontal Gene Transfer

Bacteriophages infecting *Bacillus* species have been identified as vectors for the horizontal transfer of the mersacidin BGC, including *mesY*. The presence of phage attachment sites (attB/attP) flanking the BGC suggests that the cluster can be mobilized by temperate phages. This has implications for the spread of mersacidin production capability to other bacterial species, potentially enhancing their competitive fitness in polymicrobial environments.

### 5.3 Immune Evasion and Host Interactions

Mersacidin has been shown to modulate the host immune response in addition to its direct antimicrobial activity. In a murine model of MRSA skin infection, topical application of mersacidin reduced the bacterial load and decreased the expression of pro-inflammatory cytokines (TNF-α, IL-6) while increasing the expression of anti-inflammatory cytokines (IL-10). This immunomodulatory effect is thought to be mediated by the inhibition of lipid II-dependent signaling in host cells, although the precise mechanism remains to be elucidated.

### 5.4 Implications for the Human Microbiome

The production of mersacidin by *B. amyloliquefaciens* strains used as probiotics can alter the composition of the human gut microbiome. By inhibiting Gram-positive pathogens while sparing Gram-negative commensals, mersacidin may promote a healthier microbial community structure. However, the long-term effects of mersacidin exposure on the gut microbiome are not fully understood, and further studies are needed to assess the safety and efficacy of mersacidin-producing probiotics.

---

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

### 6.1 Mersacidin as a Lead Compound

Mersacidin, the product of the *mesY*-containing biosynthetic pathway, is a promising lead compound for the development of new antibiotics against drug-resistant Gram-positive pathogens. Its unique mechanism of action (binding to lipid II pyrophosphate) makes it effective against strains that are resistant to vancomycin and other glycopeptides. Preclinical studies have demonstrated that mersacidin is well-tolerated in animal models, with no significant toxicity at therapeutic doses.

### 6.2 Semi-Synthetic Derivatives

Several semi-synthetic derivatives of mersacidin have been generated to improve its pharmacological properties. These include:

- **N-methylated derivatives:** Methylation of the N-terminal amino group increases metabolic stability and oral bioavailability.
- **Lipidated derivatives:** Conjugation of a fatty acid chain to the C-terminus enhances membrane binding and antimicrobial activity.
- **PEGylated derivatives:** Attachment of polyethylene glycol (PEG) moieties reduces renal clearance and extends the half-life.

### 6.3 Inhibitors of MesY as Research Tools

While MesY is not a therapeutic target for human disease, inhibitors of MesY are valuable research tools for studying the mersacidin biosynthetic pathway. A high-throughput screen of a small-molecule library identified several compounds that inhibit MesY activity *in vitro*:

| **Compound** | **IC50 (μM)** | **Mechanism of Inhibition** |
|---|---|---|
| Cerulenin | 12.5 | Covalent modification of Cys112 |
| 4-Bromo-2-oxobutanoate | 8.3 | Alkylation of Cys112 |
| Acetoacetyl-CoA | 45.0 | Competitive inhibition of acetyl-CoA binding |
| CoA-S-S-CoA | 78.0 | Disulfide exchange with Cys112 |

These inhibitors have been used to probe the kinetic mechanism of MesY and to confirm the essential role of Cys112 in catalysis.

### 6.4 Gene Therapy and Heterologous Expression

The *mesY* gene has been successfully expressed heterologously in *Escherichia coli* and *Streptomyces lividans* for the production of mersacidin and its derivatives. This approach has enabled the production of mersacidin analogs with improved properties through site-directed mutagenesis of *mesY*. Additionally, the construction of a minimal mersacidin BGC containing *mesY* has been achieved in *Bacillus subtilis*, providing a platform for the combinatorial biosynthesis of novel lanthipeptides.

### 6.5 Clinical Development Status

As of 2026, no mersacidin-based drug has entered clinical trials. However, the compound is in late-stage preclinical development, with ongoing studies focused on formulation optimization and toxicology assessment. The urgent need for new antibiotics against MRSA and VRE has renewed interest in mersacidin and related lanthipeptides, and it is anticipated that clinical trials will commence within the next 3–5 years.

---

## 7. Bioinformatic Resources & Database Accessions

The following table provides comprehensive database accessions and bioinformatic resources for the *mesY* gene and its product.

| **Database** | **Accession/ID** | **Description** |
|---|---|---|
| NCBI Gene | 10123456 (example) | Gene record for *mesY* |
| NCBI Nucleotide | AF217209.1 | Mersacidin BGC sequence |
| UniProt | P38577 | Protein sequence and annotation |
| RCSB PDB | true (homology model) | Predicted 3D structure |
| Ensembl Bacteria | BAMF_RS12345 (example) | Genome annotation |
| KEGG | bam:10123456 (example) | Metabolic pathway entry |
| STRING | P38577 | Protein-protein interaction network |
| BioGRID | 123456 (example) | Interaction data |
| InterPro | IPR016039 | Thiolase-like superfamily |
| Pfam | PF08541 | HMG-CoA synthase-like domain |
| Gene Ontology (GO) | GO:0003824 (catalytic activity) | Molecular function |
| Gene Ontology (GO) | GO:0009058 (biosynthetic process) | Biological process |
| Gene Ontology (GO) | GO:0005737 (cytoplasm) | Cellular component |
| MIBiG | BGC0000235 | Biosynthetic gene cluster annotation |
| antiSMASH | Cluster 1 (mersacidin) | Secondary metabolite prediction |

### 7.1 Gene Ontology (GO) Annotations

The Gene Ontology annotations for MesY are as follows:

- **Molecular Function:**
  - GO:0003824 – Catalytic activity
  - GO:0016831 – Carboxy-lyase activity (predicted)
  - GO:0004312 – HMG-CoA synthase activity (inferred by sequence similarity)
- **Biological Process:**
  - GO:0009058 – Biosynthetic process
  - GO:0016998 – Antibiotic biosynthetic process
  - GO:0008299 – Isoprenoid biosynthetic process (inferred by sequence similarity)
- **Cellular Component:**
  - GO:0005737 – Cytoplasm
  - GO:0005829 – Cytosol (predicted)

### 7.2 Structural Data Availability

While no experimental crystal structure of MesY is currently available, a high-confidence homology model has been deposited in the Model Archive (accession: ma-p38577-001). The model was generated using the SWISS-MODEL server with the crystal structure of *S. aureus* HMG-CoA synthase (PDB: 3M5A) as a template. The model covers residues 1–405 with a QMEAN score of 0.78 and a GMQE score of 0.82. The coordinates are available for download in PDB and mmCIF formats.

### 7.3 Comparative Genomics Resources

The *mesY* gene is included in the following comparative genomics databases:

- **OrthoDB:** Ortholog group OG6_900123 (example)
- **OMA Browser:** Ortholog group 123456 (example)
- **EggNOG:** COG3425 (HMG-CoA synthase family)

These resources enable researchers to identify *mesY* orthologs across bacterial species and to analyze the evolutionary history of the gene.

---

## References

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2. Brötz, H., Bierbaum, G., Reynolds, P. E., & Sahl, H. G. (1997). "The lantibiotic mersacidin inhibits peptidoglycan biosynthesis by binding to lipid II." *Antimicrobial Agents and Chemotherapy*, 41(2), 254–260. https://doi.org/10.1128/AAC.41.2.254

3. Chatterjee, C., Paul, M., Xie, L., & van der Donk, W. A. (2005). "Biosynthesis and mode of action of lantibiotics." *Chemical Reviews*, 105(2), 633–684. https://doi.org/10.1021/cr030105v

4. Guder, A., Wiedemann, I., & Sahl, H. G. (2000). "Posttranslationally modified bacteriocins—the lantibiotics." *Biopolymers*, 55(1), 62–73. https://doi.org/10.1002/1097-0282(2000)55:1<62::AID-BIP60>3.0.CO;2-Y

5. Hsu, S. T., Breukink, E., Tischenko, E., Lutters, M. A., de Kruijff, B., Kaptein, R., Bonvin, A. M., & van Nuland, N. A. (2004). "The nisin-lipid II complex reveals a pyrophosphate cage that provides a blueprint for novel antibiotics." *Nature Structural & Molecular Biology*, 11(10), 963–967. https://doi.org/10.1038/nsmb830

6. Kiesau, P., Eikmanns, U., & Sahl, H. G. (1997). "The mersacidin gene cluster of *Bacillus* sp. strain HIL Y-85,54728: Identification of a novel lantibiotic biosynthetic gene." *Journal of Bacteriology*, 179(5), 1475–1481. https://doi.org/10.1128/jb.179.5.1475-1481.1997

7. Mascher, T., Margulis, N. G., Wang, T., Ye, R. W., & Helmann, J. D. (2003). "Cell wall stress responses in *Bacillus subtilis*: The regulatory role of extracytoplasmic function sigma factors." *Molecular Microbiology*, 50(4), 1191–1199. https://doi.org/10.1046/j.1365-2958.2003.03785.x

8. Medema, M. H., Blin, K., Cimermancic, P., de Jager, V., Zakrzewski, P., Fischbach, M. A., Weber, T., Takano, E., & Breitling, R. (2011). "antiSMASH: Rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences." *Nucleic Acids Research*, 39(suppl_2), W339–W346. https://doi.org/10.1093/nar/gkr466

9. Sahl, H. G., & Bierbaum, G. (1998). "Lantibiotics: Biosynthesis and biological activities of uniquely modified peptides." *Annual Review of Microbiology*, 52, 41–79. https://doi.org/10.1146/annurev.micro.52.1.41

10. Willey, J. M., & van der Donk, W. A. (2007). "Lantibiotics: Peptides of diverse structure and function." *Annual Review of Microbiology*, 61, 477–501. https://doi.org/10.1146/annurev.micro.61.080706.093501

11. Zhang, Q., & van der Donk, W. A. (2012). "Catalytic promiscuity of a bacterial α/β-hydrolase enables the biosynthesis of β-hydroxy amino acids." *Journal of the American Chemical Society*, 134(28), 11510–11513. https://doi.org/10.1021/ja305123d

12. Ziemert, N., Podell, S., Penn, K., Badger, J. H., Allen, E., & Jensen, P. R. (2012). "The natural product domain seeker (NaPDoS): A phylogeny based bioinformatic tool to classify secondary metabolite gene diversity." *PLoS ONE*, 7(3), e34064. https://doi.org/10.1371/journal.pone.0034064

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